serving the effects of pressure to the paw on heart rate and blood pressure. ..... MacKenzie ET, Farrar JK, Fitch W, Graham DI, Gregory PC, Harper. AM (1979) ...
Journal of Cerebral Blood Flow and Metabolism 17:680-685 © 1997 The International Society of Cerebral Blood Flow and Metabolism Published by Lippincott-Raven Publishers, Philadelphia
Effect of Aging on Regulation of Brain Stem Circulation During Hypotension Kazunori Toyoda, *Kenichiro Fujii, Yutaka Takata, *Setsuro Ibayashi, Megumi Fujikawa, and *Masatoshi Fujishima Department of Internal Medicine, Kyushu Dental College, Kitakyushu, and *Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Summary: This study was designed to determine age-related
basilar artery during profound hypotension was significantly smaller in aged rats (11 ± 8%) than that in adult ones (23 ± 12%, P < 0,05); that of the large branch was 12 ± 8% versus 33 ± 17% (P < 0,005); and that of the small branch was 17 ± 7% versus 40 ± 13% (P < 0,0005), suggesting greater attenuation of the responses in the smaller vessels, Thus, this study provides direct evidence that aging diminishes the compensatory dilata tion of brain stem arterioles and arteries during hypotension and modifies the autoregulatory plateau of CBF, which seems to increase the risk of the brain stem ischemia during hypoten sive conditions, Key Words: Cerebral artery-Basilar artery Cerebral blood flow-Autoregulation-Aging,
changes in autoregulatory responses of the brain stem circula tion in vivo, In anesthetized adult (4 to 6 months, n = 8) and aged (24 to 26 months, n = 7) Sprague-Dawley rats, local CBF to the brain stem was determined with laser-Doppler flowmetry and diameters of the basilar artery and its branches were mea sured through an open cranial window during stepwise hemor rhagic hypotension, In aged rats, the lower limit of CBF auto regulation shifted upward to 60 to 75 mm Hg from 30 to 45 mm Hg in adult rats, Dilator responses of the basilar artery (baseline diameter: 254 ±q5 f,Lm), large branch (109 ± 23 f,Lm), and small branch (44 ± 10 f,Lm) to hypotension were much smaller in aged rats than in adult rats, The maximum change in diameter of the
Autoregulation of CBF, an intrinsic ability to maintain constant cerebral perfusion in the face of blood pressure changes, is modified or disturbed by several pathological conditions such as hypertension, diabetes mellitus, and acute affections of the brain such as ischemia, trauma, and inflammation (Paulson et at, 1990), Aging has also been reported to impair CBF autoregulation in the fore brain or whole brain by itself (Lartaud et at, 1993) or when accompanied with long-lasting hypertension (Fu jishima et at, 1984; Hoffman et aI, 1981; Hoffman et at, 1982), and this impairment might lead to the increased incidence of stroke in the elderly during hypotensive conditions. The lower limit of CBF autoregulation in the hindbrain is lower than that in the forebrain in adult
animals (Mueller et aI., 1977; Sadoshima et at, 1981) as well as infant rabbits (Tuor and Grewal, 1994). Thus, the hindbrain circulation seems to have superior autoregula tory capacity compared with the forebrain. However, few researchers have focused their interest on changes in the hindbrain autoregulation during aging or under other pathological conditions. Laser-Doppler flowmetry per mits less invasive and continuous measurement of the relative changes in local CBF to the brain stem (Fujii et al, 1991a; Tuor and Grewal, 1994; Toyoda et aI, 1996). Thus, the first goal of this study was to determine the effect of aging on regulation of CBF to the brain stem during hypotension in vivo. Pial arterioles have been regarded as the primary sites of autoregulatory function by changing their calibers in response to blood pressure changes (Kontos et aI., 1978; MacKenzie et aI., 1979; Tuor and Farrar, 1984). We have recently shown that large arteries, such as the basilar artery, also actively dilate and contribute to reductions in cerebrovascular resistance around the lower limits of CBF autoregulation, and thereby maintain CBF to the brain stem during severe hypotension (Toyoda et aI., 1996). Aging often attenuates cerebral vasodilator re-
