Does Blockade of Angiotensin I1 Receptors Offer Clinical Benefits over Inhibition of Angiotensin-Converting Enzyme? Marc de Gasparo and Nigel Levens Metdbohc & C~irdiovdsculdrDiseases Novdrti5 Phnrm'i AG, CH-4002 Basel, Switzeildnd (Received December I 1 1997 Accepted March 10 1998) Ah.srrcrcf: Angiotensin AT, receptor antagonists represent a new class of drugs for the treatment of hypertension. They are hpecific for the renin-angiotensin system, selective for the angiotcnsin AT, receptor, and act independently of the angiotensin I1 synthetic pathway. Blockade of the renin-angiotensin system at the receptor level should therefore be more complete. The high circulating lcvels of angiotensin 11 following angiotensin AT, receptor blockade could be beneficial in stimulating other unblocked angiotensin receptors, especially the AT: receptor. It has been proposed that the angiotensin AT: receptor. which is re-expressed or up-regulated during pathological circumstances, counterbalances the effect of the stinitilation of the angiotensin AT, receptor. Through this mechanism, angiotensin AT, antagonists may bc superior to ACE inhibitors in cardiac and vascular remodelling as well a s in kidney insufficiency. Long-term trials are required t o demonstrate the possible clinical superiority of this new class of antihypertensive agents.
In , t n m n t Chinese medicine, good health was believed lo be i h c result of a balance between the opposing life forces Yin aiid Yang. In hypertension, this concept has a modern countcrpart in that high blood pressure may be considered the consequence of either an excess of vasoconstrictor agctit\ such as angiotensin, endothelin and epinephrine or a rcdiiction in endogenous vasodilators such a s bradykinin, prostxyclin and nitric oxide. Angiotensin I I is arguably the moit btudied vasoconstrictor agent contributing to the mamicnance of blood pressure. I n addition, the role of angiotcnsin I1 in the pathogenesis of hypertension has been suggcytcd over years by the efficacy of angiotensin-converting eivymc inhibitors to lower blood pressure and to attenuatc [lie clinical consequences of congestive heart failure (Oiidc'tti 1991; Pfeffer 1993). Angiotensin receptor antagonisrs :ire a recently introduced approach to blocking the actions of Angiotensin 11 (Timmermans et a/. 1993). These coiiipc~undsare effective antihypertensivc agents but it is unknown at the present whether they are better drugs or indeed whether they possess all the beneficial actions of ani!ic,tcnsin-converting enzyme inhibitors. A first analysis was presented earlier by Levens ~t u/. (1992). The purpose of I hi5 review is both to consider new avdildJle evidence and to speculate whether angiotensin rcceptor antagonists have identi liable clinical advantages over angiotensin-converting enxyiiie inhibitors.
Aurhtii for correspondence: Marc de Gasparo. Cardiovascular & Metabolic Risk Diseases, Novartis Pharma AG, CH-4002 Basel. Suit/t.i-iand (fax +41 61 696 2651).
The renin-angiotensin system A schematic representation of the renin-angiotensin system is shown in fig. 1. Classically, angiotensin I1 has been viewed as a blood-borne hormone produced in the circulation a s the result of a cascade of enzymatic reactions and has bccn extensively reviewed (Griendling ct ul. 1993; Bernstein 1093; Riordan 1995). The recent observations that angiotensin I 1 is formed in many tissues such as brain, kidney and blood vessels has led to the suggestion that angiotensin 11 may also function as a paracrine and autocrine hormone and have a role in the maintenance of local tissue function (Dzau & Gibbons 1987; Dzau 1987). While angiotensin I1 may be formed locally, the function and coiitrol of these individual tissue pathways relative to the circulating peptide has not been clearly elucidated.
Angiotensin peptides Angiotensin 11, the most active product of the renin-angiotensin cascade, is a multifunctional hormone which plays a major role in modulating extra cellular fluid volume and systemic vascular resistancc (Sealey & Laragh 1995). Additional roles for angiotensin I 1 have come to light in recent years with the suggested involvement of the peptide in cell growth and differentiation and in fibrosis (Griffin c t ( I / . 1091; Dzau et nl. 1991; Weber et ul. 1995). Moreover, other angiotensin derived metabolites such as angiotensin 2 -8 (angiotensin 111). angiotensin 1L7 or angiotensin 3 -8 (angiotensin IV) have all been shown to have biological activity (Peach 1977; Schiavone ~t a/. 1990; Benter cf LII. 1993;
MARC DE GASPARO A N D NIGEL LEVENS
cial effects over inhibitors of angiotensin-convcrting enzyme to warrant their increasingly preferential use.
Angiotensinogen
-
(liver)
Renin (kidney)
Renin inhibitor
k--
f Angiotensin I
1
Angiotensin converting enzyme
ACE inhibitor
k"--
!
(vascular endothelium)
1+
Ang II antagonist
I
Renal actions
\
\
Aldosterone secretion
,
+
Receptors
. /
/
Thirst
Sympathetic stimulation
Antidiuretic hormone release Cellular growth
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Vasoconstriction
Fig. I . ?'tie renin-angiotensin cascade. showing the various pharmdcalogical possihilities to block the system. The multiple targcts ol' tingiotcnsin I1 have suggested the existencc of multiple receptor subtypes.
Wright et ul. 19YS; Handa ei al. 1996). For example, angiotensin 111 is equipotent with angiotensin TI at eliciting aldostcrone release (Chiu & Peach 1974). Angiotensin (1-7) elicits coronary vasodilation specifically through the release ol' endothelium-derived nitric oxide (Brosnihan r t czl. 1996). Angiotensin 1V has been shown to be involved in thc regulation of renal blood flow (Swanson r t nl. 1992). Inhibitors of the renin-angiotensin system
The important role ofangiotensin I I to a variety of physiological ptocesses has been elucidated over the years by the use of specific inhibitors. These include peptide analogues of angiotensin TI such iis saralasin (Sar', Ala')-angiotensin I [ (Pals et N / . 1979) which act as receptor antagonists, ang iot on sin -convet t i ng enzyme inhibitors, which prevent the conversion oi angiotensin I to angiotensin TI (Ondetti I Y91) and more recently the non-peptidc inhibitors of angiotensin AT, reccptors (Timmermans ci al. 1993). With augmenting market exposure these drugs are extensively used iis antihypertensive agcnts and increasingly as therapy I'or congestive heart failure. However, the question remains whether angiotensin AT, receptor antagonists have benefi-
Angicrtensin ZI rec,cytors. Shortly after the synthesis o f angiotcnsin I1 in 1957 (Bumpus ct 01. 1957; Rittel rf nl. 1957). several hundred peptide analogucs were produced. The structure-activity of these peptide analogues vary among tissues, indicating that the actions of angiotensin 11 arc mediated by different receptor subtypes (Peach 1977; Peach & Levens 1980). Only the recent synthesis of nonpeptide analogues of angiotensin made it possible to strictly characterize angiotensin I1 receptors into two major subtypes termed angiotensin AT, and angiotensin AT2 (de Gasparo et crl. 1995 a & b). Thc angiotensin ATI and AT1 receptors are all members of the seven transmembrane spanning G-protein rcceptor super family and have been cloned and well characterized (Murphy et ul. 1991; Sasaki et u1. 1991; Kambayashi et 01. 1993; Mukoyama et ill. 1993). In addition to the angiotensin ATI and AT2 receptor subtypes, other less wcll characterized receptors may also cxist. For example, a third receptor subtype named angiotensin AT4 has been described which may be a selective binding sitc for angiotensin IV (Harding e f al. 1994). Additional plasma membrane receptors which are neither AT1 nor AT2 have also been postulatcd and may be selcctive for other active angiotensin 11metabolites such as Ang (1-7). In addition to these well defined and less well defined membrane receptors, a cytosolic binding protein and ii nuclear receptor have been reported but they are still pharmacologicdly poorly characterized (Sen et a/. 1983; Hagiwara r t nl. 1989; Tang nl. 1992; Eggena et nl. 1993). cjt
The trrzgiotctzsin ATI wccpor. Various rcviews have dcscribed in detail thc characteristics of both the angiotensin AT, and AT2 receptors (Inagami et a / . 1994; Clauscr et a/. 1995; de Gasparo et al. 1995a; Goodfriend et a/. 1996; Gricndling et nl. 1996; Holland 1996; Unger et nl. 1996). This review focuses on differenccs in therapeutics bctween angiotensin-converting enzyme inhibitors and angiotensin AT1 antagonists. The ultimate biological response mediated by angiotensin I1 depends upon the effector mechanism coupled to the receptor in individual target tissues. The AT, receptor has no catalytic activity per se but is able to mimic growth factor and cytokine receptors. Recently, it was demonstrated that angiotensin I1 stimulates the JakiSTAT pathway by inducing ligand-dependent tyrosine phosphorylation and activation (Bernstein & Marrero 1996; Schieffer et aI. 1996; McWhinncy et a/. 1997; Berk & Corson 1997). Binding of Jak to the receptor tail is dependent on the amino acids 319-322 (Tyr-Tle-Pro-Pro) of the AT, receptor (Ali e/ a1. 1997). Additional protein kinases are stimulated by angiotensin I1 such as p70 S6 kinase, ERKUERK2 M a p kinase and Tyk2 tyrosine kinase (Giasson et al. 1997). Examples of conventional G-protein dependent and newly discovered G-protein independent intracellular mechanisms coupled to the angiotensin AT, receptor and the associated biological response(s) arc shown in table I . Clearly the
MiniRcvie w
ANGIOTENSIN, ANTAGONIST A N D ANGIOTENSIN-CONVERTING ENZYME Ttihle I
Thc 41 , receptor has five classical or conventional signalling pathway' thtctl phospholipases, the phospholipase C being the most imporl;ini adenylate cyclase and voltage-dependent Ca'+ channels. Recenil>.coupling of the ATl receptor to various phosphorylation patha;t!\ has been described (see Bernstein & Marrero 1996). AT,
G-protein-coupled
adenylllte ( Y C I ~ S B P l n j P L O
# c AMP #
#
AA
A
PLCp
G-protein independent
PLCY
N
OAG IP,
OAG I?,
PKL
i dllatlon
JAK? TVKZ
Y
Stat 112
C3,X
protein phosphorylation
c 4
early growlh response gene
contraction aldo. release
growlh proliferation matrix formation
P K k PKC: protein kinase A and C'; PLA>,PLC,PLD: phospli~+lip.ise A2. C, and D; DAG: diacyl glycerol; IP,: inositol triphosph,:tc C'aK'aMK: Ca/calmodulin dependent kinase: JAK: Janus kin;crL~. TYK: tyrosine kinase; STAT: signal transducer and actiV ~ I ~ J01'I transcription.
