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severe leukopenia and anemia that appeared after 72 h of adriamycin adminstration. Captopril (60 mg/kg i.p) 1 h before adriamycin injection ameliorated theĀ ...
Vol. 45, No. 2, June 1998 BIOCHEMISTRYond MOLECULAR BIOLOGY INTERNATIONAL PQges419-427

CAPTOPRIL AMELIORATES MYOCARDIAL AND HEMATOLOGICAL TOXICITIES INDUCED BY ADRIAMYCIN Othman AI-Shabanah*, Mahmoud Mansour, Hassan EI-Kashef and Abdullah A1Bekairi Department of Pharmacology, College of Pharmacy, King Saud University, P.O Box 2457, Riyadh t 145I, Saudi Arabia ReceivedMarch9, 1998 SUMMARY. Adriamycin has a wide spectrum of antitumor activity with dose related cardiotoxicity as a major side effect. The objective of this study was to investigate the influence of captopril, a sulphydryl containing angiotensin converting enzyme inhibitor, on the cardio- and hematotoxicity of adriamycin in normal rats. A single dose of adriamycin (15 mg/kg) caused myocardial toxicity after 24 h manifested biochemically by elevation of serum enzymes:- Aspartate transaminase (AST, EC: 2.61.1), lactate dehydrogenase (LDH, EC: I. I. 1.27), creatine phosphokinase (CPK, EC:2.7.3.2) and the cardiac iso-enzymes of LDH and CPK The hematotoxicity was characterized by severe leukopenia and anemia that appeared after 72 h of adriamycin adminstration. Captopril (60 mg/kg i.p) 1 h before adriamycin injection ameliorated the biochemical toxicity induced by adriamycin. This was evidenced by a significant reduction in serum enzymes, after 24 and 48 h and a significant reduction of serum cardiac iso-enzymes after 48 h. Also restoration of the white blood cell counts as well as hemoglobin concentration occured after 72 h of captopril adminstration. These results suggest that captopril may be benificial as a protective agent against cardio- and hematotoxicity induced by adriamycin. Key Words: Aspartate transaminase, Lactate dehydrogenase, Creatine phosphokinase. INTRODUCTION Adriamycin, an anthracyclin antibiotic, is used in the treatment of a variety of human tumors, including breast cancer, small cell carcinoma of the lung and acute leukemias(1) Like most of the anti-cancer drugs, adriamycin produce a number of side eftbcts, the most important are the dose-dependent cardiotoxicity and hematotoxicity (2-3-4).

'Abbreviations: Aspartate transaminase, AST; Lactate dehydrogenase, LDH; Creatine phosphokinase, CPK; Adriamycin, Adr. *: To whom correspondence should be addressed 1039=9712/98/0804 lt9-09505.00/0 419

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Vol. 45, No. 2, 1998

BIOCHEMISTRY and MOLECULAR BIOLOGY INTERNATIONAL

It has been suggested by many investigators that,

the cellular damage induced by

adriamycin is mediated by the formation of an iron-anthracyclin complex that generate free radicals (5-6)~ which in turn cause severe damage to the plasma membrane and interfere with the cytoskeletal assembly (7). Tissues with less developed antioxidant defense mechanism such as the heart are highly susceptible to injury by anthracycline induced oxygen radicals (8). On the contrary ~ liver

which contains a powerful

antioxidant systems, appeared unlikely to be injured (9). Many cytoprotective agents have been developed in order to counteract the

functional disorders induced by

adriamycin to make its use safer (10). Considerable efforts have been focused on using antioxidants, to protect the heart against adriamycin toxicity, however the results were not encourging since these cytoprotective agents only delay or decrease the development of cardio-myopathy and did not provide complete protection (11-12). Captopril is an orally active compound that inhibits angiotensin converting enzyme (ACE, EC: 3.4.15.1), resulted in a reduction of hypertension (13-14). Captopril has been found to provide protection against reperfusion induced arrythmias (15). The effect of captopril on nephrotoxicity induced by adriamycin is well documented (1617), however the role of captopril in the prevention of hemato-and cardio-toxicity induced by adriamycin treatment is not certain. The aim of the present study was to investigate the effect of captopril on myocardial and hematological toxicities induced by adriamycin. Measurements of serial changes in serum enzymes: creatine phosphokinase (CPK), lactate dehydrogenase (LDH) and aspartate transaminase (AST) as well as

cardiac iso-enzymes of CPK

(MB) and LDH assessed the cardiotoxicity, while hematotoxicity was evaluated by the counting

white blood cells, red blood corpuscles and measuring hemoglobin

concentrations. 420

Vol. 45, No. 2, 1998

BIOCHEMISTRY and MOLECULAR BIOLOGY INTERNATIONAL

MATERIALS AND METHODS Chemicals:Captopril was obtained from Sigma chemical company, St. Louis, USA.. Adriamycin was provided as a gift sample from Farmitalia, Carlo Erba, Milan, Italy. Drugs were dissolved in distilled water just before use. Animals:-Adult swiss albino rats of both sex weighing 250--300 g were obtained from the Experimental Animal Care Center of king Saud university, Riyadh-KSA. Animals were maintained under standard conditions of humidity with regular light/dark cycle and free access to food (Purina chow) and water. Experimental protocol: Sixty rats of either sex were divided into four groups, each consists of 15 rats. The first, control group, received normal saline. The second~ adriamycin group, received 15 mg/kg adriamycin i.p. The third , captopril group, received 60 mg/kg captopril i.p. and the fourth, adriamycin-captopril group, received 60 mg/kg captopril i.p and 1 h later 15 mg/kg adriamycin i.p. At 24, 48 and 72 h intervals after the adminstration of the drugs, 5 rats from each group were anasthetized with ether and blood samples were collected from each rat by intracardiac punture. Serum was separated for enzyme assay. The activities of LDH levels was measured according to the method of(18), CPK by method of (19), and AST by method of (20). LDH and CPK cardiac iso-enzymes were determined according to the methods of (21-22) respectively. White blood cells, red blood cells counts and hemoglobin concentration were performed in the heparinized samples collected after 72 h. Statistical analysis: Data are expressed as (means+_S.EM). Statistical comparison between different groups were done by using Students t test for unpaired data. Significance was accepted at P< 0.05. RESULTS A. Effect of captopril on the elevated serum LDH, AST and CPK activities induced by adriamycin adminstration:- Serum LDH, AST and CPKlevels were significantly (P