Dose-response studies with idrapril in the rat heart during acute myocardial ischaemia and reperfusion.
We assessed the effects of idrapril, a novel angiotensin-converting enzyme inhibitor, and captopril in the isolated rat heart after ischaemia and reperfusion and measured angiotensin-converting enzyme activity in myocardial tissue. Hearts were perfused and subjected to global ischaemia and reperfusion. Idrapril (0.1, 1, 10, and 50 micrograms/ml), captopril (80 micrograms/ml) or vehicle were given before ischaemia and throughout reperfusion. Post-ischaemic recovery of coronary flow was significantly decreased with 50 micrograms/ml of idrapril (43 +/- 9% compared to 64 +/- 3% in controls) whereas heart rate was unaffected. Recovery of developed pressure and activity of cardiac angiotensin-converting enzyme were significantly reduced by idrapril in a dose-dependent manner. This study suggests that protection or lack of protection by idrapril on recovery of contractile function seems to depend on the degree of inhibition of tissue angiotensin-converting enzyme activity in the setting of acute heart ischaemic insult. Our results suggest that while a certain degree of inhibition of angiotensin-converting enzyme in the heart is beneficial, marked tissue inhibition may be deleterious.
Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy. RIVA@IRFMN.MNEGRI.IT
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D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006898:Hydroxylamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D003509:Cyclohexanecarboxylic Acids; D006898:Hydroxylamines; C076966:idrapril; D002216:Captopril; D007703:Peptidyl-Dipeptidase A