angiotensin AT, receptor can immediately affect tissue biocheniistry as well as produce more long-term effects via nucleat- transcription. The cellular response to angiotensin I1 is thcrefore multiphasic, involving a selective activation of multiple pathways over time (Griendling ct u/. 1997). The. iingiotrwsin AT2 receptor. The angiotensin AT2 receptor dcspite having a similar affinity for angiotensin I1 has only 3 I",,, homology with its counterpart, the angiotensin AT, receptor (Mukoyama et al. 1993; Kambayashi et a/.1993). 111 contrast to the angiotensin ATI receptor which is highly ex pi-cssed in the majority of tissues, the angiotensin AT2 recepror is found mainly in the adrenal medulla, the ovary aird uterus and in various structures of the brain. The expitshion in these tissues is much less than the average expression of the angiotensin ATi receptor. In contrast to d u I1 tissues, the angiotensin AT2 receptor is highly expr-ehsed in foetal tissues, implying that angiotensin I1 acting tltrc )ugh this receptor subtype could play an important role i i i cnibryonic development (Grady et a/. 1991). Most importiintly, the angiotensin AT2 receptor appears to be reexpressed or up-regulated after vascular injury, myocardial iiiliii.ction, cardiac failure, skin wound healing as well as after peripheral nerve injury as part of a foetal genetic propra nime that includes atrial natriuretic peptide, skeletal aactirr and p myosin heavy chain (Dzau & Horiuchi 1996; (;;illinat Pt ul. 1997). The re-activation of embryonic expre\sion patterns therefore represents a common feature after tissue damage. A balance between the expression of the angiotensin ATl
259
and AT2 receptors has been observed (de Gasparo cr 01. 1992). In freshly isolated foetal fibroblasts, more than 90% of the receptors were of the angiotensin AT2 subtype. The proportion tended t o be reversed during culture with the angiotensin AT, receptor accounting for 60 to SO'%, of the total (Johnson & Aguilera 1991). Non-pregnant human myometrium expressed more than 95% of the angiotensin AT2 receptor. During pregnancy, the total number of receptors decreased dramatically with the change in hormonal environment with the proportion of the angiotensin AT, receptor dropping to only 40% (de Gasparo ef al. 1994). The significance of these findings will be discussed later in this review. The coupling mechanism of the AT2 receptor is still controversial. It involves a Gi, 2-3 protein susceptible to pertussis toxin (Zhang & Pratt 1996). Interestingly, the amino acid residue Aspgn and the amino acid sequence Asp'"A ~ - g ' ~ ~ - T which y r ' ~ ~is, the area of the angiotensin AT, receptor involved in G-protein coupling, are unchanged in the AT2 receptor (Mukoyama et al. 1993). Studies with chimeric constructs of ATI/AT2 have indicated that the 3rd intracellular loop is essential for the AT2 function (Lehtonen et al. 1997a). Recently, ceramide, which is linked to the activation of phosphatases, was proposed to be the second messenger for the AT2 receptor as it is for tumor necrosis factor M. (Lehtonen et al. 1997b). Depending on the tissue, activation of the AT2 receptor stimulates a number of intracellular mechanisms involving various Tyr and SeriThr phosphatases (Bottari et ul. 1992; Nahmias & Strosberg 1995; Yamada et a/. 1996; Huang er ul. 1996; Bedecs et al. 1997). As a consequence, there is inactivation of the MAP kinase, an opening of delayed-rectifier K+ channels and closing of Ttype C a + + channels (Yamada et a/.1996; Kang C I ul. 1995; Buisson c't al. 1995). Angiotensin-converting enzynw inhibitors. Angiotensin-converting enzyme is a well characterized membrane-bound ecto-enzyme specially abundant in lung and vascular endothelium. It becomes soluble in the plasma by autolysis. Although angiotensin-converting enzyme inhibitors have been available for almost 20 years, their mechanism of action is still incompletely understood. For example, acute administration of angiotensin-converting enzyme inhibitors to hypertensive man reduces circulating angiotensin I1 levels and lowers blood pressure (Nussberger et al. 1985). However, with extended treatment blood pressure remains suppressed but circulating angiotensin I1 levels return to normal (Wdeber et a1. 1989). Excluding technical artifacts in the measurements, these observations suggest that when chronically administered, angiotensin-converting enzyme inhibitors must act by mechanisms other than inhibition of the synthesis of angiotensin 11. These results also imply that angiotensin 11 can be synthesized by pathways other than angiotensin-converting enzyme (Dzau 1989; Urata et a/. 1994). Supporting evidence has been obtained in tissues for the alternate production of angiotensin 11. In man, and in contrast to rodents (Okunishi et al. 1993), the enzyme chymase
260
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MARC DE GASPARO AND NlGEL LEVENS
which is highly expressed both in heart and vascular tissue has a high affinity (Km 60 pM) and specificity for angiotensin I (Urata C t ul. 1995; Wolny et al. 1997). Recent evidence suggests that up to 80% of the angiotensin 11 produced in vascular tissues in vitro may be formed through the chymase pathway (Balcells rt al. 1996). Since chymasedependent angiotensin I1 formation appears to be preserved with angiotensin-converting enzyme inhibitor treatment, it would not be surprising to find differences in therapeutic efficacy between angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. Data obtained in the rapid pacing model of congestive heart failure in pigs indicated that combined maximal angiotensin-converting enLyme inhibition and maximal angiotensin ATI blockade h i proved cardiac function to a greater degree that of either treatments alone (Spinalc et ~il. 1997a & b). A similar additive effcct on blood pressure has also been observed in normal healthy volunteers treated with maximal doses of captopril and losartan whereas synergy was detected in sodium-depleted guinea-pigs and in spontaneously hypertensive rats (Azizi rt ul. 1995; Fossa p t ril. 1994; Mknard et trl. 1997; Webb ct ul. 1998). Angiotensin-converting enzyme is a relatively non-specific peptidyl-dipeptide hydrolase which is able to cleave multiple substrates in atldition to angiotensin 11. These substrates include bradykiniu, substance P. neurotensin, enkephalin, luteinizing-hormone releasing hormone (Chai & Johnson 1995) and the more recently described circulating peptide N-acetyl seryl-aspartyl-lysyl-prolinewhich has been implicated as a negativc regulator of hematopoietic stem cells (Azizi ct CJl. 1996). Therefore, part of the efficacy of mgiotensin-converting enzyme inhibitors, particularly with long-term treatment, may be due to the production of nonangiotensin-related peptides particularly bradykinin. Bradykinin is directly vasodilator and has been shown to stimulate nitric oxide and cyclic GMP production, prostaglandin E? and prostacyclin release from the endothelium (Vmhoutte c t (11. 1986; Gohlke e l ul. 1993). It has also, like all vasodilators, antiproliferative properties (Dubey et al. 1995). The benefit may however, be minimized by the side effects. The non-specific nature of angiotensin-converting rnzymc inhibition has been suggested to be responsible for dry cough which is a fairly common side effect of prolonged treatment (Gavras & Gavras 1983; Jenkins et ul. 1985; Alderman 1996). Effects of angiotensin mediated through the angiotensin AT, receptor
Since mgiotensin-coiivcrting enzyme inhibitors have multiple substrates, direct blockade of the angiotensin AT1 receptor should provide a more specific way of inhibiting the actions of angiotensin 11. Unlike angiotensin-converting ctvyrne inhibitors, blockade of angiotensin AT1 receptors would prevent the actions of angiotensin I1 derived from all sources whether from angiotensin-converting enzyme or from the above described alternative pathways (Urata ct al.
Cl
losartan
vaisartan
A
irbesartan
candesartan
Fig. 2 . Chemical structure of various angiotensin AT, antagonis~s (Wong el ttl. 1991: Cazaubon e f a!. 1993, Morimoto & Ogiham 1994; Criscione e t a / . IY95).
1995). Various non-peptide angiotensin I1 antagonists h a w been described (Buehlmayer 1993). Example5 include losartan, valsartan, irbesartan and candesartan which are all highly selective for the angiotensin AT, receptor (fig. 2). Hypertension. Recently reported clinical trials have shown that both losartan, valsartan and irbesartan are as efficacious as angiotensin-converting enzyme inhibitors in treating hypertension (Goa & Wagstaff 1996; Markham & G o a 1997; Gillis & Markham 1997). In animal studies, angiotensin ATI antagonists like angiotensin-converting enzyme inhibitor appear to prevent the vascular and cardiac remodeling associated with hypertensive disease (Kim et a/. 1995; Zierhut et NI. 1996; Ledingham & Laverty 1996). Long-term treatment with angiotensin AT1 antagonists also improves cardiac function as well as the metabolism of the e x vivo isolated perfused heart (Gohlke ct ul. 1996). Congestive heart fuilure. In patients with congestive heart failure, losartan and valsartan produce beneficial haemodynamic effects. Cardiac output increases while left ventricular filling pressure, left ventricular volume and pulmonary capillary wedge pressure all decrease in response to inhibition of angiotensin ATI receptors. These beneficial effects of the drugs tended to increase with time, in marked contrast to the tachyphylaxis often seen after treatment with vasodilators. Exercise tolerance did not deteriorate after treatment with losartan (Gottlieb et al. 1993; Crozier et al. 1995a & b; Baruch et ul. 1996).
MiniREview
161
ANGIOTENSIN, ANTAGONIST AND ANCIOTENSIN-CONVERTING ENZYME
R w , t l protective functions. Animal data as well as limited information from clinical studies indicate that angiotensin A r , receptor antagonists possess renal protective effects similar to those previously reported for angiotensin-convcrting enzyme inhibitors (Mackenzie et (11. 1994; Maschio ('I u/ 1996).In patients with non-diabetic, chronic renal disease. four months treatment with losartan 50-100 mgiday reduced blood pressure without changing glomerular filtr;rtion rate. Renal plasma flow increased, consistent with viisotiilation of the efferent arterioles which is bclieved to slow down renal damage by lowering intraglomerular pressUI'IL' and proteinuria (Gansevoort et al. 1994; Toto et a/.
possible consequences of concurrently stimulating the angiotensin AT2 receptor subtype and other unblocked angiotensin binding sites. Because of the increasing volume of knowledge concerning the effects of angiotensin 11 acting through the angiotensin AT2 receptor, it is possible to assess the potential effects of angiotensin peptides observed after angiotensin AT, receptor blockade.
1"X
The importance of various kinases in the coupling mechanism of the ATI receptor has been clearly emphasized over the last two years (Bernstein & Marrero 1996). In contrast and as discussed above, the angiotensin AT2 receptor is coupled to various phosphatases (table 2). Moreover, the re-expression of the AT2 receptor in pathological situations has lead to the hypothesis of a possible balance between the AT, and AT2 receptor (de Gasparo et a/. 1992). In this hypothesis it was proposed that the AT2 receptor opposed the effect of the stimulation of the ATI receptor in a Yin Yang manner. Whereas angiotensin TI stimulates cell growth and proliferation through the AT, receptor, recent data have indicated that angiotensin I1 acting through the angiotensin AT2 receptor inhibits the proliferation of rat coronary endothelial, pheochromocytoma cells (PC 12W) and neonatal cardiac myocytes in vitm (Stoll et al. 1995; Meffert et (11. 1996; kinkesteren et a/. 1997). Angiotensin I1 and CGP
).
P w iwtion of stroke and c.er.ehrovu.sc.ulluclisecrse. Long-term trt:ati-rient with angiotensin AT, antagonists decrease the incitleiice of stroke-related behaviour and end-organ damage in ;I \troke-prone strain of spontaneously hypertensive rats ( h - n c s et (I/. 1993; Kometani et a/. 1997; lnada et al. 1997). The \urvival curve over 58 weeks treatment with valsartan ( 3 10, 30 mgikg orally) was dose-dependent and related t o t h e antihypertensive action of the drug. In contrast, the anpie)tensin AT, antagonist candesartan at a dose of 0.1 m g k p reduced stroke incidence without affecting blood prt:sstire (Inada et al. 1997). Tested in deoxycorticosterone actt;iie-salt treated rats, a model of hypertension independenr of the renin-angiotensin system, candesartan also preven1r.d brain oedema, an effect with little relationship to the prwiiling level of blood pressure (Wada ct u/. 1995). 7idcrtrncc~.Angiotensin ATI receptor antagonists are surprisingly well tolerated. Data reported with losartan as well as with valsartan, demonstrate no adverse signs o r symptoms. changes in clinical laboratory parameters, abnormalitie.$ 01' the electrocardiogram or signs of disordered renal fuiict Ion that could be associated with the drug. Headache, di/ziiiess and fatigue are the most common symptoms reportccl with an incidence comparable to or less than that ob.;crvcd after placebo. The incidence of cough, one of the must frequent and disturbing side-effects of angiotensincoiivcrting enzyme inhibitors. is similar to that observed in the pliicebo groups in patients treated with angiotensin AT, reccpior antagonists (Goldberg et al. 1995a; Oparil et ul. I9%: Corea et ( I / . 1996).
E f / k l Y cf ungiotensin mrdiated though the angiotensin A T , r.('( vp/or. Angiotensin I1 acting through the angiotensin ATl reccpror on the juxtaglomerular cells exerts a direct negative feeL1b;ick on renin release from the kidney. Angiotensin AT, antagonists break this negative feedback loop and lead to incre;isied renin release and angiotensin I1 production (Bunkenburg et ul. 1991; Goldberg et ul. 1995b). The inc r e ~ s cin renin production following administration of angioiensin AT, receptor antagonists is enhanced by the coirciirrent reduction in blood pressure. Iiweased circulating levels of angiotensin I1 after ATI rectptor blockade have concerned clinicians because of the
Actions of angiotensin I1 mediated by the angiotensin AT2 receptor The Yin - Yang hypothesis
~
Trtblr 2
The signalling pathway of the AT? receptor involves both tyrosine and Ser/Thr Phosphatases (PTPdse).(Ydmada rt ul. 1996; Kang
-
uI 1995).
