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)