Angiotensin-converting enzymeinhibitors and angiotensin iireceptor blockers synergistically increasecoronary blood flow in canine ischemic myocardium: Role of bradykinin

Objectives We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts. Background Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts. Methods In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 μg/kg/min) or ARB (RNH-6270, 10 μg/kg/min) into the coronary artery. Results Perfusion pressure of the left anterior descending coronary artery was reduced from 104 ± 8 to 42 ± 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 ± 6 to 98 ± 5 pg/ml). Coronary blood flow (29 ± 2 to 44 ± 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 ± 1.9 to 17.5 ± 3.2 μm) also increased, with these changes being attenuated by either Nω-nitro-image-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 ± 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 ± 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF. Conclusions The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.