Abstract

Inhibition by zatebradine, a specific bradycardic agent, of the negative inotropic but not chronotropic responses to adenosine has been briefly reported in the isolated, perfused dog heart. We therefore investigated whether subtypes of adenosine receptors or postreceptor transduction mechanisms differentiated the negative chronotropic and inotropic responses to adenosine in the isolated, blood-perfused atrial and ventricular preparations of the dog. Adenosine (1-3000 nmol), adenosine A1 receptor agonists, 2-chloroadenosine (CAD, 0.1-300 nmol) and N6-cyclohexyladenosine (CHA, 1-300 nmol) and a nonselective adenosine receptor agonist, 5'-N-ethyl-carboxamidoadenosine (NECA, 0.1-100 nmol), induced the negative chronotropic and inotropic responses. The potency order was NECA > CAD > adenosine > or = CHA. An adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10-300 nmol), dose-dependently inhibited the negative chronotropic and inotropic responses to adenosine, CAD and NECA in the isolated, perfused right atrium. DPCPX also blocked the negative inotropic responses to adenosine, CAD and NECA in the isolated left ventricle. However, an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 300 nmol), did not affect the negative cardiac responses to adenosine and NECA. Although the negative inotropic but not chronotropic responses to CAD and adenosine were dose-dependently inhibited by zatebradine, K+ channel inhibitors 4-aminopyridine and E-4031 did not modify the cardiac responses to adenosine and CAD. These results suggest that the negative cardiac responses to adenosine are mediated by adenosine A1 receptors and the negative chronotropic and inotropic responses to adenosine are differentiated at the postreceptor transduction level(s) in the dog heart.