THE IMPORTANCE OF METABOLIC PATHWAYS FOR THE POSITIVE INOTROPIC ACTIONS OF CARDIAC GLYCOSIDES AND CALCIUM IONS

¹ Department of Pharmacology, Temple University School of Medicine, Philadelphia 40, Pa.

The ability of the hypodynamic frog's heart to produce a positive inotropic response to strophanthin-k, increased calcium ion concentration, and epinephrine has been determined under conditions of limited metabolic activity induced by treatment of the hearts with nitrogen in place of air, sodium fluoroacetate, sodium iodoacetate, iodoacetamide, or 2,4-dinitrophenol. With each metabolic inhibitor glucose has been tested as an exogenous source of substrate for energy production. Adenosinetriphosphate has been tested for its ability to counteract the metabolic block induced by dinitrophenol.

Under anaerobic conditions the positive inotropic effects of strophanthin-k, calcium ions, and epinephrine were present when glucose was present. In the absence of added glucose anaerobic conditions prevent the effects of all three cardiotonic substances.

Sodium fluoroacetate interfered with the actions of the three agents, but glucose added to the perfusion fluid of the fluoroacetate-treated hearts restored the responses toward normal.

Treatment of hearts with sodium iodoacetate or iodoacetamide, until anaerobic activity was possible only for a few minutes, did not interfere with the positive inotropic actions of strophanthin-k, calcium ions, or epinephrine.

Dinitrophenol in low concentrations interfered with the positive inotropic effects of all three agents. The positive inotropic effects could not be restored to dinitrophenol-poisoned hearts by adenosinetriphosphate. Dinitrophenol prevented the positive inotropic effect of adenosinetriphosphate on the hypodynamic heart.

These data suggest that the positive inotropic effects of strophanthin-k, calcium ions, and epinephrine are not dependent upon the functional integrity of oxidative metabolism, the Krebs-tricarboxylic acid cycle, or the Embden-Meyerhof metabolic chain as long as an adequate metabolism for producing energy remains. This places the site of action of these agents in the area of metabolism involved in utilization of chemical energy for muscular work.