REGULATION OF ATRIAL-NATRIURETIC-PEPTIDE SECRETION BY ALPHA-1-ADRENERGIC RECEPTORS - THE ROLE OF DIFFERENT 2ND MESSENGER PATHWAYS

A critical problem in determining the intracellular mechanisms regulating atrial natriuretic peptide (ANP) secretion is the extrapolation of data obtained in cultures of atrial myocytes isolated from neonatal animals to that obtained in intact atria isolated from adult animals. We have therefore examined ANP secretory responses in primary cultures of atrial myocytes isolated from adult rats to more closely approach the adult phenotype. Activation of α1-adrenergic receptors by norepinephrine (in the presence of propranolol) increased the rate of ANP secretion approximately two-fold (EC50 = 0.32 μM). This response was mediated predominately by the α(1A)- like subtype of α1-receptors. Phorbol esters increased the rate of ANP secretion approximately 2.4-fold independently of α1-receptor occupancy. Kinetic analysis showed that the secretory responses to either agonist did not appear to diminish within 2 h. The responses to both α1-adrenergic stimulation and phorbol ester addition were inhibited by the protein kinase C inhibitor, H-7, but not by structurally related isoquinolines. Influx of extracellular Ca2+, independently of its effects on contraction of the myocytes, was also necessary for a full secretory response to α1-receptor activation. Additionally, the secretory response to α1-adrenergic agonists was attenuated by calmodulin inhibitors. In contrast to the response to α1- adrenergic receptor activation, stimulation of β-adrenergic receptors or addition of a membrane permeable cAMP analog reduced the rate of both basal and α1-stimulated ANP secretion. These results show that activation of α1-adrenergic receptors in adult rat atrial myocytes directly increases the rate of ANP secretion. This response is dependent upon protein kinase C and supported by extracellular Ca2+ influx. Conversely, activation of β- adrenergic receptors, which increases intracellular cAMP, directly inhibits ANP secretion. © 1993 Academic Press Limited.