The adrenal gland plays a crucial role in maintaining homeostasis during stressful situations by releasing cortical and medullary hormones into the blood stream. For over 10 years we have been particularly interested in the control of adrenal medulla by its preganglionic sympathetic neurons. These splanchnic neurons are cholinergic in nature and acetylcholine (ACh) released from the their terminals is the known stimulus of catecholamine secretion from chromaffin cells. In 1987 our analysis hinted that other substances, in addition to ACh could be released from nerve endings to stimulate the chromaffin cells. We used a series of physiological, pharmacological and immunohistochemical techniques together with radioimmunoassay to identify the nature of the non-cholinergic transmitter as vasoactive intestinal polypeptide (VIP). The new concept of non- cholinergic participation in the adrenal medulla has received wide acceptance because VIP, but not ACh, proved to be the stimulus for elevation of cAMP and consequent events in chromaffin cells. Within the last few years a new polypeptide, pituitary adenylate cyclase; activating polypeptide (PACAP), was identified as a member of the VIP-secretin family. PACAP has many similarities with VIP and has been found in neural tissues. These developments have opened new areas of research to further understand the physiological significance of multiple transmitter control of adrenal medullary secretion. In the present proposal we are raising three important questions. First, because of two lingering concerns regarding the role of VIP as a sole non-cholinergic transmitter, we question whether PACAP could be the other non-cholinergic transmitter. Second, our demonstration that ACh and VIP are released by different frequencies of splanchnic nerve stimulation raises the question of whether cholinergic and peptidergic transmitters are located in the same or different nerve endings. Third, because it is well known that there are two populations of chromaffin cells, epinephrine and norepinephrine rich, which lead to different proportions of the two catecholamines under different stressor conditions, we question whether ACh and peptides preferentially secrete epinephrine or norepinephrine. These issues will be addressed using techniques of immunohistochemistry, molecular biology, biochemistry and physiology with the combined expertise of our own laboratory and that of our most able colleagues.

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National Heart, Lung, and Blood Institute (NHLBI)
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Neurological Sciences Subcommittee 1 (NLS)
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Wayne State University
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Wakade, A R; Wakade, T D; Poosch, M et al. (1996) Noradrenaline transport and transporter mRNA of rat chromaffin cells are controlled by dexamethasone and nerve growth factor. J Physiol 494 ( Pt 1):67-75
Lopez, M G; Shukla, R; Garcia, A G et al. (1992) A dihydropyridine-resistant component in the rat adrenal secretory response to splanchnic nerve stimulation. J Neurochem 58:2139-44
Carmichael, S W; Brooks, J C; Malhotra, R K et al. (1989) Ultrastructural demonstration of exocytosis in the intact rat adrenal medulla. J Electron Microsc Tech 12:316-22
Malhotra, R K; Wakade, T D; Wakade, A R (1988) Comparison of secretion of catecholamines from the rat adrenal medulla during continuous exposure to nicotine, muscarine or excess K. Neuroscience 26:313-20
Malhotra, R K; Bhave, S V; Wakade, T D et al. (1988) Protein kinase C of sympathetic neuronal membrane is activated by phorbol ester--correlation between transmitter release, 45Ca2+ uptake, and the enzyme activity. J Neurochem 51:967-74
Wakade, A R; Wakade, T D; Malhotra, R K et al. (1988) Excess K+ and phorbol ester activate protein kinase C and support the survival of chick sympathetic neurons in culture. J Neurochem 51:975-83
Malhotra, R K; Wakade, T D; Wakade, A R (1988) Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis. J Biol Chem 263:2123-6
Harish, O E; Kao, L S; Raffaniello, R et al. (1987) Calcium dependence of muscarinic receptor-mediated catecholamine secretion from the perfused rat adrenal medulla. J Neurochem 48:1730-5
Malhotra, R K; Wakade, A R (1987) Vasoactive intestinal polypeptide stimulates the secretion of catecholamines from the rat adrenal gland. J Physiol 388:285-94
Malhotra, R K; Wakade, A R (1987) Non-cholinergic component of rat splanchnic nerves predominates at low neuronal activity and is eliminated by naloxone. J Physiol 383:639-52

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