Vasoactive intestinal peptide stimulation of cyclic guanosine monophosphate formation: further evidence for a role of nitric oxide synthase and cytosolic guanylate cyclase in rat pinealocytes.

In the rat pineal gland vasoactive intestinal peptide (VIP) and beta-adrenergic agonists stimulate cyclic guanosine monophosphate (cGMP) formation and their action is amplified by alpha 1-adrenergic agonists. Since beta-adrenergic stimulation of cGMP is suggested to involve activation of nitric oxide (NO) synthase and NO-mediated activation of cytosolic guanylate cyclase (GC), we investigated the effects of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) and of the cytosolic GC inhibitor methylene blue (MB) on VIP receptor-stimulated cGMP formation. Both L-NMMA and MB depressed VIP-induced cGMP formation as well as alpha 1-adrenergic potentiation of VIP-stimulated cGMP formation to the level of unstimulated pinealocytes. Further, L-arginine (L-arg) antagonized the effect of L-NMMA. However, L-arg did not antagonize the effect of MB, indicating that activation of NO synthase does not appear to compensate inhibition of cytosolic GC. On the basis of these findings it is concluded that VIP-stimulated cGMP response requires NO synthesis followed by activation of cytosolic GC. Major similarities between the regulation of VIP- and beta-adrenergic-induced cGMP formation suggest a similar/common intracellular pathway which can be modulated by alpha 1-adrenergic stimulation.