Antagonism and supersensitivity to phenylephrine-induced chronotropic responses.

Abstract

Right atria from rats were analyzed for chronotropic responses to phenylephrine in face of various drugs and procedures. Propranolol, 10(-8) M, produced a competitive antagonism against the agonist which concentration-effect curve was closely similar to that obtained from reserpinized animals. Prazosin, but not phentolamine (both 10(-6) M) showed inhibition of the phenylephrine-induced changes in heart rate, as judged by their -log EC50. Either of the alpha-adrenoceptor antagonists exhibited a greater steepness in the curve slope with respect to control. The simultaneous exposure of tissues to phentolamine and propranolol proved to effectively antagonize the chronotropic effect of the agonist. This held true for phentolamine assayed in atria from reserpine-pretreated rats. Previous incubation of tissues with papaverine, 10(-5) M, brought about supersensitivity to phenylephrine which was thoroughly inhibited by either phentolamine or propranolol. These results strongly suggest that beta-adrenoceptor stimulation of heart rate by phenylephrine takes place indirectly via norepinephrine release. There is also alpha 1-adrenoceptor stimulation (blocked by prazosin). Finally, it is hypothesized that supersensitivity develops by papaverine-enhanced Ca2+ influx, since numerous evidences are against a phosphodiesterase inhibition-dependent cAMP accumulation mechanism triggered by papaverine in the presence of phenylephrine.