Positive inotropic effects of the endogenous Na+/K(+)-transporting ATPase inhibitor from the hypothalamus

Bovine hypothalamus contains a nonpeptidic substance that inhibits purified Na+/K(+)-transporting ATPase [ATP phosphohydrolase (Na+/K(+)-transporting), EC 3.6.1.37] reversibly with high affinity by a mechanism similar to, but not identical to, that of the cardiac glycosides. It possesses some of the characteristics ascribed to a putative endogenous "digitalis-like" compound that has been implicated in the control of renal sodium excretion and the pathogenesis of essential hypertension in man. To determine whether this hypothalamic Na+/K(+)-transporting ATPase inhibitor might have physiologic properties in cardiac tissues, its effects on Na+ pump inhibition, accumulation of cytosolic free calcium, and contractile response were studied in cultured, spontaneously contracting neonatal rat cardiocytes. The hypothalamic factor potently inhibited the Na+ pump in these cells, increased myoplasmic free calcium in a dose-dependent manner, and reversibly enhanced myocyte contractility by up to 40%, comparable in degree to maximal positive inotropic effects caused by the cardiac glycoside ouabain. Comparative studies further indicate that cardiotoxic effects of ouabain in the myocytes may be more complex than simple progressive elevation of intracellular free calcium concentration because at a free calcium concentration in excess of that produced by a toxic dose of ouabain, no toxicity with the hypothalamic Na+/K(+)-transporting ATPase inhibitor occurred.