Ca-agonists: a new class of inotropic drugs

The basic pharmacology of dihydropyridine Ca-agonists published so far (BAY k8644, CGP 28-392, H 160/51, YC 170, and 202-791) is described. The importance of the potency of the enantiomeres for the effect of a racemic compound is underlined. The Ca agonist prototype BAY k8644 leads to an increase of the maximal rate of rise of left ventricular pressure (LV(dP/dt)) and an increase of left ventricular stroke work in conscious dogs. When the vascular effects of BAY k8644 are counterbalanced by intravenous injection of sodium-nitroprusside, the left ventricular functions curves show markedly increased stroke work against the same mean arterial blood pressure at the same filling pressure. BAY k8644 stimulates the heart economically: the net efficiency in isolated working guinea-pig hearts is about 20%, identical to a stimulation by calcium or ouabain. Cardiotonic drugs acting via cAMP-dependent mechanisms like isoprenaline, amrinone, or pimobendane however, stimulate the heart about 1/3 less economically. The mechanism of action of Ca-agonists is explained from electrophysiological findings: Ca-agonistic dihydropyridines increase the open probability of the Ca-channels by a shift of the open-probability curve to more negative membrane potentials. As a consequence, the steady-state inactivation curve of the Ca-channel is also shifted in the same direction. While the effect on open-probability is the underlying mechanism for Ca-agonism, the latter effect results in Ca-antagonism. Therefore, depending on drug concentration and on membrane resting potential, a single chemical compound can act either as a Ca-agonist or a Ca-antagonist. A kinetic model of dihydropyridine action on the Ca-channel is described.