I AT2 I i
I G-protein coupled I
I SerlThr PTPase I
1 Tyr PTPase I
protein dephosphorylation
I anti-proliferation apoptosis differentiation vasodilation tissue regeneration
262
MiniRcvicw
MARC DE GASPARO AND NlGEL LEVENS
321 12, an AT2 receptor agonist (Brechlcr ef a/. 1993), inhibit DNA synthesis in fibroblasts stably expressing the recombinant angiotensin AT2 receptor. This effect was abolished by an AT2 selective antagonist as well as by pertussis toxin (Ozawa 1996). Low expression of the angiotensin AT2 receptor in mcsangial cells from stroke-prone spontaneously hypertensive rats may be rclated to the higher cell proliferation observed in this strain compared to normotensive Wistar Kyoto rats (Goto et al. 1997). Indeed, cultured vascular smooth muscle cells transfected with the angiotensin AT2 receptor grow less in the prcscnce of angiotensin I 1 than contrnl cells which express only the angiotensin AT, receptor. Extending this data to a disease situation, experimental overexpression of the angiotensin AT, receptor by trnnsfcctioii of the expression vector to balloon-injured rat carotid arleries attenuated neointimal formation (Nakajima ci d.1995). In an elegant study, Scheidegger & Wood (1997) delivcred angiotensin locally to the left carotid artery of normotensive rats with a perivascular drug delivery system in doses that did not affect systemic blood pressure. Angioknsin. but not adrenaline, induced a dosc-dependent thickening of thc adventitia with increased DNA synthesis, neovascuiarization and collagen deposition. This phenomenon, mediated via the AT, receptor, was inhibited through the AT, rcccptor. I t has also bccn recently observed that stimulation of the angiotensin A12 receptor in vitro induced apoptosis by stimulaling a MAP-kinase phosphatase-l and by controlling the phosphoryhtioii of Bcl-2 (Yamadn Cf d.1996; Horiuchi et al. 1997). The role o f iingiotcnsin TI in mediating programmed cell dcath appears complex as the angiotensin AT2 receptor is probably not the only trigger for apoptosis. Indeed, the stimulation o f the angiotcnsin AT, receptor of neonatal ventricular myocytes exposed to angiotcnsin 11causes apoptosis ;+pparentlythrough an elevation of intracellular calcium (Cigola r t d.1997). In contrast, other investigators have described an increased number of apoptotic cells in the thoracic aorta of spontaneously hypertensive rats after blockade of the renin-angiotensin system (deBlois (11. 1997). This observation appeared independent of concurrent changes in blood pressure since hydralazine did not affect vascular mass, :ipoptosis or D N A synthesis in this model. Taken together, the most recent results suggest that the angiotensin AT2 receptor has a negative effect on the growth stimulatory effects of the angiotensin AT, receptor its well iis on the cffects of other polypeptide growth factors either in inhibiting proliferation or in stimulating programmed ccll death. Beside this antiprolifcrative effecl of the angiotensin AT2 reccptor, ii role for the angiotensin 11 in oocyte maturation and in neuronal differentiation characterized by neurite outgrowth, namcly neurite outgrowth and tubulin polymerization through an increase in the levels of MAP2c, has also been reported (Yoshimura et ul. 1996; Laflamme et ( I / . 1996; Meffert et al. 1996). AT2 receptors have been implicated in the process of nerve regeneration (Bleuel et a/. 199s). Surprisingly, howcvcr, angiotensin 11 via the AT2 re(11
ceptors down-regulated middle-sized neurofilaments in PCl2W at both mRNA and protein levels (Gallinat et t i / . 1997 a & b). This observation suggests an interference of the AT? receptor with the transcription rate o r a receptorinduced destabilization of the neurofilamcnts. Clearly, the AT2 receptor is involved in neuroregeneration or neuronal apoptosis (Gallinat et al. 1997 a & b). An important recent development that has shed light on the physiological role of the angiotensin AT2 reccptor has been the generation of mice with targeted disruption of the angiotensin AT2 receptor gene. Interestingly, these animals reach maturity at the same rate as normal mice with no deformations, suggesting that the angiotensin AT2 receptor is not as essential for growth and dcvelopinent as previously thought. However, there is a delayed differentiation of vascular smooth muscle cells resulting in an increased vascular tone in AT2 knock out mice (Yamada et al. 1997). This could explain the higher sensitivity to angiotensin I1 of these mice and suggest a role for the angiotensin AT2 reccptor to counteract the classical pressor response to angiotensin TI. In summary, it is therefore hypothesized (table 3) that stimulation of the AT2 receptor counterbalances the effects of stimulation of the AT, receptor in dephosphorylating those proteins phosphorylated through the AT1 receptor (Dzau & Horiuchi 1996). Stimulation of the angiotensin channels ATr receptor also induces inhibition of Ca which have been activated through thc angiotensin ATI receptor (Buisson ~t al. 1995). This “Yin Yang hypothesis” does not appear exceptional in nature when one considers the metabolism of glycogen, which involves a cascade of phosphorylated and dephosphorylated enzymes or when one compares the opposite cffects of the ortho- and para+
+
Tulrble 3 Thc stimulation of the phosphatase activity trough the AT, receptor caiises dephosphorylatian of the enzymcs, which were phosphorylated through the AT, receptor-dependent kinases. ‘The AT2 receptor counterbalances the effect of the AT,. Hypothesis: the AT, receptor counterbalances the effect of the AT, receptor
/AT,/
!
I 1 angiogenesis
1
I
dephorphorylation .
1 apoptosis dlfferentiationtregeneration
vasoconstrlction
vasodilation
MiniReriew
ANGIOTENSINI ANTAGONIST AND ANGIOTENSIN-CONVERTING ENZYME
sympathetic stimulation observed in most instances. A distortioil in this coordinated balance between angiotensin AT, ;ind ATI: receptors may occur as a compensatory responsc to angiotensin AT, receptor blockade and the net growth effect of angiotensin I1 may depend on the cellular ATIiA'I'2 receptor ratio as observed in cultured neonatal cardiac rnyocytes and fibroblasts (vdnkesteren et a/. 1997).
Mechanism of action of angiotensin AT1 receptor antagonists The nicchanism of action of the angiotensin ATI receptor antagonists appears complex. Nitric oxide participates in the antihypertensive action of losartan (MunozGarcia et al. 199";. Recently, microdialysis studies in conscious rats have demonstrated an independent modulation of renal prostaglandin PGE2 synthesis mediated through the angiotensin AT, receptor and guanylate cyclase activation through anglo(cnsin AT2 receptor. Furthermore, the angiotensin AT2 receptor modulates PGE, production by angiotensin I1 at the angiotensin AT, receptor level (Siragy &Carey 1996 & 1997). Thu;,, ,I link between angiotensin I1 and the nitric oxide system through the angiotensin AT2 receptor is suggested. These obscn 'itions were made after feeding a low salt diet or during nori'ixil sodium balance with infusions of angiotensin 11. Sirnki I. observations have been obtained in stroke prone spoiit;ineously hypertensive rats. In these studies, treatment with Itjsartan alone or with angiotensin 11 increased aortic cyclic ( ; M P by an angiotensin AT2 receptor mediated mechanihen. which involved bradykinin and nitric oxide synthase and was independent of blood pressure (Gohlke et al. 1998). In heart failure after coronary ligature in the rat, the beneficial :.l'li.ct of an angiotensin AT, antagonist on left ventricular dia\tolic and systolic volume as well as cardiomyocyte size applrai-.;clearly related to stimulation of the angiotensin AT2 receptor (Liu et u1. 1997). In contrast the effect on blood pressure depends directly on blockade of the angiotensin ATl rece pic) r. 11 appears therefore in various animal models that some angiorcnsin AT, mediated effects are blunted by an angiotensin .AT2 receptor antagonist as well as by a bradykinin or iiti nitric oxide synthase inhibitor. This suggests that an angiorcnsin AT2 receptor-mediated increase in cyclic GMP formar ion may occur through bradykinin and nitric oxide stimu1;ition. Pollinan ei al. (1996) recently proposed that the cellular signiill ing pathways involved in regulating vessel tone were also coupled to the regulation of programmed cell death. Indeed. apoptosis is induced in cultured smooth muscle celli i n the presence of nitric oxide donor molecules through a gitan.;late cyclase signaling pathway. Angiotensin 11 antagoiiixs this effect through the activation of the angiotensin .4Tl receptor. A balance between angiotensin AT2 regularid nitric oxide production and angiotensin ATI receplor stimulation may determine the overall cell population in the heart and the vessels by regulating a genetic program determining cell death as well as cell growth. The high
263
circulating levels of angiotensin 11 following angiotensin AT, receptor blockade may therefore potentiate the beneficial effect of the antagonists through a stimulation of the angiotcnsin AT2 receptor. Thus, angiotensin AT2 receptorinduced nitric oxide production may counterbalance the growth-promoting effect of the angiotensin AT, receptor. Consequently, the increased concentrations of angiotensin I1 and its metabolites following angiotensin AT, blockade may therefore be beneficial for kidney function and cardiac and vascular remodeling.
Possible advantages of angiotensin AT1 receptor blockade over inhibitors of angiotensin-converting enzyme 1. Kidney rli.ceuse. Renal angiotensin receptor distribution. In contrast to the adult rat where essentially only the angiotensin ATI receptor subtype is detected, both the angiotensin AT, and angiotensin AT, receptors are expressed in human kidney. In man, both angiotensin receptor subtypes are expressed in the renal vasculature. Glomeruli and their efferent vessels largely express the angiotensin AT, receptor whereas the angiotensin AT2 is mainly located on large preglomerular vessels and on arcuate, inter- and iiitra-lobular arteries (Goldfarb et al. 1994; Zhuo et al. 1996). Both angiotensin AT, and angiotensin AT, receptors are found on the rend tubules and in the tubulo-interstitium of the kidney. a ) Renal / ? a ~ ~ ~ ) ~ ~ By~preferentially ~ i ~ z i ~ ,constricting . ~ . efferent glomerular vessels, angiotensin 11 acting through the angiotensin AT, receptor subtype helps to prevent decreased glomerular filtration rate when renal perfusion pressure is low. The relatively weak effect of angiotensin I1 on the affcrent arteriole is not only a consequence of the relative paucity of angiotensin ATI receptors there but may also involve the local production of vasodilator prostaglandins o r endothelium-derived relaxation factor by angiotensin 11 acting through the angiotensin AT2 receptor at this vascular site (Jaiswal PI ul. 1992; Siragy & Carey 1997 a & b). These observations support the use of an angiotensin AT, antagonist over an angiotensin-converting enzyme inhibitor in settings of low renal perfusion pressure. Experimental preclinical data have shown that the angiotensin ATI antagonist caused less reduction in glomerular filtration rate compared to an ACE inhibitor (Kon et al. 1993). Evidence for the possible superiority of an angiotensin I I antagonist over an ACE inhibitor comes from studies of renal adaptation to dietary sodium restriction. Unlike angiotensin I1 antagonists, ACE inhibitors have an adverse effect on glomerular filtration rate in states of extreme volume depletion (Jover & Mimram 1994). Gloinerular filtration rate decreased to a greater extend in one-kidney, one clip hypertensive rats subjected to dietary sodium depletion treated with enalapril than in losartan-treated rats (Demeilliers et ul. 1995). ACE inhibitors reduce efferent arteriolar resistance through an effect on bradykinin. Angiotensin antagonists should potentially better maintain glomerular filtration rate under conditions when glomerular filtration is
2 64
MAKC DE GASPARO A N D NlCEL LEVENS
dependent upon activation of the renin-angiotcnsin system, since they do not affcct bradykinin. In fact, after 8-12 wccks of losartan treatment in renal patients with normal 1-cnal function or with different degrees of rcnal dysfunction, glomerular filtration ratc and renal blood flow were maintained (Fauvcl ct (11. 1996). In settings of renal artery stenosis, renal blood flow inC ~ C B S C Sonly slightly or not at all following ACE inhibition. Under these circumstanccs, dilation of the efferent renal arteriole can lead to a dramatic fall in glomerular filtration r a ~ e which . may progress to overt renal failure. Unlike ACE inhibition, treatmcnt with an angiotcnsin AT, antagonist is accompanied by a persistent increase in circulating angiotcnsin I I which could stimulate angiotensin AT2 receptors in large preglomcrular vcssels. The angiotensin I I mediated increase in preglonicrular resistance may therefore be attenuatcd by prostaglandin and E D R F release because of thc predominance of angiotcnsin AT:, receptors at this location (J:iiswal et id. 1992; Siragy & Carey 1997a & b). This mcchan i sin, al t ho ug ti st i 1I hypothetical may help to different iatc angiotensin AT, antagonists from ACE inhibitors. h i 7irhrrkrv
