Relationship between cyclic AMP metabolism and inotropic response of perfused rat hearts to phenylephrine and other adrenergic amines.

A positive correlation between inotropic response and increment of cyclic AMP levels and labeling (from 14-C-adenine in the perfusate) was found after isoprenaline, dopamine, and phenylephrine alone, and after isoprenaline in the presence of chlorpromazine. 2. a lack of correlation between contractile activity and cyclic AMP levels and labeling was found when the hearts were exposed to phenylephrine in the presence of propranolol. The contractile activity increased, but the parameters for cyclic AMP did not change. These resuls together with findings by other workers indicate that the inotropic response to beta-stimulation always is associated with cyclic AMP accumulation, while the inotropic response to alpha-stimulation (when present) is not correlated to cyclic AMP elevation. Other differences between alpha- and beta-adrenergic effects on heart (course of development of the inotropic response, effect of theophylline on the response, effects on relaxing processes, action potential, and on refractory period) also indicate different mechanisms of action. On the basis of the available data we suggest as a conclusion that the inotropic response after alpha-adrenergic stimulation does not involve cyclic AMP as a mediator whereas beta-adrenergic effects are mediated by cyclic AMP. This means that the naturally occurring adrenergic amines norepinephrine and epinephrine, both of which are able to stimulate both alpha and beta myocardial receptors (twenzel and Su, 1966), elicit the inotropic response through two different mechanisms. Usually the beta-adrenergic effect on the heart is the more important. The contribution from alpha-stimulation, however, may increase under certain conditions: hypothyroidism or proplythiouracil treatment per se (Nakashima et al., 1971) or hypothermia (Kunos and Szentiványi, 1968; Buckley and Jordan. 1970; Benfey et al., 1973; Kunos, Yong, and Nickerson, 1973; Nickerson, 1973). Thus a single physiologic response may be mediated by more than one mechanism. Multiple mechanisms of action for one agent might have more general biologic significance; e.g., they may serve to maintain the responsiveness of a tissue under various conditions.