Inotropic and chronotropic effects of vasodilators.

Although vasodilators are used with increasing frequency for the treatment of heart failure and myocardial ischemia, their direct effects on cardiac muscle have not been completely characterized. To delineate the action of vasodilators on mammalian myocardium, the chronotropic and inotropic effects of vasodilators on isolated guinea-pig atria (n = 163) have been determined. The spontaneous frequency and the peak rate of isometric force development at a fixed frequency of 200/min were used as indexes of chronotropy and inotropy. The potency series for negative chronotropy was diltiazem greater than D600 greater than verapamil greater than lidoflazine greater than bepridil greater than prenylamine greater than perhexiline greater than nifedipine. The potency series for negative inotropy differed substantially, exhibiting the sequence nifedipine greater than D600 greater than verapamil greater than bepridil greater than lidoflazine greater than prenylamine greater than perhexiline greater than diltiazem. Therefore, nifedipine acted as an "inoselective" and diltiazem as a "chrono-selective" depressant. Other vasodilators, including papaverine, nitroglycerin, nitroprusside, adenosine, dipyridamole, diazoxide and hydralazine exerted no or negligible negative chronotropic or inotropic effects even at high concentration (10(-5) M). Therefore, only vasodilators classified among the calcium antagonists proved to have appreciable direct myocardial effects. This supports the view that these drugs constitute a category of agents distinct from classical vasodilators.

Myocardial contracture and accumulation of mitochondrial calcium in ischemic rabbit heart.

The relationship between myocardial contracture and cell calcium was studied in electrically paced, isolated perfused rabbit hearts. Isovolumic left ventricular dP/dt and end-diastolic pressure were utilized as indexes of contractility and ventricular stiffness. After 60 min of low flow (ischemia) without or with reperfusion at high flow for 10 min, calcium was measured in the mitochondrial fraction and used as an indicator of intracellular calcium. Low flow led to ventricular standstill and contracture, and reperfusion produced partial mechanical recovery with end-diastolic pressure remaining markedly elevated. Nifedipine (10(-7) M), an antagonist of myocardial calcium uptake, prevented contracture and permitted nearly complete mechanical recovery without elevation in diastolic pressure. Increases in mitochondrial calcium paralleled the severity of contracture and the lack of diastolic relaxation after reperfusion. Mitochondrial calcium did not increase in hearts protected by nifedipine. Results demonstrate a close relationship between mechanical changes induced by ischemia and accumulation of intracellular calcium.