[email protected]. Angiotcnsin 11 can directly influence prox i ma1 tubular sod i it ni re;i bsorption. In nor motensivc rats, losiirtm, but not enalaprilat, incrcascd sodium excretion (Hurton et rrl. 1991) and it has been suggested that it is the most potent diuretic to act on the SI segment of tlic proximal tubule (Xie et d . 1990). A kaliurctic effect has bccn attributed to losartan’s action on sodium reabsorption in proximal tubulc which increases delivery of sodium to the distal tubule (Chan & Uurnett 1992). Burnier et al. (1995) demonstrated that in healthy subjccts, losartan caused signilicant natriurcsis, in particular during salt depletion, and uricosuria. This may not be true for other aiigiotensin ATI antagonists (IJurnier et NI. 1996). Data obtaincd with chronic microdialysis of the renal cortex i n sodium-dcpleted rats indicated that angiotensin AT, rcccptor blockade produced a marked diuresis whereas atigioknsin AT? blockade with PD 123319 was devoid of any effect on water clearance and natriuresis. Moreover, P D 1233 I9 decreased c C M P in the niicrodialysate (Siragy & Carey IY96). (‘,I Rend protection. From the preclinical studies and the limited clinical datzi accumulated so far. angiotensin IT appeiirh to exert significant renal-tissuc damaging effects when renal mass or cellular function is compromised. I t is not clear how much is ‘pressure-dependent’ and how much is ’prcssure-independent’. I t is obvious, howcvcr. that angiott‘nsin AT,-selective blockadc (Lafayette C/ ul. 1992; Keniuzzi et n/. 1993; Kim ci ul. 1994; Gansevoort rt a/. 1994; Wu cz (11. 1997) as well a s ACE inhibition (Anderson et ul. 1986; Kamper et 01. 1992) can produce significant renal tissuc protection i n the majority of experimental models and i n non-diabetic hypertensive patients. Antihypertensive t w t m e n t with valsartan in male Munich Wistar Fischer rats which spontaneously develop nephrosclerosis and in which single ncphron glomerular filtration ratc was further incrcascd by the induction of diabctes almost completely
MiniReviw
prevented systemic and glomerular capillary hypcrtcnsion, proteinuria and renal structural changes despite sustained hypcrglycaemia (Remuzsi r t uI. 1996). Stroke-prone spontaneously hypertensive rats cvcntually succumb to renal damagc including renal tubular atrophy, basement membrane hypertrophy, arteriole fibrinoid necrosis and hypertrophy. Hyaline cast formation, dilation and interstitial fibrosis are also manifestations of renal disease in this animal model. Comparative treatment of sodium-loaded stroke-prone spontaneously hypertensive rats with angiotensin ATI receptor antagonists o r angiotensinconverting enzyme inhibitors has demonstrated a significant protection of angiotensin AT, blockade versus ACE inhibition on the progression of renal damage with a decreasc in tratisforniiiig growth factor fibronectin and collagen (Kim (?I ~ 1 1 .1994; Kometani et ul. 1997). Moreover, vascular fibrinoid development remained strongly prevented or fully suppressed after trcatment withdrawal (Fornes et a/. 1993). These observations in genetically hypertensive rats arc in contrast t o a recent report by Levy et nl. (1996) in normal rats chronically infused with angiotcnsin TI. In this model, chronic blockade of thc angiotensin AT, receptor resulted in aortic hypertrophy and fibrosis which was antagonized with PD 123319, an angiotensin AT2 rcccptor blocker, suggesting that collagcn formation was dependent on the angiotensin AT2 receptor. This report, which was not reproduced by Li et (11. (1997) although they were using thc same protocol, is also in contrast to other observations in heart failurc following myocardial infarction in rat (Liu et a/. 1997). Subpressor doses a s well as elevated endogenous levels of aiigiotensin I1 aftcr sodium restriction cause ciirdiac inyocyte necrosis, followed by fibroblast proliferation, and replacement fibrosis and scarring (Tan et a/. 1991; Weber r t al. 1993). In our hands, tritiated thymidine incorporation into fibroblasts was nearly times higher after 2 days of angiotensin I I infusion but totally blocked by equimolar doses of valsartan. After 2 weeks of angiotensin IT infusion, valsartan but not PDI 233 19 prevented myocytes injury and scar formation (Ramjoue r t al. 1994). These results suggest that fibrosis in rodents is angiotensin AT2 rcceptor-independent . Komers & Cooper (1995) have previously observed that, in contrast to ACE inhibition, acute angiotcnsin I1 receptor blockitde with valsartan did not affcct hyperfiltration in experimental diabctcs suggesting an important role for kinins. However, chronic administration of valsartan for 24 weeks attenuated the glomerular ultrastructural changcs and prcvented the increasc i n albumin excretion with an efficacy similar to ramipril. Neither a bradykinin B,-receptor antagonist nor a calcium channel blocker influenced albuminuria (Allen et al. 1996). These findings, which may be clinically rclcvant. suggest that ACE inhibitors and angiotensin I1 antagonists have different targets in experimental diabctcs.
2. Cardiac anti vcrscular rernodcling. The angiotensin AT, receptor appears to be re-cxprcsscd or up-regulated after vascular injury (Pratt et ul. 1992). Rcccnt
MiniKcvir N'
ANGIOTENSIN, ANTAGONIST AND ANGIOTENSIN-CONVERTING ENZYME
stirlie\ that have compared the actions of ACE inhibitors with angiotcnsin I1 receptor antagonist have shown angiotetisiti 4Tl antagonists to be as effective as ACE inhibition in Itre\cnting the injury and lesion formation that occurs follrming experimental balloon angioplasty in animals (Kaull'man c't al. 1991: Laporte & Escher 1992; Azuma et a/. IW?: Taguchi et al. 1993 ). It appears, however. that ACE inhibitors prevent cellular migration but d o not affect cellula I proliferation, whereas angiotensin ATI receptor blo~,k;deinhibits both proliferation and migration, althoiipli both classes of drug produce a similar effect on blot id pressure (Prescott ot ul. 1991 ). The beneficial effect of angiotensin AT, receptor stimulation was observed with CC;I' .1?I 12. a specific angiotensin AT2 receptor agonist ( B r ~ d i l c Ct r ul. 1993; Janiak ct a/. 1992). In angiotensin AT? receptor knockout mice, the expression of caldesmon and calponin, markers of differentiation of vascular smooth niuxclc cells, was dramatically delayed in comparison with the - k v ~ i ttype l aorta (Yamada et al. 1997). This observation sugp,esi>a role for the angiotensin AT2 receptor in promoting v a s ~ ~ r ldifferentiation ar and vasculogenesis. Angiotensin receptor antagonists may therefore be superior to ACE inhibiioi., when it comes to completely blocking the reninangiotcnsin system. Human clinical trials with ACE iiihibitors (klercator and Marcator) have shown no beneficial effect> O I I overall clinical outcome after percutaneous translumin'rl coronary angioplasty (Mercator study group 1992: Faxon 1995). This may be due to the formation of angiotensin II in human vessels despite ACE blockade through an altc.i.native pathway e.g. chymase (Okunishi et ul. 1993; WOII'I?i ' / a / . 1997). Tlic re-expression or up-regulation of the angiotensin AT? ri.ccptor in experimental cardiac hypertrophy, after myoi:oi-ilial infarction in animal models and in human failing Iieiirt suggests a role for the angiotensin AT2 receptor in tlic pithophysiology of cardiac dysfunction (Lopez ct a/. 1994: Nio rt ul. 1995; Regitz-Zagrosek rt al. 1995 & 1997: ril. 1996; Gallinat ot a/. 1997). Angiotensin AT, Ropy recqitoi density is reduced in human failing heart and there is in1 rriised density of the angiotensin AT2 receptor in atrial tissui: I!ith increased atrial pressure and left ventricular ejection I't-action. Thus, because of the change in the relative propcoriions of cardiac angiotensin ATI and AT, receptors, the cffccts of a selective angioteiisin AT, antagonist and ACF inhibitor may be different in the setting of heart failui,c. Tlre ,timillation of the angiotensin AT-, receptor by angiotciisin I 1 following angiotensin AT, blockade may thus ;ii'lcct cardiac and vascular remodeling and have interestinp effects which have not yet been appreciated. Apoljtosis may be a prerequisite for remodeling. After aortic stcnosis. apoptosis occurs and peaks at day 4 in cardiomyoc! tes (Teiger et ul. 1996). It is conceivable that hypertroplq iiiay represent a failure of compensatory apoptosis. Diirrng chronic ACE therapy, angiotensin 11 content deni the atria which may produce an antiarrhythmic effeci. I n contrast the synthesis of angiotensin I I is main-
265
tained in the ventricles probably due to the high concentration of chymase (Urata et d.1995). This may contribute to volume-overloaded cardiac hypertrophy. In contrast to angiotcnsin-converting enzyme inhibitors, the renin-angiotensin system is more completely blocked with angiotensin I1 receptor antagonists and the effect of locally produced angiotensin I1 may be better inhibited. I n cardiac remodelling, the beneficial effect ofangiotensinconverting enzyme inhibitors appears related more to the inhibition oftissue ACE rather than to plasma ACE activity. In addition to the decreased vasoconstriction, the local production of vasodilatory substances such as bradikinin and nitric oxide and also interference with the fibrinolytic system is increased. Angiotensin I I inhibits tissue plasininogcn activator and stimulates plasminogen activator inhibitor- 1. As a consequence, there is increased fibrosis, extracellular matrix turnover and risk of clotting. The beneficial effect of angiotensinconverting enzyme inhibitors on fibrinolysis has been demonstrated in various cardiovascular trials. Could a similar result be expected with angiotensin antagonists? It is not clear at thc moment which angiotensin receptor subtype is implicated in this angiotensin 11-induced plasminogen activator inhibitor- I stimulation. A difference between tissues may exist. The angiotensin AT, receptor appears involved in brain cells in culture and in vivo in kidney injury following irradiation (Rydzewski et al. 1992; Yang et n/. 1996; Oikawa et t i l . 1997). In contrast, in cultured endothelial cells. Ang IV mediated the induction of plasminogen activator inhibitor expression through the AT4 receptor (Kerins rt 01. 1995). I f blockade of the angiotensin AT, receptor is associated with elevated plasma levels of angiotensin 11 and its metabolites amongst them Ang IY there may be an increased risk of thrombosis and fibrosis after treatment with angiotensin receptor antagonists. No clinical data supports this theoretical possibility. Moreover, four weeks treatment of hypertensive patients with losartan or placebo did not modify either basal or insulin-stimulated plasminogen activator inhibitor-1 activity (Seljeflot et a/. 1996). More work is clearly req ui red.
3. Microcirculation.
Increased vascular resistance may be attributed to three possible causes, one is increased vasoconstriction due to increased sympathetic activity o r increased sensitivity to vasoactive agents, second, vascular remodelling may reduce thc lumen of the vessel and contribute to the resistance observed in hypertension, and third possibility may be linked to reduction of microcirculation. ACE inhibitors and angiotensin antagonists are equipotent on the two first mechanisms. Four weeks treatment of spontaneously hypertensive rats with valsartan however did not affect the density of arterioles and veinules in striated muscles whereas ACE inhibition did. Blood pressure returned to control values after the treatment with angiotensin-converting enzyme inhibitor has been stopped whereas it remained lowered in the valsartan-treated group (Scheidegger r t u / . 1996). This property
266
MiniRcvicw
MARC DE GASPARO AND NTCEL LEVENS
may help to differentiate angiotensin-converting enzyme inhibitor and angiotensin antagonist during long-term treatment.
Conclusion Angiotensin ATI receptor antagonists represent a new approach for inhibiting the renin-angioteiisin system. This new class of drugs appears t o have a n efficacy similar to that of angiotensin-converting enzyme inhibitors. However, they may have properties that are not shared with angiotensin-converting enzyme inhibitors. These additional properties are due t o the stimulation of the angiotensin AT2 and other angiotensin receptors by the increased circulating angiotensin I1 produced by blockade of angiotensin AT, receptors (“Yin - Yang hypothesis”). For example, stiniulation o f the angiotensin AT2 receptor may be involved in vascular and cardiac remodeling a n d be the basis of greater renal protective effect of angiotensin ATI receptors over angiotensin-converting enzyme inhibitors. Data are now available suggesting that part of the beneficial effect of angioteiisin AT, receptor antagonists are clearly mediated through the angiotensiii AT2 receptor (MunozGarcia et (11. 199.5; Siragy & Chrey 1996; Liu et al. 1997). Current antihypertensive therapies reduce stroke risk but are not very effective at reversing hypertension-induced renal failure and coronary artery disease. Since o u r clinical experience with angiotensin ATI receptors is currently limited it is perhaps too early to clearly see the long-term henefits of selective and specific blockade of angiotensin ATl receptors. The perspectives however are exciting and time will show the potential of such a n approach. Since the renin-angiotensin system plays a n important role in hypertension-induced functional and structural abnormalities, blockade of angiotensin ATI receptors being more specific, more selective and irrespective of the angiotensin II-producing pathway could offer better cardiovascular and renal protection than A C E inhibitors. Comparative long-term studies of ACE inhibitors and angiotensin AT, receptor antagonists are rcquired t o appreciate their effect o n cardiovascular and renal structure and function. Retrospective sub-group analysis of the E L l T E (Evaluation of Losartati in thc Elderly) study has indicated an unexpected decrease in mortality in elderly patients with congestive heart failure treated with an angiotensin ATI antagonist compared t o captopril (Pitt et a/. 1997). This stimulating observation however, has 10 be interpreted with caution since it was not the primary end-point of the study. Long term trials such as ELITE 11, LIFE (Losartan Intervention For Endpoint lieduction in Hypcrtensionf comparing the effect of losarta n and atenolol on cardiovascular mortality and morbidity, VALUE (Diovan Antihypertensive Long-term Use Evaluation) comparing the long-term benefits of valsartan with those of :imlodipine and ValHeFt (Valsartan in Heart Failure Trial) will show the real place of this new class of drugs in cardiovascular therapy.
