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We have recently shown that vasoactive intestinal polypeptide (VIP) is as potent as acetylcholine in inducing the secretion of catecholamines from the rat adrenal medulla. In the present study we have investigated the molecular mechanism involved in the exocytotic secretion of catecholamines by VIP and the effects of VIP on Ca45 uptake and phosphoinositide breakdown and compared them with those of the classical cholinergic agonists. We now show that omission of Ca2+ from the perfusion medium had almost no effect on VIP-induced secretion; however, addition of 1 mM EGTA to calcium-free medium abolished the secretion. Stimulation with VIP did not result in a net increase in Ca45 uptake and it was not modified by a protein kinase C activator, phorbol ester. All these effects of VIP were comparable to those of muscarine. VIP (0.3 to 10 microM) and muscarine (30 to 100 microM) produced time-and concentration-dependent increase (up to 700%) in the production of 3Hinositol phosphates. The production of 3Hinositol phosphates by VIP and muscarine occurred in calcium-free and EGTA medium. The effect of VIP on 3HIP, 3HIP2, and 3HIP3 production was reduced by (1 to 30 microM) VIP antagonist (an analogue of growth hormone-releasing factor, Ac-Tyr1hGRF) and 1 to 20 microM naloxone. Although nicotine produced a brisk secretory response, there was no change in 3Hinositol phosphates. We conclude that inositol 1,4,5-trisphosphate generated upon activation of VIP and muscarine receptors is linked to exocytotic secretion of adrenal medullary hormones through release of internal Ca2+ ions.
Malhotra et al. (Mon,) studied this question.