enalaprilat-anhydrous and zofenopril

We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs, zofenopril and S-benzoylcaptopril, hydrolyzed rapidly by cardiac esterase, were more effective than their component ACE-inhibitors, whereas fosinopril, ramipril and enalapril were poorly active. For studies in ischemic rat hearts, vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity, only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid, ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations, despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril, however, had any effect on coronary flow before or after ischemia. Thus, it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or, at least, that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and, thus, this group appears to be important in mediating their cardioprotective actions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Coronary Disease; Drug Stability; Enalaprilat; Fosinopril; Heart; In Vitro Techniques; Male; Myocardium; Organophosphorus Compounds; Prodrugs; Proline; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

We have previously reported that antioxidant drug intervention protects against magnesium deficiency-induced myocardial lesions. In the present study, Golden Syrian male hamsters were fed either a magnesium-deficient diet or a magnesium-supplemented diet. Animals from each group received sulfhydryl-containing angiotensin converting enzyme inhibitors: captopril, epi-captopril (a stereoisomer of captopril), and zofenopril* (arginine blend of zofenopril containing a free SH group); another group of animals received the non-sulfhydryl-containing angiotensin converting enzyme inhibitor enalaprilat. The animals were killed after 14 days, and their hearts were isolated for morphological and morphometric analyses. Hematoxylin and eosin-stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Captopril reduced both the density of lesions, from 0.32 to 0.08 lesions/(mm2) (p less than 0.01), and the area fraction of lesions, from 7.42 x 10(-4) to 2.03 x 10(-4) lesion area/(mm2) (p less than 0.01), as well as the degree of inflammatory infiltration around the blood vessels. Epi-captopril and zofenopril* were virtually equipotent to captopril, but enalaprilat afforded only slight (nonsignificant) protection. These results indicate that a significant component of the protective effect of captopril in this model was attributable to its sulfhydryl moiety, rather than solely due to the inhibition of the angiotensin converting enzyme. These data further support our previous findings of possible free radical participation in cardiomyopathy due to magnesium deficiency.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Captopril; Cardiomyopathies; Cricetinae; Diagnosis, Computer-Assisted; Enalaprilat; Magnesium Deficiency; Male; Myocardium

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 less than 0.05), zofenopril (p less than 0.01), and enalaprilat (p less than 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 less than 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: enalapril

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Captopril; Coronary Circulation; Dogs; Enalaprilat; Indomethacin; Myocardial Contraction; Myocardial Reperfusion Injury; Prostaglandins; Sulfhydryl Compounds

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Drug Synergism; Enalaprilat; Fibrin Fibrinogen Degradation Products; In Vitro Techniques; Molecular Sequence Data; Rats; Vasodilation

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Captopril; Coronary Circulation; Enalaprilat; Epoprostenol; In Vitro Techniques; Indomethacin; Male; Rats; Rats, Inbred Strains