THE HEMODYNAMIC BASIS FOR THE CARDIAC EFFECTS OF PARATHYROID-HORMONE (PTH) AND PTH-RELATED PROTEIN

PTH and PTH-related protein (PTHrP) have been regarded to have positive inotropic effects on the heart as well as positive chronotropic and vasodilator effects. However, inotropy due to a direct effect of these peptides has not heretofore been distinguished from an indirect inotropic effect;asa result of altered heart rate or coronary now. The aim of this study was to determine whether PTH and PTHrP have direct inotropic effects in isolated perfused rat-hearts. Three groups of hearts were studied; in all groups, hearts contracted isovolumically and were perfused with a constant coronary pressure. In the control group, heart rate, coronary now, peak pressure (LVP(max)), peak rate of rise of LV pressure (dP/dt(max)), and peak intracellular calcium (measured by aequorin) all increased with PTH and PTHrP in a dose-dependent manner. When heart rate was fixed by pacing in a second group of rats, PTH and PTHrP increased coronary flow, LVP(max), and dP/dt(max), significantly, indicating that inotropic actions were not mediated solely by chronotropic effects. However, when heart rate was fixed by pacing and, additionally, coronary now was held constant (by maximal prevasodilation with nitroprusside) in a I third group of rats, there was no significant effect of either PTH or PTHrP on LVP(max), dP/dt(max), or peak intracellular calcium. To demonstrate the responsiveness of this latter preparation to inotropic stimulation, the beta-adrenergic agonist, isoproterenol, increased LVP(max), dP/dt(max), and peak calcium even when heart rate was fixed and vasodilation was maximal. Thus, PTH and PTHrP are inotropic agents by virtue of their influence on coronary now and heart rate, but not by any direct effect on contractile elements in the heart.