References Alderman, C. P.: Adverse effects of the angiotensin-converting enzyme inhibitors. Ann. Pharmacotherap. 1996, 30, 55-61. Ali, M. S., €? I? Sayeski, L. B. Dirksen, D. J. Hayzer, M. B. Marrcro & K. E. Bernstein: Fdependence of the motif YIPP for the physical association of Jak2 kinase with the intracellular carhoxyl tail of the angiotensin I I AT(1) receptor. J. Biol. C h r . 1997. 272. 23382 23388. Allen, T., U. L. Hulthen. Z . Cao & M. E. Cooper: Albuminuria in experimental diabetes: role of angiotensin and bradykinin. Diahctcs 1996, 45, Suppl 2; 3A. Allen, T. J., Z. Cao. U. L. Hulthen & M. E. Cooper: The role ol‘ angiotensin I1 and bradykinin in experimental diabetic nephropathy: functional and structural studies. Diabete.y 1997,46, 16121618.
Anderson, S., H. G. Rennke & B. Brenner: Therapeutic advantage of converting enLyme in arrestiug progressive renal disease associated with systemic hypertension in the rat. J. Chi. Inimr. 1986, 77. 1993-2000. Azizi. M., G. Chatcllier, T. T. Guyene, D. Murietageol‘froy, & J. Minard: Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin ii antagonism on blood pressurc and reiiin release in sodium-depleted normotensives. Circuhtion 1995, 92, 825-834. Azizi, M., A. Rousseau, E. Ezan, T. T. Guyene, S. Michelet, J. M. Grognct, M. Lenfant, P. Corvol & J. Menard: Acute angiotcnsinconverting enzyme inhibition increases the plasma icvei of the natural stem cell regulator n-acetyl-seryl-aspartyl-lysyl-proline. J.C‘lin. Invcst. 1996, 97, 839-844. Azuma, H., Y. Niimi & H. Hamasaki: Prevention of intimal thickcriing after endothelial removal by a nonpeptide angiotcnsin-TI receptor antagonist, losartan. Brit. J . Pharrntrcal. 1992, 106, 665671. Balcells, E., Q. C. Meng, G. R. Hageman, R. W. Palmer, J. N. Durand & L. J. Dell Ttalia: Angiotensin 11 formation in dog heart is mediated by dil‘ferent pathways in vivo and in vitro. Arncr. J. Phy.siol. 1996, 271, H417-H421. Baruch, L., I. S. Anand. D. L. Judd & J. N. Cohn: Hemodynamic response to ATI receptor blockade with valsartan in ACE inhibitor-treated patients with heart failure. Circulation 1996. 94. I 428. Bedecs. K., N. Elbaz, M. Sutrcn, M. Masson, C.Susini. A. D. Strosberg & C. Nahmias: Angiotensin I1 type 2 receptors mediate inhibition of mitogcn-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase. Binchcm. J. 1997. 325, 449454. Benter, 1. F.,D. 1. Diz & C. M. Ferrario: Cardiovascular actions of angiotcnsin( 1-7). Peprides 1993, 14. 679-684. Berk, B. C. & M. A. Corson: Angiotensin TI signal transduction in vascular smooth muscle - role of tyrosine kinases [review]. Circ. Res. 1997, 80, 607-616. Bernstcin, K. E.: The renin-angiotensin system: a biological machine. Ann Med. 1993, 24. 113-115. Bernstcin, K. E. & M. B. Marrero: The importance of tyrosiric phosphorylation in angiotensin IT signaling. Trends Ccir(liovtisc. Med. 1996. 6 , 179-187. Bleuel, A., M. de Gasparo. S. Whitebread, 1. Puttner & D. Monnard: Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin I1 receptors. J . Ncurosci. 1995, 15, 750-761. Bottari, S. P., I. N. King, S. Reichlin, 1. Dahlstroem, N. Lydon & M. de Casparo: The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. Biochem. Biophys. Rex Cornmun. 1992, 183, 206-21 1. Brechler, V., P. W. Joncs, N. R. Levens, M. de Gasparo & S. I? Bottari: Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul. Pcpt. 1993, 44, 207-213. ~
MiniRcj siew
ANGIOTENSIN, ANTAGONIST A N D ANGIOTENSIN-CONVERTING ENZYME
Brosiiih;in. K . B., P. LI & C. M . Ferrario: Angiotensin-(1-7) dilates canttic coronary arteries through kinins and nitric oxide. Hjper/ P ~ / o / I 1996, 27, 523-528. Buehlniayer. P : Angiotensin I1 antagonists: patent activity since the di\cc>iery of DuP-753. C'urr. Opin. Ther Pu/rn/.s 1993. 2, 1693I7IX
Buismii. B., L. Laflanime, S. P. Bottari, M . de Gasparo, N. Gallopayet fi "vl. D. Payet: A G protein is involved in the angiotensin AT(2) rctq7ii)r inhibition of the T-type calcium current in non-differenti,rted NG108-15 cells. J . Biol. Clzern. 1995, 270, 1670-1674. Bunipu\. F. M . , H. Schwarz & I . H. Page: Synthesis and pharmacolopq of the octapeptide angiotonin. .~Cle~lCc,1957. 125, 886-887. Bunkeiihurg, B., C. Schnell, H. I? Baum, F. Cumin & J. M. Wood: PIolonged angiotensin 11 antagonism in spontaneously hypertens l w I .its. Hemodynamic and biochemical consequences. Htyer/ c ~ I , \ / o1991, /I 18, 278-288. Burtiier. M . , M . Hagman, J. Nussberger. J. Biollaz, C. Armagnac. R Htouard R, B. Waeber & H. R . Brunner: Short-term and sust;linccl renal effects of angiotensin IIii receptor blockade in hr-alt hy subjects. Hyprrtemion. 1995, 25, 602-609. BurtiiL-t. M., F. Rochramel & H. R . Brunner: Renal effects of angiotcilihiti 11 receptor blockade in normotensive subjects. Kirlnej, I n t . I ' W k 49\ 1787-1790. Ca?,iuhon, C.. J. Gougat, E Bousquet, P. Guiraudou. R . Gayraud, C I s x u r , A. Roccon, G. Galindo, G. Barthelemy, B. Gautret, ( Hcrnhart. P Perreaut, J. C. Breliere. G. Le Fur & D. Nisato: Pliat macological characterization of SR 47436, a new nonpept i d e , \ I l subtype angiotensin receptor antagonist. J . Pharmucol. t.\ll 7 % t ~ r t i l 1993, ~. 265, 826-834 Chili. S. Y. & C. I . Johnston: Tissue distribution of' angiotensinCI ,n\ L,rting enzyme. In: f3ypertmsion: Prirhopli?.Fiology, diugriosi.?. u i i d /~icinugiwen/. Eds.: J. H. Laragh and B. M. Brenner. Raven Ltd. New York, 1995,1683-1694. Ch;ln, I > P , E. K. Sandok, L. L. Aarhus, D. M. Heublein & J. ( . I%urnet,Jr.: Renal-specific actions of angiotensin I1 receptor antxgonisni in the anesthetized dog. Amer. J. Hjper/ens. 1992, 5, 3 41 160. Chii.t. \. T. fi M. J. Peach: Inhibition of' induced aldosterone biohirnilicsis with a specific antagonist of angiotensin 11. Proc. Null. . I ( < ! ( / Sci. L'SA. 1974, 71, 341-344. Cip>I:i E.. J . Kajstura, B. Li, L. G. Meggs & I? Anversa: Angiotcnsin I I activates programmed myocyte cell death in vitro. E.17~. Cell Rrs. 1997, 231. 363- 371. C 1 a t . i ~ E. . L., K. M. Curnow, S. Conchon. E. Davies, B. Teutsch. H. Z tanello. C. Monnot & P Corvol: Molecular structure and nicihanisms of action of mammalian angiotensin 11 receptors. ' i r r @in. Endorrind Diuhrtes 1995. 2, 404 -41 1. Cotex L.. 0. Cardoni, R . Fogari, I? Innocenti, C. Porcellnti. M. Pro\ videnza, S. Meilenbrock, J. Sullivan & F.Bodin: Valsartan, i~ nc'w angiotensin I1 antagonist for the treatment of essential Iiypcrtension A comparative study o f the efficacy and safety : ~ g ; i i n b tamlodipine. Clin.Phtrrmucol. Tllerup. 1996, 60, 341-346 CrI.,cit>ne, L.. W. A. Bradley, P. Buehlmayer, S. Whitebread, R. (;lam. I? Lloyd, P. Mueller & M . de Gasparo: Valsartan: Prec linlc;iI and clinical profile of an antihypertensive angiotensin-I1 ;int.igonist. Curdiovusr. Drug Rei: 1995, 13, 230--250. Cnriici. I. & H. Ikram: The acute and chronic effects of losartan 111 lieart failure. J . Hjporten.?. 1995a, 13, S 59-S 61. CrixiL,r. I . , H. Ikram, N. Awdn, J. Cleland. N. Stephen, K. Dick\tcin. M. Frey, J. Young, G. Klinger, L. Makris & E. Rucinska: 1,osirtan in heart failure - hemodynamic effects and tolerability. (''//.[ u/tr/io/, 1995b, 91, 691-697. del4lc)ih. D.. B. S. Tea, V. D. Than, J. Tremblay & P. Hamet: Smooth init \cle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertmsion 1997, 29, 340-349. de Gi\paro. M.. St. Whitebread, N. Levens, H. I? Ramjoue, L. Cris~ ~ ( i i iH. c . Rogg, H. P. Baum, V. Brechler, I? Buehlmayer, J. M. Wibod & S. Bottari: Pharmacology of angiotensin 11 receptor subt>pes. In: Cellulur and moleculur biology of /hi. udrenul cortex.
