alpha-Adrenergic reduction of cyclic adenosine monophosphate concentrations in rat myocardium.

Abstract

SUMMARY We determined the effect of a-adrenergic receptor stimulation on cyclic adenosine monophosphate (cyclic AMP) concentrations in isolated myocytes derived from adult rat hearts and in isolated perfused rat hearts. Activation of a-adrenergic receptors with either phenylephrine (10~8 M to 10~6 M) or epinephrine (10" M to 10~6 M) plus propranolol (10 ' ! M) resulted in a reduction in cyclic AMP levels in isolated myocytes. The action of phenylephrine was antagonized by phentolamine (10~6 M). Phenylephrine (10 s M) attenuated cyclic AMP generation in response to isoproterenol (10" s M and 10 s M). However, this effect of phenylephrine was not antagonized by phentolamine. Elevation of cyclic AMP concentrations produced by glucagon and by theophylline in isolated myocytes was attenuated by phenylephrine and by epinephrine plus propranolol and the attenuation was antagonized by phentolamine. In isolated perfused rat hearts epinephrine (10 (i M), when given with propranolol, diminished the rate of development of tension and also reduced tissue levels of cyclic AMP. Epinephrine alone, as well as isoproterenol, increased contractility and myocardial cyclic AMP concentrations as expected. These results indicate that catecholamines may increase or decrease cyclic AMP levels in rat myocardium, depending on the intensity of stimulation of receptor types. Increases are mediated by /3-adrenergic receptors, whereas decreases appear to be mediated by a-adrenergic receptors. IN 1967, Robison et al. 1 hypothesized that activation of either a-adrenergic or /3-adrenergic receptors may modify the activity of adenylate cyclase and result in changes in the rate of conversion of ATP to cyclic adenosine monophosphate (cyclic AMP). They further predicted that asympathomimetic agents could induce a decrease in the activity of the enzyme in some tissues. This original hypothesis has since been corroborated by studies which indicate that some a-adrenergic effects are mediated by a reduction in the tissue level of cyclic AMP. 2 " 5 Although there is an abundance of evidence that activation of a-adrenergic receptors can lead to alterations in the electrophysiological and mechanical functions of the heart, 6 " 18 no intracellular mediator or biochemical basis for these effects has been identified. It has been fairly convincingly shown that these a-adrenergic effects are not mediated by an increase in myocardial cyclic AMP concentrations. 1920 The question remains, however, whether any of the a-adrenergic effects on the heart might be mediated by a decrease in tissue cyclic AMP levels. The purpose of the present study was to attempt to demonstrate whether stimulation of myocardial a-adrenergic receptors is associated with a fall in cyclic AMP concentrations. The studies were carried out using isolated adult rat heart cells. To extend the findings to the intact heart, we also performed a limited parallel study of a-adrenergic effects on contractility and cyclic AMP levels of isolated, perfused rat hearts. Methods ISOLATION OF CELLSOur me...

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