Actions of sympathomimetic amines on the Ca2+ transients and contractions of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca2+ mediated through alpha- and beta-adrenoceptors.

Abstract

The effects of sympathomimetic amines on Ca2+ transients and isometric contractions were assessed in isolated rabbit papillary muscles in which multiple superficial cells had been microinjected with the calcium-sensitive bioluminescent protein aequorin. In the presence of beta-adrenoceptor blockade, the alpha-receptor agonist phenylephrine increased both the amplitude of the aequorin signals and the force of contraction in a concentration-dependent manner. However, the maximum increase in the aequorin signals was less than 10% of that produced by the beta-receptor agonist isoproterenol, while the maximum increase in force of contraction produced by alpha-stimulation was about 50% of that elicited via beta-adrenoceptors. For a given increase in the force of contraction, stimulation of alpha-adrenoceptors produced much less change in the amplitude of the aequorin signals than did elevation of the extracellular Ca2+ concentration; we interpret this to mean that the positive inotropic effect of alpha-adrenoceptor stimulation is in large part the result of an increase in myofibrillar sensitivity to Ca2+. Stimulation of alpha-adrenoceptors produced little change or a slight decrease in the duration of the aequorin signal and an increase in the duration of contraction, while stimulation of beta-adrenoceptors significantly decreased the time to peak and duration of both the aequorin signals and the contractions. For a given level of inotropic effect, high concentrations of isoproterenol often increased the aequorin signals more than did elevations of Ca2+, which is consistent with other evidence that the cyclic AMP-dependent phosphorylation of troponin I leads to a decrease in myofibrillar Ca2+ sensitivity. However, concentrations of isoproterenol that did not produce evidence of this sort of desensitization also abbreviated the contractions much more than they did the aequorin signals. This suggests that the traditionally accepted mechanisms--a decrease in the Ca2+ affinity of troponin C and an acceleration of Ca2+ uptake by the sarcoplasmic reticulum--may not be sufficient to account for the actions of beta-receptor stimulation on the time course of contraction. In the absence of blocking agents, the naturally occurring catecholamines norepinephrine, epinephrine, and dopamine appear to influence the function of the rabbit papillary muscle through both alpha- and beta-adrenoceptors. Dopamine has a relatively greater effect on alpha-adrenoceptors than the other catecholamines.