267
Eds.: J. M. Saez, A. C. Brownie. A. Capponi, E. M . Chambaz & E Mantero. John Libbey Eurotext Ltd., 1992, pp. 3-17. de Gasparo. M.. S. Whitebread, M. K. Kalenga, R. de Hertogh. P. C'revoisier & K. Thomas: Down regulation of the angiotensin I I receptor subtype AT, in human myometrium during pregnancy. Regul. Pep/. 1994, 53, 3 9 4 5 . de Gasparo, M., S. Bottari & N. R . Levens: Characteristics of angiotensin II receptors and their role in cell and organ physiology. In: Hyper/ension: Phjsiologj, r/iugnosi.s, and m~muget~iivi~. Eds.: J. H. Laragh and B. M. Brenner. Raven Press: New York, Ltd. 1995a, 1695-~1720. de Gasparo, M., A. Husain, W. Alexander, K. J. Catt, A. T. Chiu, Harding, T. lnagami & I? B. M. M . Drew. T. Goodfriend, J. W., W. M. Timmermans: Proposed update of angiotensin receptor nomenchture. Hjpertension 1995b. 25, 924927. Denxilliers. B., B. Jover & A. Mimran: Renal function in onc-kidney, one clip sodium-restricted rats: influence of enelapril and losartan. J. H y p e r f m s . 1995, 13, 1764-1766. Dubey, R . K., E. K. Jackson & T. F. Luscher: Nitric oxide inhibits angiotensin I1 induced migration of rat aortic smooth muscle cell Role of cyclic nucleotides and angiotensin receptors. .I. Ciin, I n w s f . 1995, 96, 141-149. Dzau, V. J. & G. H. Gibbons: Autocrine-paracrine mechanisms of vascular myocytes in sytemic hypertension. Amer. J. Curtiid. 1987, 60. 991-1031. Dzau. V. J.: Implications of local angiotensin production in cardiovascular physiology and pharmacology. Amer. J . Curdiol. 1987, 59, 59A 65A. Dzau, V. J.: Multiple pathways of angiotensin production in the blood vessel wall: evidence, possibilities and hypotheses. J. Hyperleris. 1989, 7, 933-936. Diau, V. J., G. H. Gibbons & R. E. Pratt: Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. H p e r t e n s i o n 1991, 18 (suppl II), 100-105. Drau, V. J. & M. Horiuchi: Differential expression of angiotensin receptor subtypes in the myocardium: a hypothesis. E w . H w r i .I. 1996, 17, 978-980. Eggena, P.. J. H. Zhu, K. Clegg & J. D. Barrett: Nuclear angiotensin receptors induce transcription of renin and angiotensinogen messenger RNA. Hypertension 1993, 22, 496-501. Fauvel. J. I?, S. W o n , N. Berra, N. Pozet, 0. Madonna, I? Zech & M . Laville: Effects of losartan on renal function in patients with essential hypertension. J. Curdiovusc. Phurmucol. 1996, 28. 259 263. Faxon, D. P.: Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the Marcator study. a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multiple American Research Trial with Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J. Amer. Cali. Curu'io/. 1995, 25. 362-369. Fornes, I?. C. Richer, E. Vacher, I? Bruneval & J. F. Giudicelli: Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J . C'ur(/iovasr. Pharmucol. 1993, 22. 305--313. Fossa, A. A,, M. J. DePasquale, L. J. Ringer & R. L. Winslow: Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor o r an angiotensin-converting enzyme inhibitor with an angiotensin ii receptor antagonist. Druz Dev. Rev. 1994, 33, 422-428. Gallinat, S., T. Csikos, S. Meffert, T. Herdegen, M . Stoll & T. Unger: The angiotensin AT2 receptor down-regulates neurofilamcnt in PC12W cells. Neurosci. Lett. 1997, 227, 29-32. Gallinat, S., M. H. M i , Y. 2. Zhu, T. Herdegen & Th. Unger: Upregulation of angiotensin receptors after myocardial infarction and sciatic nerve transection: a common expression pattern. Hi.pertension 1997, 30, 999. Gansevoort, R. T., D. Dezeeuw, S. Shahinfar, A. Redfield & I? E. Dejong: Effects of the angiotensin I1 antagonist losartan in hy-
268
MARC D E GASPARO A N D NIGEL LEVENS
pertensive paticuts with renal disease. J. Hypertetis. 1994, 12, S 37 s 4 1 . Gavras. I . & H. Gavras H: Captopril and enalapril (letter). Ann. I n t w n . M e t / . 1983. 98, 556457. Ciasson. E,, M. J. Servant & S. Meloche: Cyclic AMP-mediated inhibition of angiotensin 11-induced protein synthesis is associated with supression of tyrosine phosphorylation signalling in vascular smooth niuscle cells. .I. B i d Chetii. 1997. 272, 2687926886. Gillis3J. L. & A. Markham: Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management o f hypertension. Drugs 1997, 54, 885-902. Goa. K. L. & A. J. Wagstaff: Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the managcmcnt of hypertension. Drugs 1996. 51, 820-845. Gohlke. P.. V. Imiiberty, 1. Kuwer, S. Bartenbach, A. Schnell, W. Linr, R. A . Scholkcns, C. Wiemer & T. Unger: Long-term lowdose angiotensin converting enzyme inhalation treatment increases cyclc guenosine 3'5'-monophosphate. Hypertension 1993, 22. 682-687. Gohlkc, I?. W. Linz. B.A . Scholkens, G. Wiemcr & T. Unger: Cardiac and vascular cffects of long-term trcatment i n stroke-prone spontaneously hypertensive rats. Hyperieti.vion 1996. 28, 397 -402. Gohlkc. P Ch. Pees & T. LJnger: AI2 receptor stimulation increases aortic cyclic G M P in SHRSP by a kinin-dependent mechanism. Hiperioi.siotl 1998, 31, 349~-355. Goldberg, A. 1.. M. C . Dunlay & C. S.Sweet: Safety and tolerability 01' 1os;irtan potassium, and angiotcosiri I I receptor antagonist, compared with liydrochlorotliiazide, atenolol, felodipinc ER. and 3ngiotensin-converting enzymc inhibitors for the treatment of systemic hypertension. Ainer. J . C(irrlio1. I995a, 75, 793.-795. Goldbcrg, M. R.. T. E. Bradstreet, E. J. Mcwilliams, W. K. Tanaka, S. Lipert. T. D.B,iornsson, S. A . Waldman, B. Osborne. L. Pivadori. G. Lewis, K.H u m , T. Herman, P A. Abraham, C . N. Halstenson, M. W. Lo, H. 1.u & R . Spector: Biochemical effects of losartan, a nonpeptide angiotensinll receptor antagonist, on the rcnin-angiotensiii-aldosteronesystem in hypertensive patients. Hjpcriensiotl I995b. 25, 31 46. Guldt'drh. D. A , , 11. 1. Diz, R. R . Tubbs, C. M . Ferrario & A. C. Novick: Angiotensin-11 receptor subtypes in the human renal cortex and renal cell carcinoma. J. U r d . 1994, 151, 208-213. Goodfricnd, T. L., M. E. Elliott & K. J. Catt: Drug therapy angiotensin receptors and their antagonists [review]. Nevi. E q l . J . M ~ t l 1996. . 334, 1649-1654. Cioto. M.. M. Mukoyama, S. Suga, T. Matsumoto, M. Nakagawa, R . Ishibashi, M . Kasahara. A. Sugawara, I . Tanaka & K. Nakao: Growth-dcpcndent induction ol' angiotensin IT type 2 receptor in riit mcsarigial cells. H)pr/etrsion 1997, 30, 358-362. Gottlicb. S. S., K . Dickstcin, E. Fleck, J. KostiL, T. B. Levine. T. Lc-jemtel Ir, M . Dckock: Hemodynamic and neurohornional cfk c t s of thc aiigiotensin IT antagoiiist losartan in patients with congestive heart Ikilure. Circrduiiun I Y93, 88, 1602-1609. Griidy. E. F,,L. A. Sechi, C. A. Grirfin? M . Schariibelan & J. E. Kaliiiyak: Expression of AT2 receptors i n thc developing rat fctiih. J . Cliti. fni~est.1991, 88, 921-933. Griendling, K . K., 1'.J. Murphy & R . W. Alexander: Molecukar biology of the rcnin-angiotensin system. Cirrirlntiun 1993, 87, 1816-1 x2x. Criendling, K. K., B. 1,asseguc & R. W. Alexander: Angiotensin rcccptors and their thcrapeutic implications. Annu. Rev. Phnrmucol. To.virn/. 1996, 36, 28 1 306. Griendling. K . K., M. Ushiofukai, B. Lassegue & R . W. Alexander: Angintensin 11 signaling i n vascular smooth musclc - New concepts. Hipertrtz.sinti 1997, 29, 366 373. Griffin, S. A,, W. C. Brown, E MacPherson, J . C. McGrath, V. G. Wilson, N. Korsgaard, M. J. Mulvany & A. F Lcver: Angiotensin 11 causes V ~ S C U ~ Hhypertrophy Iin part by a non-pressore nicchan, F ~ 17, U W626-635. ism. H ~ ~ P ~ I C W1991. liagiwnrn, H.. N. Sugiura, K. 1. Wakita & S. Flirose: Purification ~
MiniRrvic w
and characterization of angiotensin-binding protein from porcine liver cytosolic fraction. Eur. J. Biochem. 1989, 185, 405 410. Handa, R. K., C. M. Ferrario & J. W., Strandhoy: Renal actions of angiotensin (1-7): in vivo and in vitro studies. Amo.. J. Phy.riu/. 1996, 270, F141LF147. Harding, J. W., J. W. Wright, G . N. Swanson, J. M. Hanesworth & L. T. Krebs: AT(4) receptors - spccificity and distribution. Kiclnq In?. 1994, 46, 1510 ~1512. Harton, P, K. Engels & C. Baylis: Differing renovascular responses to three methods of angiotensine I1 (AH) blockade. J . Anier. Sor. Hephol. 1991. 2, 402 (abstract). Holland, 0. B.: Angiotensin I1 receptors. C'urr. Opiiz. Endocrinol. Dicihetrs 1996, 3, 258 264. Horiuchi, M., W. Hayashida, T. Kambe, T. Yamada & V. J. Dzau: Angiotensin typc 2 receptor' dephosphorylate Bcl-2 by activating mitogen-activated protein kinasc phosphatase-1 and induces apoptosis. J. Bid. Clierri. 1997, 272, 19022-19026. Huang, X. C., E. M. Richards & C. Sumncrs: Mitogen-activated protein kinases in rat brain neuronal culturcs are activated by angiotensin TI typc 1 receptors and inhibited by angiotensin 11 type 2 receptors. J. Bid. Chem. 1996, 271, 15635-15641. Tnada, Y, T. Wada, M. Ojinia, T. Sanada. Y. Shibouta, R. Kanagawa, Y. Ishiniura, Y. Fyjiwasa & K . Nishikawa: Protective effccts of candesartan cilexetil (TCV- I16) against stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypcrtensive rats. Clin. Exp. ftypertens. 1997, 19, 1079-1 099. Tnagami, 'r., D. Fuo & Y. Kitami: Molecular biology ofangiotensin TI receptors: an overview. J . Hpwten.P. 1994, 12 (suppl. 10). S83s94. Jaiswal. N.. D. I. Diz, M. C. Chappell, M. C. Khosla & C. M. Ferrario: Stiniulation of endothelkl cell prostaglandin production by angiotensin peptides. Characterization of receptors. 11.1)pertension 1992, 19, 1149-1155. Janiak, P, A. Pillon. J. E Prost & J. I? Vilaine: Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. flypertemion 1992, 20, 737- 145. Jenkins, A . C., G. R.Dreslinski, S. C. Tadros, J. T. Grocl, R. Fand & S. A. Herszcg: Captopril in hypertension: seven years later. J. Cnrdiovrrsc. Pliarmarol. 1985, 7, S96-SIOI. Johnson, M. C. & A. Aguilera: Angiotensin I1 receptor subtypes and coupling to signaling systems in culture foetal fibroblasts. Endoerinnlogy 1991, 129, 1261-1274. h e r , 8 . & A. Mimran: Angiotensin 11 receptor antagonists versus angiotensin-converting enzyme inhibitors - effects on renal function. J . HpI7prten.r. 1994, 12, S 3- S 9. Kambayashi, Y., S. Bardhan. K. Takahashi, S. Tsuzuki, H. Tnui. T. Hamakubo & T. Inagami: Molecular cloning of a novel angiotensin-1 I receptor isoform involved in phosphotyrosine phosphatase inhibition. J. Biol. Chetti. 1993. 268, 24543-24546. Kaniper, A. L., S. Strandgaard & I? F? Leyssac: Effect of enalapril on the progression of chronic renal failure. A randomized controlled trial. Anier. J. Hypcrtem. 1992, 5, 423 430. Kang, J.. E. M. Richards, P. Posner & C. Sumners: Modulation of the delayed rcctilier K + current in neurons by an angiotensin 11 type 2 receptor fragment. A m w . J . Pliysiol. 1995, 37, C 278 C282. Kaui'l'man. R. E, J . S. Bean, K. M . Zinimcrman, R. E Brown & M. 1. Steinberg: Losartan. a nonpeptide angiotensin TI receptor anragonist, inhibits neointinia formation following balloon injury to rat carotid arteries. Lifi. Sci. 1991. 49, 223-228. Kerins, D. M., Q. Hao Q & D. E. Vaughn: Angioteiisin induction of PAI-1 expression in endothelial cells is mediated by the hcxaI . 96, 2515 ~2520. pcptide angiotensin 1V. J. Clin. I ~ I Y P S1995, Kim, S. K., K . Ohta, A. Hamaguchi, T. Omura, T. Yukimura, K. Miura. Y. Inada, T. Wada, Y. Ishimura, E Chatani & H. Iwao: Ccontribution of renal angiotensin 11 type1 receptor to gene expressions in hypertension-induced renal injury. Kidney Int. 1994, 46, 1346 1358.
