Adrenergic–cholinergic interactions in left atria. II. Comparison of the antagonism of inotropic responses to α- and β-adrenoceptor stimulation and BAY K 8644 by carbachol, D-600, and nifedipine

Abstract

The muscarinic agonist carbachol has previously been shown to reverse positive inotropic responses of rabbit left atrial strips to equiactive doses of the β-adrenoceptor agonist isoproterenol and to the α-adrenoceptor agonist phenylephrine. Responses to phenylephrine were measured in the presence of the β-blocker timolol. However, carbachol was not able to reverse the increase in tension produced by elevating the extracellular Ca2+ concentration. To gain more information about the nature of the functional interaction of carbachol with α- and β-receptor stimulants in left atria, the interaction of carbachol with these agonists, as well as with elevated Ca2+ and the Ca2+ activator compound BAY K 8644, was compared with that of the Ca2+ antagonists D-600 and nifedipine. The results demonstrate that the Ca2+ antagonists exhibit a selectivity similar to that of carbachol, in that responses to both isoproterenol and phenylephrine plus timolol were blocked by low concentrations of D-600 and nifedipine, which had no effect on positive inotropic responses to elevated Ca2+. Higher concentrations of these antagonists shifted the Ca2+ dose–response curve to the right. In addition, although phenylephrine and BAY K 8644 increased tension to a similar extent, responses to phenylephrine were more sensitive than responses to BAY K 8644 to inhibition by both carbachol and D-600. These similarities between the effects of low concentrations of D-600 and nifedipine and those of carbachol are consistent with the hypothesis that carbachol antagonizes responses to α- and β-receptor stimulation in left atria primarily by blocking increases in Ca2+ influx produced by these agonists. In addition, the observation that responses of left atria to α- and β-adrenoceptor agonists are blocked more readily than responses to elevated Ca2+ and those to BAY K 8644 by both carbachol and the Ca2+ antagonists may be indicative of differences in the way agonists on one hand, and elevated Ca2+ and BAY K 8644 on the other, increase Ca2+ influx into myocardial cells.