Effects of the angiotensin converting enzyme inhibitor, ramipril, in isolated ischaemic rat heart are abolished by a bradykinin antagonist.
To elucidate the role of bradykinin in the cardiac actions of angiotensin converting enzyme (ACE) inhibitors, experiments were performed in isolated ischaemic hearts from guinea pigs and rats treated with the ACE inhibitor ramipril and the bradykinin-antagonist D-Arg[Hyp2,Thi5,8,D-Phe7]BK. In guinea pig hearts bradykinin increased coronary flow. Single oral pretreatment with ramipril (10 mg/kg) potentiated but perfusion with the bradykinin antagonist abolished this effect. In ischaemic working rat heart preparations perfusion with ramiprilat (2.58 x 10(-7) mol/l) or single oral pretreatment with ramipril (1 mg/kg) protected the heart from the ventricular fibrillations that invariably occurred upon reperfusion after ischaemia. Lactate dehydrogenase and creatine kinase activities, as well as lactate formation, were decreased in the venous effluent of pretreated hearts. Moreover, ACE inhibition in the heart improved cardiodynamic and metabolic parameters; left ventricular pressure, (dp/dt)max and coronary flow were increased and myocardial tissue levels of glycogen, ATP and creatine phosphate were elevated. A comparable array of changes was seen when rat hearts were perfused with bradykinin (1 x 10(-10) mol/l), which reduced enzymatic activities in the perfusate and improved the metabolic parameters in the myocardium. These cardioprotective effects produced by both the ACE inhibitor ramipril and bradykinin were completely abolished when the bradykinin-antagonist (1 x 10(-5) mol/l) was added to the perfusate. They were only partially attenuated when indomethacin (1 x 10(-6) mol/l) was perfused. Higher concentrations of bradykinin (1 x 10(-7) mol/l) or ramiprilat (2.58 x 10(-5) mol/l) overcame the actions of the bradykinin-antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Schölkens
B A
BA
Department of Pharmacology, Hoechst AG, Frankfurt-am-Main, Federal Republic of Germany.
Linz
W
W
König
W
W
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D017257:Ramipril; D051381:Rats
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril; D001920:Bradykinin; D007213:Indomethacin