ANGIOTENSIN CONVERTING ENZYME-INHIBITORS IMPROVE CONTRACTILE FUNCTION OF STUNNED MYOCARDIUM BY DIFFERENT MECHANISMS OF ACTION

被引:81
作者
PRZYKLENK, K [1 ]
KLONER, RA [1 ]
机构
[1] UNIV SO CALIF,LOS ANGELES,CA 90089
关键词
D O I
10.1016/0002-8703(91)90134-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Angiotensin converting enzyme (ACE) inhibitors enhance contractile function of myocardium "stunned" by a brief episode of coronary artery occlusion, yet their mechanism(s) of action remain unresolved. In addition to possible hemodynamic effects, ACE inhibitors may stimulate the synthesis of cardioprotective prostaglandins. Furthermore, the beneficial effects of ACE inhibitors that contain a sulfhydryl group may be due in part to the ability of thiol compounds to act as nonspecific antioxidants or direct scavengers of cytotoxic oxygen-derived free radicals. To investigate this question we compared the effects of (1) the sulfhydryl-containing ACE inhibitor zofenopril, (2) the sulfhydryl-containing stereoisomer of captopril (SQ 14,534) with essentially no ACE inhibitor properties, (3) the nonsulfhydryl-containing ACE inhibitor enalaprilat, and (4) solvent alone, given at the time of reperfusion, on recovery of contractile function after 15 minutes of coronary occlusion in the anesthetized open-chest dog. Segment shortening in control animals remained depressed or "stunned" after reperfusion, recovering to only -5 +/- 12% of baseline preocclusion values at 3 hours after reperfusion. In contrast, all three treatment agents attenuated postischemic dysfunction: segment shortening was restored to 33 +/- 12%, 54 +/- 6%, and 83 +/- 5% of baseline values at 3 hours after reflow in dogs treated with SQ 14,534 (p < 0.05), zofenopril (p < 0.01), and enalaprilat (p < 0.01), respectively (all vs control value). These improvements in segment shortening did not appear to be the result of altered oxygen supply or demand after reperfusion, inasmuch as no significant differences in systemic hemodynamic parameters or myocardial blood flow were observed among the groups. In the second phase of the study, we found that the improved contractile function associated with enalaprilat treatment could largely be reversed by infusion of the potent cyclooxygenase inhibitor indomethacin: segment shortening was reduced from 69 +/- 12% at 2 hours after treatment/reperfusion to 38 +/- 12% at 2 hours after indomethacin infusion (p < 0.01 vs 2 hours after reperfusion). Infusion of indomethacin had no effect, however, on the improved contractile function associated with zofenopril treatment. We therefore conclude that sulfhydryl- versus nonsulfhydryl-containing agents enhance contractile function of stunned myocardium by different mechanisms of action: enalaprilat attenuates postischemic dysfunction at least in part by a prostaglandin-mediated mechanism, whereas the salutary effects of zofenopril and SQ 14,534 may be due in part to the antioxidant properties of the sulfhydryl moiety.
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页码:1319 / 1330
页数:12
相关论文
共 54 条
[1]   DIRECT SCAVENGING OF FREE-RADICALS BY CAPTOPRIL, AN ANGIOTENSIN CONVERTING ENZYME-INHIBITOR [J].
BAGCHI, D ;
PRASAD, R ;
DAS, DK .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 158 (01) :52-57
[2]   DEMONSTRATION OF FREE-RADICAL GENERATION IN STUNNED MYOCARDIUM OF INTACT DOGS WITH THE USE OF THE SPIN TRAP ALPHA-PHENYL N-TERT-BUTYL NITRONE [J].
BOLLI, R ;
PATEL, BS ;
JEROUDI, MO ;
LAI, EK ;
MCCAY, PB .
JOURNAL OF CLINICAL INVESTIGATION, 1988, 82 (02) :476-485
[3]  
BURTON KP, 1986, AM J PATHOL, V124, P238
[4]   CAPTOPRIL - A FREE-RADICAL SCAVENGER [J].
CHOPRA, M ;
SCOTT, N ;
MCMURRAY, J ;
MCLAY, J ;
BRIDGES, A ;
SMITH, WE ;
BELCH, JJF .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1989, 27 (03) :396-399
[5]   ANTIARTHRITIC DRUGS CONTAINING THIOL-GROUPS SCAVENGE HYPOCHLORITE AND INHIBIT ITS FORMATION BY MYELOPEROXIDASE FROM HUMAN-LEUKOCYTES - A THERAPEUTIC MECHANISM OF THESE DRUGS IN RHEUMATOID-ARTHRITIS [J].
CUPERUS, RA ;
MUIJSERS, AO ;
WEVER, R .
ARTHRITIS AND RHEUMATISM, 1985, 28 (11) :1228-1233
[6]  
Cushman D W, 1980, Prog Med Chem, V17, P41, DOI 10.1016/S0079-6468(08)70157-7
[7]  
DEGRAEFF PA, 1986, ARCH INT PHARMACOD T, V280, P181
[8]  
DEVI PU, 1983, J NUCL MED ALLIED S, V27, P327
[9]   TOTAL AND REGIONAL CORONARY BLOOD FLOW MEASURED BY RADIOACTIVE MICROSPHERES IN CONSCIOUS AND ANESTHETIZED DOGS [J].
DOMENECH, RJ ;
HOFFMAN, JIE ;
NOBLE, MIM ;
SAUNDERS, KB ;
HENSON, JR ;
SUBIJANTO, S .
CIRCULATION RESEARCH, 1969, 25 (05) :581-+
[10]   INTERACTIONS BETWEEN CORONARY-OCCLUSION AND THE RENIN-ANGIOTENSIN SYSTEM IN THE DOG [J].
ERTL, G ;
ALEXANDER, RW ;
KLONER, RA .
BASIC RESEARCH IN CARDIOLOGY, 1983, 78 (05) :518-533