A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs

Abstract

Objectives. This study was undertaken to examine whether a dihydropyridine Ca channel blocker, benidipine, increases cardiac NO levels, and thus coronary blood flow (CBF) in ischemic hearts.Background. Benidipine protects endothelial cells against ischemia and reperfusion injury in hearts.Methods and Results. In open chest dogs, coronary perfusion pressure (CPP) of the left anterior descending coronary artery was reduced so that CBF decreased to one-third of the control CBF, and thereafter CPP was maintained constant (103 ± 8 to 42 ± 1 mmHg). Both fractional shortening (FS: 6.1 ± 1.0%) and lactate extraction ratio (LER: −41 ± 4%) decreased. Ten minutes after the onset of an intracoronary infusion of benidipine (100 ng/kg/min), CBF increased from 32 ± 1 to 48 ± 4 ml/100g/min during 20 min without changing CPP (42 ± 2 mmHg). Both FS (10.7 ± 1.2%) and LER (−16 ± 4%) also increased. Benidipine increased cardiac NO levels (11 ± 2 to 17 ± 3 nmol/ml). The increases in CBF, FS, LER and cardiac NO levels due to benidipine were blunted by L-NAME. Benidipine increased cyclic GMP contents of the coronary artery of ischemic myocardium (139 ± 13 to 208 ± 15 fmol/mg protein), which was blunted by L-NAME.Conclusion. Thus, we conclude that benidipine mediates coronary vasodilation and improves myocardial ischemia through NO-cyclic GMP-dependent mechanisms.