ENDOTHELIUM-DEPENDENT VASOMOTOR RESPONSES TO ENDOGENOUS AGONISTS ARE POTENTIATED FOLLOWING ACE-INHIBITION BY A BRADYKININ DEPENDENT MECHANISM

Objective: The aim was to investigate the effects of angiotensin conve rting enzyme inhibition on agonist induced endothelium dependent vasod ilatation in vivo. Methods: Chronically instrumented conscious dogs (n = 8) were prepared for the measurement of coronary blood flow, diamet er of the left circumflex coronary artery, mean arterial blood pressur e, and heart rate. Intracoronary infusions of acetylcholine, adenosine , and bradykinin that induced dose dependent increases in coronary blo od flow and diameter were performed with and without intracoronary adm inistration of captopril (1 mg.kg(-1)) and enalapril (0.4 mg.kg(-1)). The effects were studied of concomitant inhibition of bradykinin actio ns by the specific B-2 kinin antagonist HOE-140 (10(-7) M), NO-synthes is by N-G-nitro-L-arginine-methyl ester (L-NAME, 2 X 10(-5) M), or cyc lo-oxygenase by indomethacin (10(-7) M) (all intracoronary). Results: Neither captopril nor enalapril had significant vasodilating effect on the coronary vasculature when given alone. In contrast, both ACE inhi bitors potentiated the agonist induced increases in coronary blood flo w by bradykinin and acetylcholine (p less than or equal to 0.01). HOE- 140 strongly antagonised the effects of infused bradykinin and prevent ed the potentiation of acetylcholine responses by ACE inhibition. L-NA ME caused hypertension and bradycardia and abolished the responses to acetylcholine and adenosine, but only partially attenuated the bradyki nin induced increases in coronary blood flow. Simultaneous ACE inhibit ion reduced the hypertensive effect of L-NAME and partially restored t he responses to bradykinin. Indomethacin reduced the responses to brad ykinin but did not affect acetylcholine and adenosine induced coronary vasodilatation. The potentiation of the response to acetylcholine ind uced by ACE inhibition was, however, diminished by indomethacin. Concl usions: In the coronary vasculature of the dog, ACE inhibitors enhance vasomotor responses to endothelium dependent agonists by facilitating the release of both NO and PGI(2), a mechanism which is coupled to en dogenously formed bradykinin. ACE inhibitors may thus mediate their ef fects in vivo partly by increasing the capacity of the endothelium to release autacoids.