The effects of p-chloromercuriphenylsulfonic acid (PCMBS) on force of contraction of mammalian myocardium and on ATP hydrolysis by sarcolemmal ATPase

Summary

• 1. In guinea-pig papillary muscle PCMBS (0.03–0.6 mmol/l) produced, after a transient negative inotropic phase, a pronounced positive inotropic effect. Finally a contracture developed, while the force of contraction declined continuously.

• 2. Endogenously released noradrenaline contributed to the time course but not to the maximum of the positive inotropic effect of PCMBS. The latter was equal to the maximal effect obtained by noradrenaline. For further evaluation of PCMBS effects, only muscles from animals pretreated with reserpine were used.

• 3. The increase of the concentration of PCMBS (from 0.03–0.6 mmol/l) did not significantly alter the magnitude of its negative or positive inotropic effects, but distinctly accelerated their development. When contraction force was plotted versus timex[PCMBS], the time curves of the development of the inotropic effects became superimposable. The similar dependence of negative as well as positive inotropic effects on the concentration of PCMBS suggested that the same type of receptor, probably sulfhydryl groups, is involved in the mediation of both effects.

• 4. A mathematical analysis made evident that either the rate of permeation of PCMBS across some barrier far from equilibrium or the rate of binding of supramaximal concentrations of PCMBS to a receptor may be rate-limiting. Permeation is most likely the rate-limiting step, since the rapid inactivation of isolated sarcolemmal ATPase indicates a fast binding of PCMBS.

• 5. The negative inotropic effects of PCMBS correlated with a shortening of both contraction time and plateau duration of the action potential. This made it probable that the negative inotropic effect and the shortening of action-potential duration were causally related.

• 6. A reduction of [Na⁺]₀ (from 140 to 70 mmol/l) or of stimulation frequency (from 1 to 0.004 Hz) or an increase of [K⁺]₀ (from 2.4 to 9.6 mmol/l) delayed the appearance of the positive inotropic effect of PCMBS (t _50% of maximal effects was 4 min at 2.4 mmol/l K⁺ and 27 min at 9.6 mmol/l).

• 7. Mg²⁺+Na⁺+K⁺- and Mg²⁺-dependent ATPases of sarcolemmal particles were inhibited by PCMBS (1–30 μmol/l).

• 8. The similarities in the influence of variation of contraction frequency and of [Na⁺]₀ or [K⁺]₀ on the positive inotropic effects of PCMBS and of cardioactive glycosides and their common inhibitory action on membrane ATPase suggest that inhibition of this enzyme by the Hg-compound is the cause of its positive inotropic effect.