Blockade of putative β4- and β1-adrenoceptors by carvedilol in ferret myocardium

The putative beta(4)-adrenoceptor mediates positive inotropic effects, action potential shortening and arrhythmias in ferret ventricle. Here we compared the affinity of carvedilol at the putative beta(4)-adrenoceptor and beta(1)-adrenoceptor, activated by (+/-)-CGP 12177 and (-)-isoprenaline, respectively. In paced right ventricular preparations, carvedilol (0.01-10 mu mol/l) was a simple competitive antagonist of the positive inotropic effects of (+/-)-CGP 12177 (slope of Schild-plot = 1.02, pK(B) = 6.8) and (-)-isoprenaline (slope of Schild-plot = 0.98, pK(B) = 8.1). Carvedilol also blocked putative beta(4)- and beta(1)-adrenoceptors of left ventricle, left atrium and sino-atrial pacemaker. Carvedilol therefore interacts with the putative beta(4)-adrenoceptor according to the law of mass action and may provide a lead in the development of putative beta(4)-adrenoceptor-selective antagonists.