MiniHtview
369
ANGIOTENSIN 1 ANTAGONIST A N D ANGIOTENSIN-CONVERTING ENZYME
Kim. 4 K.. K. Ohta, A. Hamaguchi, T. Omura, T. Yukimura, K. M I I I I : ~Y., Inada, Y.Ishimura. E Chatani & H. Iwao: Angiotensin I I typc I receptor antagonists inhibit the gene expression of transfc3rniing growth factor-beta-1 and extracellular matrix in cardiac aixd vascular tissues of hypertensive rats. J . Pharmucol. Exp. I h c ~ i / / 1995, ~ . 273, 509-515. Koiiiei-\. R. & M. E. Cooper: Acute renal hemodynamic effects of AC'I. inhibition in diabetic hyperfiltration: role of kinins. Amer. J P/ii,sinl. 1995. 268, F588-F594. Komel,ini, M . . N. Hayashi, S. Yamamoto, K. Nakao & T. Inukai: Phai macological profile of valsartan, a non-peptide angiotensin I 1 t) pc 1 receptor antagonist. Valsartan prevents end-organ dama:;re iii spoiitaneously hypertensive stroke-prone rats during 1y v ~ Ir reatmcnt. A,.--,reimitte.!~~r..rch./Drirl: Rex 1997, 47, 613-619. Kori. \ A. Pogo & I. Ichikawa: Bradykinin causes selective efferent 111tei-iolar dilation during angiotensin I converting enzyme inhihiltitti. k'idtiq In!. 1993, 44, 545S.550. ,af:i.yettc. R. A,, G. Mayer, S. K. Park & T. W. Meyer: Angiotensin I I I-cccptor blockade limits glomerular injury in rats with reduced rcw,il mass. J. C'lin. Invest. 1992, 90. 766 771. all;:inirne, L.. M . de Gasparo. J. M. Gallo, M. D. Payet & N. Gallop;i!et: Angiotensin I1 induction of neurite outgrowth by AT(2) r w p t o r s in NG108-15, cells - Effect counteracted by the AT(I) rccz!)iors. .i. Bid. Chmi. 1996, 271, 22729-22735. apcir IC. S. & E. Escher: Neointima formation after vascular injury is airgiotcnsin II mediated. Biochern. Biophj,s. Res. Cowitnun. l'W2. 187, 1510-1516. Letlrn~li~im, J. M. & R. Laverty: Remodelling of resistance arteries it: genetically hypertensive rats by treatment with valsartan, an atigiotensin I1 receptor antagonist. C'lin. Ex/) Phurniucol. Physioi I 'Mi. 23, 576-578. Lehioilen, J. Y., W. Hayashida. M. Horiuchi & V.J. Dzau: Angiot ~ n < i rI1 i receptor subtype specific effects are mediated by intractdliilar third loops: chimeric receptor approach. Circularion liW:i. 96, suppl.1, 1-478 (abstract 2667). Lehi:oiien, J. Y., M. Horiuchi & V. J. Dzau: Ceramide as a second nles,;inger tor angiotensin I1 type 2 receptor mediated apoptosis. ( i r ~iilctfion 1997h, 96, supp1.l. 1-554 (abstract 3099). Le\k-ns N. R., M. de Gasparo, J. M. Wood & S. Bottari: Could tire Ihtrmacological differences observed between angiotensin I1 aiitaponists and inhibitors of angiotensin convering enzyme be clinically beneficial? Phurmucology 6i To.vico/ogj, 1992. 71, 241249 (Mini Review). L o \ . I( 1.. J. Benessiano, D. Henrion, L. Caputo, C. Heymes. M. 1 ) u i . i ~ ~I? . Poitevin & J. L. Samuel: Chronic blockade of AT2subt\pe receptors prevents the effect of angiotensin 11 o n the rat \,is&ular structure. J . Clin. Invi36. 1996, 98, 418-425. Li I 4 . R. M. Touyz & E. L. Schiffrin: Effect of AT, and AT2 arigiotensin receptor antagonism on blood pressure and small artcr! \tructure in angiotensin 11-infused rats. C'ircukurion 1997, 96, iiippl. I , 1L477 (abstract 2666). Liu. )' H., X. I? Yang, V. G. Sharov. 0. Nass, H. N. Sabbah, E. I'i:tmon & 0. A. Carretero: Effects of angiotensin-converting en~ : ~ i iinhibitors ic and angiotensin 11 type 1 receptor antagonists in r . i t \ with heart failure role of kinins and angiotensin I1 type 2 r~:ccptors.J . C ' h Inve.rr. 1997, 99, 1926-1935. Lopel J. J.. B. H. Lorell, J. R. Ingelfinger, E. 0. Weinberg, H. Schunkert. D. Diamant & S. S. Tang: Distribution and function oi'c..irdiac angiotensin AT( 1)- and AT(?)-receptor subtypes in hypcrLrophied rat hearts. Amer. J. Phj,siol. 1994, 267, H 8 4 C H 8 52 Ma,:kciir~e,H . S., J. L. Troy, H. G. Rennke & B. M. Brenner: TCV 116 prevents progressive renal injury in rats with extensive renal ablation. J . Hypertivs. 1994, 12, S 11-S 16. Markli.im. A . & K. L. Goa: Valsartan - a review of its pharmac ~ ) l ( y yand therapeutic use in essential hypertension [Review]. l j r ~ t ! ! \ 1997. 54, 299- 31 I . M a d i i o . G., D. Alberti, G. Janin, E Locatelli, J. F. E. Mann, M. hlotolese. C. Ponticelli, E. Ritz, I? Zucchelli. and the Angio-
tensin-Converting-Enzyme Inhibition in Progresive Renal Instifticiency Study Group: Effect of the angiotensin-converting-ciiryme inhibitor benazepril on the progression of chronic renal insufficiency. Netc Engl. J. Met/. 1996, 334. 939-945. McWhinney C. D., R . A. Hunt, K. M. Conrad, D. E. Dostal & K. M. Baker: The type I angiotensin 11 receptor couples to STAT1 and STAT3 activation through JAK2 kinase in neonatal rat cardiac myocytes. J. Mol. Cell. Carttiol. 1997, 29, 2513-1524. Mcffert. S.. M. Stoll, U. M . Steckeling, S. l? Bottari & T. Linger: The angiotensin I1 AT(2) receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol. C'oll. E~idouc~rinvl. 1996. 122. 59-67. Mtnard, J., D. J. Campbell, M. Azizi & M . E Gonzales: Synergistic effects of ACE inhibition and Ang 11 antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. C'ircitlution 1997. 96, 3072-3078. Mercator Study Group: Does !he new angiotensin-converting enzyme inhibitor cilazapril prevent restenosis after percutaneaous transluminal coronary angioplasty? The results of the Mercator study: ti multicenter, randomized, double-blind placebo-controlled trial. Circulrrtion. 1992, 86, 100-1 10. Morimoto. S. & T. Ogihara: TCV-116: a new angioteiisin I1 type-I receptor antagonist. Curdiovasc. Drug Rev. 1994, 12, 153--164. Mukoyamii, M., M. Nakajima, M. Horiuchi, H. Sasamura. R. E. Pratt & V. J. Dzau: Expression cloning of type-2 angiotensin 11 receptor reveals a unique class of seven-transmembrane receptors. J. B i d . Chem. 1993, 268, 24539-24542. MunozGarcia, R., R. Maeso, E. Rodrigo, J. Navarro, L. M. Ruilope, M . C. Casal, V. Cachofeiro & V. Lahera: Acute renal excretory actions of liosartan in spontaneously hypertensive rats role of AT(2) receptors, prostaglandins. kinins and nitric oxide. .J. f j y p c r t c ~ i . ~1995, . 13, 1779-1784. Murphy. T. J., R . W. Alexander, K. K. Griendling, M. S. Runge & K. E. Bernstein: Isolation of a cDNA encoding the vascular typeI angiotensin 11 receptor. Nuture 1991, 351, 233-236. Nahmias, C. & A. D. Strosberg: The angiotensin AT(2) receptor .~ searching for signal-transduction pathways and physiological function. Tf'c??d.YPh(/r~nr/cul. sfi.1995, 16, 223-225. Nakajima. M.. H. G. Hutchinson. M. Fujinaga, W. Hayashida. R . Morishita. L. Zhang, M . Horiuchi, R. E. Pratt & V. J. D Z ~ LThe I: angiotensin I1 type 2 (AT(2)) receptor antagonizes the growth effects of the AT(1) receptor - Gain-of-function study using gene transfer. Proc. N d . Acud, Sci. USA 1995, 92, 10663-10667. Nio. Y., H. Matsubara, S. Murasawa. M. Kanasaki & M . Iiiiida: Regulation of gene transcription of angiotensin I1 receptor subtypes in myocardial infarction. J. Clh. fnvesr. 1995, 95, 46-54 Nussberger, J.. D. Brunner, B. Waeber & H. R. Brunner: True versus immunoreactive angiotensin I1 in human plasma. H , p c ~ i c w .sirin 1985, 7, 1-1-1-7. Oikawa, T., M. Freeman, W. Lo, D. E. Vdughan & A. Fogo: Modulation 01' plasminogen activator inhibitor-1 if7 v i w - a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney Ini. 1997, 51, 164172. Okunishi, H., Y. Oka, N. Shiota, T. Kawamoto, K. Song & M. Miyazaki: Marked species-difference in the vascular angiotensin 11-forming pathways -human versus rodents. J q x J. P h u r m m / , 1993, 62, 207-210. Ondetti, M. A.: Angiotensin-converting enzyme inhibitors: an overview. H~pertension1991, 18 Suppl.3, 111134~I11135. Oparil, S.. S. Dyke, E Harris, J. Kief, D. James, A. Hestcr & S. Fitzsimmons: The efficacy and safety of valsartan compared w t h placebo in the treatment of patients with essential hypertension. Clin. T h r . 1996, 18, 797-810. OZawd, Y . , Y. Suzuki, K. Murakami & H. Miyazaki: The angiotensin 11 type 2 receptor primarily inhibits cell growth via pertussis-toxin-sensitive G proteins. Binchem. Biophys Re.s. C ' o n i tnun. 1996, 228, 328-333. Pals. D. T., G. S. Denning & R . E. Keenan: Historical development of saralasin. Kidne)' In?. 1979. 15, S7- S10. ~
210
MARC DE GASPARO A N D NIGEL LEVENS
Peach. M. J. Renin-angiotcnsin system: biochemistry and mechanisms of action. Physiol. Re): 1977, 57, 313-370. Peach, M . J. & N. R . Levens: Molecular approaches t o the study of angiotensin receptors. Atlv. E,xp. Med. B i d . 1980, 130, 171191. Pfeffer, M. A,: Angiotcnsin-converting enzyme inhibition in congestive heart failure benefit and perspective. Amer. Hcurt J. 1993, 126, 789 793. Pitt, B., R. Segal, E A. Martinez, G. Mcurers, A. J. Cowley. I. Thomas, I? C. Deedwania, D. E. Ney, D. B. Snavely & I? I. Chang: Randomised trial of losartan versus captopril in patients over 65 with heart failure (cvaluation of losartan in the elderly study, Elite). Luncet 1997, 349, 747-752. Pollman, M. J.. 'I. Yamada, M. Horiuchi & G. H. Gibbons: Vdsoactivc substances regulate vascular smooth muscle ccll apoptosis countervailing influences of nitric oxide and angiotensin 11. Circ. Hc.s. 1996, 79, 748 756. I'ratt. R. E.. D. Wing, L. Hein, V. J. Drau: The AT2 isoforms of the iingiotensin receptor mediates myointimal hyperplasia following vascular injury. Hypertension 1992, 20. 432452. Prescott. M. F.,R . L. Webb & M . A. Reidy: Aiigiotcnsin-converting enLynic inhibitor versus angiotensin AT, receptor antagonist: effects on smooth muscle cells migration and proliferation afyer balloon catheter injury. A n w . J . P u t / i d . 1991. 139. 1291-1296. Raiiijoult., H. I?,E. Hermes, V. Nogues V & M. de Gasparo: Valsarta ti prevents angiotcnsin I1 induced cardiac myocyte necrosis. Eur. Hrtrr/ J . 1994, 15, 567. Regitz-Zagrosek, V., N. Friedel, A. Heyniann, I? Bauer, M . Neuss, A. RolfS, C. Steffen, A. Hildebrandt, R. Hetzer & E. Flek: Regulation, ch;imhcr localization and subtype distribution of angiotensin TI receptors in human hearts. Circulntror~1995, 91, 14611471. Regitz-Zagrosek, V., J. Fielitz. R. Dreysse. A. G . Hildebrandt & E. Flek: Angiotensin receptor type I mRNA in human right ventricular endoniyocardial biopsies downregulation in heart failure. Cordiowsc. Rrs. 1997, 35, 99-105. Remimi. A,, N. l'crico, C. S. Amuchastegui. B. Malanchini, M . Mazcrska, C . Battuglia. T. Bertani & G. Remuzzi: Short-term and long-term eflect of angiotensin-11 receptor blockade in rals with experimental diabetes. J A / w r , Soc. Nephrul. 