Interaction of the cardiotonic agent DPI 201-106 with cardiac Ca2+ channels

The cardiotonic agent DPI 201-106 was investigated for its effects on (a) contractile force in guinea pig left atria, (b) membrane currents in isolated guinea pig cardiac myocytes, and (c) 3H]nitrendipine binding in guinea pig cardiac membranes. The compound elicited a positive inotropic effect in normally polarized (5.9 mM extracellular KCl) and a negative inotropic effect in partially depolarized (20 mM KCl) isolated, electrically stimulated left atria. This decrease in contractile force was probably caused by inactivation of the fast Na+ inward current and concomitant blockade of the inward Ca2+ current. The blocking effect on Ca2+ channels was directly shown in voltage-clamp experiments using isolated cardiocytes. Further evidence for interaction of DPI 201-106 with Ca2+ channels was obtained from the 3H]nitrendipine binding studies. Thus, Ca2+ antagonism contributes to the complex pharmacologic profile of DPI 201-106, and is probably responsible for the bradycardia and lowering of systemic vascular resistance observed in vivo.