A comparison of inotropic actions of p-chloromercuribenzoate, ouabain, digitoxin and digitoxigenin

Abstract

We have shown previously that sulfhydryl blocking agents, such as p-chloromercuribenzoate (PCMB), produce positive inotropic effects associated with inhibition of sarcolemmal Na +,K + -ATPase or the sodium pump. Since these compounds and digitalis derivatives bind to the enzyme at the internal and external surface of the cell membrane, respectively, the difference in sites of interaction with Na +,K + -ATPase may result in the development of the inotropic effect to be affected differently by conditions which alter properties of the cell membrane. Thus, inotropic actions of these agents were compared in the electrically stimulated left atrial preparation of guinea-pig heart. Propranolol delayed the development of the positive inotropic action PCMB to a greater extent than that of ouabain, digitoxin or digitoxigenin. The action of propranolol is due to membrane stabilization, rather than β-adrenoceptor blockade. The maximum inotropic effect achieved was not affected by propranolol. The onset of action of PCMB was influenced to a greater extent by the beat interval than was ouabain whose action was affected by the interval more than was digitoxin or digitoxigenin. The onset rate of the inotropic action of PCMB was slower and slower and that of ouabain or digitoxin was more rapid at higher temperature. The onset rate of the action of digitoxigenin was relatively temperature insensitive. The initial force of contraction is not the sole determinant of the onset rate of the action of PCMB, since a simultaneous decrease in extracellular sodium and calcium concentration delayed the onset rate without altering the developed force. Moreover, a decrease in the force of contraction caused by lower resting tension did not alter the onset rate. Thus, several conditions which affect properties of the cell membrane alter the onset rate of the inotropic action of PCMB to a greater extent than those of actions of digitalis derivatives; a finding which is consistent with the requirement of PCMB to penetrate the cell membrane for its action.