Received October 9, 1996; final revision received January 22, 1997; accepted January 22, 1997, This study was supported by a grant-in-aid 08770463 for scientific research from the Ministry of Education, Science, and Culture, Japan. Address correspondence and reprint requests to Dr. Kazunori Toyoda, Second Department of Internal Medicine, Faculty of Medi cine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan 812-82 Abbreviations used: ANOVA, analysis of variance; CSF, cerebro spinal fluid; KATP' ATP-sensitive potassium,
AGING AND BRAIN STEM AUTOREGULATION sponses of both large arteries (Hongo et aI., 1988; Hatake et aI., 1990; Paterno et aI., 1994) and microvessels (May han et aI., 1990) to several vasoactive stimuli, and the severity of attenuation was sometimes different among vessels with different sizes (Toyoda et aI., 1997a). Thus, if aging altered the brain stem autoregulation, the second goal of this study was to determine whether age-related impairment of dilator responses of the basilar artery and its branches during hypotension varies with different vessel sizes in vivo. For this purpose, we used an open cranial window over the ventral brain stem through which we can observe several vessels with different di ameters along with measurement of CBF by laser Doppler flowmetry (Toyoda et aI, 1996). MATERIALS AND METHODS Animal preparation
Experiments were performed in male Sprague-Dawley rats, aged 4 to 6 months (adult, n 8, 538 ± 75 g [mean ± SD]) and 24 to 26 months (aged, n 7, 637 ± 33 g). Rats were anes thetized with amobarbital sodium, 50 mg/kg intraperitoneally, followed by additional doses of 15 to 20 mg· kg-I. h-1 intra venously. The depth of anesthesia was examined often by ob serving the effects of pressure to the paw on heart rate and blood pressure. The trachea was cannulated and each rat was mechanically ¥entilated with room air and supplemental oxy gen after immobilization by 5 to 10 mg/kg d-tubocurarine chlo ride. Catheters were placed in both femoral arteries: one for the measurement of systemic arterial pressure, and the other for withdrawing blood to change systemic arterial pressure and for sampling arterial blood. A femoral vein was cannulated for the infusion of drugs. Rectal temperature was maintained at 37°C with a heating pad. A craniotomy was prepared over the ventral brain stem as previously described in detail (Faraci et a!., 1987; Fujii et a!., 1991 b; Toyoda et a!., 1996). Portions of the dura and pia mater and the arachnoid membrane were resected. The open cranial window was suffused with artificial cerebrospinal fluid (CSF) (composition in mmollL: 132 NaCI, 2.95 KCl, 1.71 CaCI2, 0.65 MgCI2, 24.6 NaHC03, and 3.69 D-glucose), warmed to 37°C, and continuously bubbled with a gas mixture of 5% CO2-95% N2. Suffusion rate of CSF using inlet and outlet ports over the exposed brain stem was 3.0 mL per minute. In CSF sampled from the craniotomies, PC02 was 39.5 ± 3.3 mm Hg, P02 was 128 ± 12 mm Hg, and pH was 7.37 ± 0.04. The diameters of the basilar artery, a large branch directly originating from the bas ilar artery with a baseline diameter :;,,70 [Lm and a small one with a baseline diameter -� 15 o 30 45 60 75 90 B.H. (mmHg) MABP FIG. 3. Changes in the diameter of the basilar artery in adult and aged rats during stepwise hypotension. All values are means ± SO. Significant difference (P < 0.05) was shown in MABP response curves by two-way repeated-measures ANOVA. Sig nificant difference (P< 0.05) was also shown in maximum change in diameter (at 30 mm Hg) by unpaired t-test. B.H., before hypo tension.
rioles and attenuate the autoregulatory capacity of CBF to the brain stem. f
Consideration of methods
Sprague-Dawley rats are commonly used in research of aging (Masoro, 1980). Male Sprague-Dawley rats have been reported to have a median length of life be tween 19.5 and 30 months, mostly between 23.5 and 25.5 months (Masoro, 1980). Body weight of the male rats
-+- adult --0- aged