STIMULATION OF CYCLIC-GMP ACCUMULATION BY SODIUM-NITROPRUSSIDE IS POTENTIATED VIA A G(S) MECHANISM IN INTACT PINEALOCYTES

Cyclic GMP accumulation in pinealocytes is elevated >100-fold by norep inephrine (NE) through a mechanism involving conjoint activation of al pha(1)-and beta(1)-adrenergic receptors. Little or no stimulation occu rs if either alpha(1)- or beta(1)-adrenergic receptors alone are activ ated. It appears that alpha(1)-adrenergic effects are mediated by Ca2 acting in part through nitric oxide (NO), and beta(1)-adrenergic effe cts are mediated by G(s). In the study presented here we investigated effects of adrenergic agonists or related postreceptor-active agents o n stimulation of pineal cyclic GMP accumulation by the NO generator so dium nitroprusside (NP). The cyclic GMP response to NP (1 mM) was pote ntiated by NE and isoproterenol (ISO) but not by phenylephrine, indica ting that activation of beta(1)-adrenergic receptors potentiates the e ffects of NP. Similarly, vasoactive intestinal peptide (VIP), cholera toxin (CTX), and forskolin, all of which are known to mimic the effect s of ISO in this system, also potentiated the effects of NP. In contra st, neither dibutyryl cyclic AMP nor agents that elevate intracellular Ca2+ levels caused marked potentiation of the effects of NP on pineal cyclic GMP. Depletion (90%) of G(s) alpha by 21-h treatment with CTX reduced beta-adrenergic potentiation of NP. These findings indicate th at beta-adrenergic agonists and VIP potentiate the effects of NP throu gh a mechanism involving G(s). The molecular basis of this action may be an increase in guanylyl cyclase responsiveness to NO.