1993,4,40 49. Remuzzi, A,. A . Fnssi. E Sangalli, B. Malanchini & G. Remuzzi: Effect of henazepril and valsartan on glomerular injury i n experimental diabetcs in MWFiZtm rats. .I. Amer. Soc. Nephrol. 1996, 7, 1877. Kiurdan, J. F : Angiotensin TI - Biosynthcsis, molecular recognition. and signal transduction. Gel/. Mol. Bid. 1995, 15,637 651. Rittel, W., B. Iselin. H . Kappeler, B. Riniker & R. Schwyzer: Synthese eines hochwirksamen Hypertensin 11-amid [L-AparaginylL-arginyl-L-L-valy l-L- tyrosyl-1.-isoleucyl-L-histidyl-L-L-proly lL-phcnylalanin]. H r h . Chim A c f u 1957, 40, 614619. Rogg, H . . M. de Gasparo, E. Gracdel, P S l u l ~E, Burkart, M. Eberhard & I? Erne: Angiotensin 11-receptor subtypes in human atria and evidencc for alterations in patients with cardiac dysfunction. B r r Heor/ 1. 1996. 17, 1112 1120. Kydrcwski, B,, B. Zelezna, W. Tang, C. Snmners & M. K. Raizada: Angiotensin 11 stimulation of plasminogen activator inhibitor-l gene expression in astroglial cells from [ h e brain. Endocriiiolog.~: 1992. 130, 1255-1262. Saraki. K., Y. Yamano, S. Bardhan, N. Iwai, J. J. Murray, M . Hascg~iw;,, Y. Mats~ida8 T. lnagaini : Cloning and expression of a complementary DNA encoding ii bovine adrenal angiotcnsin 11 type-1 receptor. Nuturr I991 351, 230-233. Scheidegger, K . J., J. M . Wood, H. Vancssen & H. A. J. StruijkerRoudier: Effects of prolonged blockade of the renin angiotensin system on stiiatcd I I I U S L ~microcirculation of spontaneously hypertcnsivc rats. J . Phurrnucol. E.p. Ther. 1990, 278, 1276-128 1. Sclicidcggcr. K. J. & J. M. Wood: Local application of angiotensin I 1 to the rat carotid artery induces adventitial thickening. J . Vcrsc. Re.,. 1997. 34, 436 446. -
MiniReview
Schiavone, M. T., M . C . Khosla & C:. M. Ferrario: Angiotensin-( I 7): evidence for novel actions in the brain. J . Curdiovnsc. PhurtrroCOI. 1990, 16, SUPPI 4, S19-S24. Schieffer. B., W. G. Paxton, M. B. Marrero & K. E. Bernstein: Iniportance o f tyrosine phosphorylation in angiotensin 11 typc I receptor signaling. Hyperlci~,sion1996, 27, 476-480. Sealey, J. E. & J. H. Laragh: The renin-angiotensin-aldosteronc system for nornial regulation of blood pressure and sodium and potassium homeostasis. In: Hypertension: Pmihophysiolog),, tliugnosis mid r m ~ ~ g ~ i n e J. t i tH. . Laragh and B. M. Brenner. Raven Press Ltd; Eds.: New York, 1995, 1763-1796. SeljeHot, I., A. Moan, S. Kjeldsen, E. Sandvik & H. Arnesen: Effect of angiotensin I1 receptor blockade on fibrinolysis during acute hyperinsnlinemia in patients with essential hypertension. Hypertension 1996, 27, 1299-1 304. Sen. I . , K . E Jim & R. L. Soffer: Solubilization and charactcrintion of an angiotensin I1 binding protein from liver. Eur. J . Biocheni. 1983, 136, 41 4 9 . Siragy, H. M . & R . M. Carey: Thc subtype-2 (AT(2)) angiotensin receptor regulates renal cyclic guanosine 3',5'-nionophosphate and AT(I) receptor-mediated prostaglandin E2 production i n conscious rats. J. Clin. Invest. 1996, 97, 1978-1982. Siragy, H . M . & R . M. Carey: The subtype 2 angiotensin receptor regulates renal prostaglandin F2 formation in conscious rats. Amcr. .I. Phyyiol. 1997, 273, R1103-Rl107. Siragy, H. M. & R . M. Carey: The subtype 2 (AT(2)) Angiotensin receptor mediates renal production of nitric oxide in conscious rats. J.Clin. Invest. 1997, 100, 264-269. Spinale, E G., M . de Gasparo, S. Whitebread, L. Hebbar, M. J . Clair, M. Melton, S. Krombach, R . Mukherjee & 0. Scung-Jun: Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing induced heart failure. T. Effect on left ventricular performance and neurohor. 2385-2396. monal systems. Circulution 1 9 9 7 ~96, Spinale, E ti, R. Mukherjee J. I? Tannini, S. Whitebread, L. kicbbar. M. J. Clair, M . Melton. M . H. Cox, I? B. Thomas & M. de Casparo: Modulation of the reiiin-aiigiotcnsin pathway through enzyme inhihition and specific receptor blockade in pacing induced heart failure. 11. Effects on myocyte contractile processes. CircuIutiotr 1997b, 96, 2397 -2406. Stoll M, U. M. Steckelings, M. Paul, S. P. Bottari, R . Mctzgcr & T. Unger: The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothclial cells. J. Clin. Iniwf. 1995, 95, 651-657. Swanson, G. N., J . M. Hanesworth, M . E Sardinia, J. K. Coleman. J. W. Wright, K. L. Hall, A. V. Miller Wing, J. W Stobb, V. 1. Cookm & E. C. Harding: Discovery of a distinct binding site for angiotensin I1 (3-8) a putative angiotensin IV reccptor. Regul. P e p . 1992.40, 409-419. Taguchi, J.. J. Abc, H. Okacdki, M. Ochiai, M . Ohno, Y. Takuwa & K . Kurokawa: Angiotcnsin-converting enzyme inhibitors or Dup753 prevent neointimal formation following balloon injury with single topical o r multiple systemic application. Bioclzen7. Biophys. Rcs. Cortinzun. 1993, 196, 969-974. Tan, L. R.,J. E. Jalil. R . Pick, J. S. Janicki & K. T. Weber: Cardiac myocyte necrosis iiiduced by angiotensin 11. Cireulution 1991. 69. 1 1 85-1 195. Tang, S. S., H . Rogg, R. Schumacher & V. J. Dzau: Characterization of nuclear angiotensin-TI-binding sites in rat liver and comparison with plasma membrane receptors. Enntlocriiiology 1992, 131, 374 380. Teiger, E.. T. Dam, L. Richard. C. Wisnewsky. B. Tea. L. Gaboury. J . Tremblay, K. Schwarlz & F! Hamet: Apoptosis in pressure overload-induced heart hypertrophy in the rat. J. C/irr. Invest. 1996. Y7, 2891 2897. Timmermans, F! R. M . W. M.. F? C . Wong, A. T. Chiu, W. F. Herblin, I? Benfield, D. J. Carini, K. J. Lee, R. R. Wexler. J. A. M . Saye & R . D. Smith: Angiotensin-I1 receptors and angiotensin-11 receptor antagonists. Phurrtiucol. Rrv. 1993, 45. 205-251.
MiniKcvie w
Tot(!. K . I? Schultz, L. Raji, H. Mitchell, W. Shaw, D. Ramjit, J. 'loh & S. Shahinfar: Efficacy anf tolerability of losartan in hypertcn\iw patients with renal impairment. Hyprrteizsion 1998, 31, 6x4 691.
Unp,ei- 1.,0. Chung, T. Csikos, J. Culman, S. Gallinat, P. Gohlke, S. tlohic. S. Meffert. M. Stoll, U. Stroth & Y . 2. Zhu: Angiotensin rcccplors. J . Hyperlens, 1996, 14 (suppl. S), S95-SIO3. Urata. H,, E Strobel & D. Ganten: Widespread tissue distribution o f iitiman chymase. J. Hjpertens. 1994, 12, S 17-S 22. UraILi,, li,, H. Nishimura & D. Ganten: Mechanism of angiotensin I I lormation in humans. Eur. Heart J . 1995. 16, 79-85. Watla. T:. R. Kanagawa, Y. Ishimura, Y . Inada & K. Nishikawa: ROIL. of angiotensin I1 in cerebrovascular and renal damage in tiro\ycorticosterone acetate-salt hypertensive rats. J. Hjperrens. I W i . 13. 113-122. Wachcr. B.. J. Nussberger, L. Juillerat & H. R Brunner: Angiotcn>rn-convcrting enzyme inhibition: discrepancy between anti1iypr.rtensive effect and suppression of enzyme activity. J . Lirrdior i i \ i Plirtrnzud. 1989, 14, 53-59. Vaiihoiitte. I? M., G. M. Rubanyi, V. M . Miller & D. S. Houston: Mcdtilation of vascular smooth muscle contraction by the endoihclitim. Ann. Rev. Physiol. 1986, 48, 307-320. Vuilhc\teren. C. A. M., H. A. A , Vanheugten, J. M. J. Lamers, I? I(. Yaxena. M. A. D. H. Schalekamp & A. H. J. Danser: Angiolensin II mediated growth and antigrowth effects in cultured neoiiat.il rat cardiac myocytes and fibroblasts. J. Mol. Cell. Cordid. I90 '. 29, 2 147-2 157. Wehh K . L . A . E. Navarrette, S. Davis & M. de Gasparo: Synerc i b l i i effects of combined converting enzyme inhibition and ,inpiotensin II antagonism on blood pressure in conscious-telerneiered spontaneously hypertensive rats (SHR). J. Hypertens. I9OS (in press). Wchel. K. T.. C. G. Brilla. S. E. Campbell, E. Guarda, G. Zhou & ti Sriram: Myocardial Fibrosis - Role of Angiotensin-I1 and .Aldosterone. Basic Rex Cardiol. 1993, 88, 107-124. Wel~ei.K. T.. Y. Sun, L. C. Katwa & J. P M. Cleutjens: Connective iih\iic a metabolic entity [Review]. .I. Mol. CeIl. Cardiol. 1995, 27. 107 120. Woln\. A,, J. I? Clozel, J. Rein, I? Mory, P Vogt, M. Turino, W. KriiLvski & W. Fischli: Functional and biochemical analysis of ,ingrotensin 11-forming pathways in the human heart. Circ,. Res. IY')7. 80, 219-227. ~
27 I
ANGIOTENSIN I ANTAGONIST A N D ANGIOTENSIN-CONVERTING ENZYME
Wong. P. C., T. B. Barnes, A. T. Chiu, D. D. Christ, J. V Duncia, W. F. Herblin & I? B. M. W. M . Timmermans: Losartan (Dup 753). an orally active nonpeptide angiotensin 11 receptor antagonist. Curdiovusc. Drug Rev. 1991. 9, 317-339. Wright, J. W.. L. T. Krebs, J. W. Stobb & J. W. Harding: Tthe angiotensin 1V system - functional implications [Review]. Front. A"woendocrinol. 1995, 16, 23-52. Wu, L. L.. A. Cox, C . J. Roe, M. Dziadek, M. E. Cooper & R. E. Gilbert: Transforming growth factor beta-I and renal injury following subtotal nephrectomy in the rat role of the reninangiotensin system. Kidney Int. 1997, 51, 1553-1567. Xie, M. H., E Y. Liu, I? C. Wong, P B. Timmermans & M . (i. Cogan: Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin I1 receptor antagonist. Kidney Int. 1990, 38. 473479. Yang, H.. D. Lu, K. Yu & M . K. Raizada: Regulation of neuromodulatory actions of angiotensin I1 in the brain neurons hy the ras-dependent mitogen-activated protein kinase pathway. J. Neurosci. 1996, 16, 40474058. Yunada. T., M. Horiuchi & V. J. Dzdu: Angiotensin I1 type 2 receptor mediates programmed cell death. Proc. NfitI. Atad. Sri. USA 1996, 93. IS6-lhO. Yamada, H., A. Masahiro & M. Horiuchi: Regulation of vascular development and differentiation by angiotensin type 2 receptor. Cirrukrrion 1997, 8, suppl.1, I 4 7 8 (abstract 2668). Yoshimura. Y., M. Karube, H. Aoki. T. Oda, N. Koyama, A. Nagai, Y. Akimoto. H. Hirano & Y. Nakamura: Angiotensin 11 induces ovulation and oocyte maturation in rabbit ovaries via the AT(2) receptor subtype. Endocritiology. 1996, 137, 1204-121 I . Zhang, J. S. & R. E. Pratt: The AT(2) receptor selectively associaks with G(i-alpha-2) and G(i-alpha-3) in the rat fetus. J . Bio/. Chrm. 1996, 271. 15026-15033. Zhuo, J. L., R. Dean, D. Macgregor, D. Alcorn & E A. 0. Mendelsohn: Presence of angiotensin I1 AT(2) receptor binding sites in the adventitia of human kidney vasculature. Clin. ESP. PhtrrinrtcOL P/zJ.sIuI. 1996, 23, S 147-S 154. Zierhut. W., R. Studer. D. Laurent, S. Kastner. I? Allegrini. S. Whitebread. F. Cumin, H. I? Baum, M. de Gasparo & H. Drexler: Left ventricular wall stress and sarcoplasmic reticulum Ca'+ATPase gene expression in renal hypertensive rats - dose-dependent effecls of ace inhibition and AT(1)-receptor blockade. C'urdiova.v. Ree. 1996, 31. 758 768. -
