Studies on beta-adrenoceptors mediating changes in mechanical events and adenosine 3',5'-monophosphate levels. Rat atria.
Increasing concentrations of the functional antagonist carbachol resulted in a shift to the right of the dose-response curves for (--)-isoproterenol-induced positive chronotropic and inotropic responses and a reduction of the maximum degree of response that could be produced relative to that produced by theophylline. Carbachol only reduced the maximum responses to the partial agonist (--)-soterenol. The ED50 value for isoproterenol-induced increases in adenosine 3',5'-monophosphate (cyclic AMP) levels was more than 10-fold larger than those for production of mechanical events and soterenol did not produce a measurable increase in cyclic AMP above baseline values. Soterenol was analyzed as a competitive antagonist of isoproterenol-induced responses and the apparent dissociation constants (KA) for soterenol calculated to be 1.21 X 10(-7) M for receptors mediating positive chronotropic responses, 3.56 X 10(-7) M for receptors mediating positive inotropic responses, and 2.96 X 10(-7) M for receptors mediating increases in cyclic AMP levels. By two additional theoretical models of drug-receptor interactions, the KA values for soterenol were between 1.5 and 4.5 X 10(-7) M. These KA values were essentially the same as the ED50 values for soterenol-induced mechanical effects. By one of the models, the KA for isoproterenol was calculated to be about 2.14 X 10(-8) M, a value close to the ED50 value for isoproterenol-induced increases in cyclic AMP (5.45 X 10(-8) M). These results suggest that the beta-adrenoceptors mediating the three responses in rat atria are of the same type and that differences in concentrations required to produce mechanical vs. cyclic AMP changes results with agonists possessing high efficacy for which there is a receptor reserve.
Studies on beta-adrenoceptors mediating changes in mechanical events and adenosine 3',5'-monophosphate levels. Rat atria. Increasing concentrations of the functional antagonist carbachol resulted in a shift to the right of the dose-response curves for (--)-isoproterenol-induced positive chronotropic and inotropic responses and a reduction of the maximum degree of response that could be produced relative to that produced by theophylline. Carbachol only reduced the maximum responses to the partial agonist (--)-soterenol. The ED50 value for isoproterenol-induced increases in adenosine 3',5'-monophosphate (cyclic AMP) levels was more than 10-fold larger than those for production of mechanical events and soterenol did not produce a measurable increase in cyclic AMP above baseline values. Soterenol was analyzed as a competitive antagonist of isoproterenol-induced responses and the apparent dissociation constants (KA) for soterenol calculated to be 1.21 X 10(-7) M for receptors mediating positive chronotropic responses, 3.56 X 10(-7) M for receptors mediating positive inotropic responses, and 2.96 X 10(-7) M for receptors mediating increases in cyclic AMP levels. By two additional theoretical models of drug-receptor interactions, the KA values for soterenol were between 1.5 and 4.5 X 10(-7) M. These KA values were essentially the same as the ED50 values for soterenol-induced mechanical effects. By one of the models, the KA for isoproterenol was calculated to be about 2.14 X 10(-8) M, a value close to the ED50 value for isoproterenol-induced increases in cyclic AMP (5.45 X 10(-8) M). These results suggest that the beta-adrenoceptors mediating the three responses in rat atria are of the same type and that differences in concentrations required to produce mechanical vs. cyclic AMP changes results with agonists possessing high efficacy for which there is a receptor reserve.