ON THE MECHANISM OF ACTION OF PHENYLEPHRINE IN RAT ATRIAL HEART-MUSCLE

Both in rat left atrial heart and in aortic smooth muscle preparations, phenylephrine (PE) caused a concentration-dependent increase in force of contraction (Fc) in the presence of atenolol (10 mu mol/l), which was antagonized by phentolamine, prazosin and WB 4101 in a competitive manner. The pA(2) values of the antagonists in the cardiac tissue were 10-20fold lower than those in the rat thoracic aorta. In the spontaneously beating right atrium, PE exerted a positive chronotropic action, which was not significantly antagonized by phentolamine or prazosin. It is therefore assumed that the effects of phenylephrine in the left atrium and in the aorta are mediated by different subtypes of alpha(1)-adrenoceptors, whereas the effects in the sino-atrial node are probably unrelated to alpha(1)-adrenoceptors. To further elucidate the mechanisms of the positive inotropic effect of PE, action potential configuration and Ca-45(2+) fluxes were monitored in the rat left atrium. The increase in F-c by PE was associated with an increase in action potential duration (APD) and a reduction in resting membrane potential (RP). In the presence of (-)-devapamil (D888), the effects of PE on APD and RP persisted, whereas the increase in Fe was antagonized in a non-competitive manner. Forskolin (300 nmol/l) enhanced the positive inotropic effect of PE. PE exerted a significant increase in (45)CA(2+) uptake in beating preparations, which was abolished in the presence of (-)D888 (1 mu mol/l). In addition to the PE-induced increase in Ca-45(2+) uptake, a decrease in Ca-45(2+) efflux was observed. Similarly, depolarization of the membrane by raising [K+](o) to 85 mmol/l revealed an increase in Ca-45(2+) uptake and a decrease in Ca-45(2+) efflux . The latter observations support the view that the membrane potential strongly determines the movement of Ca-45(2+) across the membrane. It is assumed that the alpha(1)-adrenoceptor-mediated changes in APD and RP may enhance F-c, first, by increasing net Ca2+ entry from the extracellular space through voltage-dependent Ca2+ channels and, second, by decreasing Ca2+ efflux possibly via the Na+/Ca2+ exchange mechanism.