Local Inhibition of Angiotensin II Formation and Bradykinin Degradation in Isolated Hearts

ABSTRACT

The interaction of the converting enzyme (CE)-inhibitor ramipril and the bradykinin (BK)-antagonist D-Arg-[Hyp⁵,Thi^5,8,D-Phe⁷]BK with angiotensin I (ANG), ANG II and BK were studied in isolated hearts of rats and guinea pigs.

In isolated working rat hearts perfusion with ANG I and ANG II reduced cardiac function and coronary flow, increased the activities of lactate dehydrogenase (LDH) and creatine kinase (CK) in the perfusate, decreased high-energy rich phosphates and glycogen in the myocardium and increased duration and incidence of postischemic reperfusion arrhythmias. BK on the other hand reduced LDH and CK activities, improved metabolic parameters in the myocardium and reduced reperfusion arrhythmias.

In isolated rat hearts pretreatment with ramipril protected against reperfusion arrhythmias and reduced enzyme activities of LDH and CK in the coronary effluent. Cardiodynamic parameters and coronary flow improved and myocardial tissue levels of glycogen, ATP and creatine phosphate (CP) were elevated. Almost identical changes were seen during perfusion with BK. The cardioprotective effects produced by both, the CE-inhibitor and BK, were completely abolished when the BK-antagonist was added to the perfusate, while a smaller inhibition was obtained by indomethacin perfusion.

In isolated guinea pig hearts BK increased coronary flow. Single-dose oral pretreatment with ramipril potentiated, whereas perfusion with the BK-antagonist abolished this effect.

These data add support to the hypothesis that local inhibition of CE = kininase II contributes to the beneficial effects of CE-inhibitors in the heart.

KEY WORDS::

• isolated heart
• bradykinin
• angiotensin converting enzyme (ACE)
• ACE inhibition
• ramipril