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United Companies Distinguished Professor of Biomedical Science

M.D.: 1948, University of Pennsylvania School of Medicine

We are one of the founders of neuroendocrinology and are currently active in research in neuroimmunomodulation, and in the control of hypothalamic pituitary and peripheral function by brain peptides, nitric oxide and cytokines.

A circadian rhythm of leptin (L) release in human and rat may be controlled by secretion of prolactin (PRL), since PRL stimulates L release and an inhibitor of PRL, bromocryptine, lowers it. Nitrate/nitrite (NO₃/NO₂) in plasma reflects production of NO and the circadian rhythm of NO3/NO2 parallels that of L suggesting that L mediates the rhythm of NO production. Indeed, incubation of L with epididymal fat pads induces NO release. Anesthesia alters both plasma L and NO₃/NO₂ providing evidence of neural control of both. Bacterial lipopolysaccharide (LPS) rapidly releases TNF-alpha, progressively L and a delayed release of NO. Release of L and TNF-alpha are inhibited by bromocryptine or dexamethasone. Leptin release is pathophysiologically inhibited by adrenergic receptors. The TNF-alpha response to LPS is blocked by anesthesia and a beta-adrenergic agonist, but is controlled by stimulatory, instead of inhibitory, alpha-adrenergic receptors. The remarkable TNF-alpha response to surgical stress is delayed by anesthesia. Stress induces a rapid decline in plasma (NO₃/NO₂), caused by neurally mediated inhibition of NO synthase. Release of cytokines and NO is controlled by the CNS, although local control is exerted in tissues.

In other experiments we have shown that vitamin C acts as a transmitter to control LHRH release from the hypothalamus as well as gonadotropin release from the pituitary gland. Vitamin E also acts as a transmitter in the hypothalamus. We hypothesize that most, if not all vitamins have acute functions as transmitters in the brain, pituitary and other organs. These actions are brought about either by release or scavenging of NO and may play an important role in the protective effects of vitamin C and E on the cardiovascular system, and their antiaging effects in other tissues.

Our research indicates that atrial natriuretic peptide (ANP), oxytocin (OT) and NO act together in the brain, cardiovascular system, and kidney following blood volume expansion to return body fluid volume to normal by decreasing fluid and salt intake, cardiac output, and inducing vasodilation, followed by natriuresis. All three of these agents activate guanylyl cyclase that converts guanosine triphosphate into cyclic guanosine monophosphate that acts by protein kinase G to mediate the actions of ANP, OT and NO. An orally active activator of guanylyl cyclase would have great clinical utility in treatment of hypertension and congestive heart failure.

We identified lamprey gonadotropin-releasing hormone (l-GnRH) III as a physiologically significant FSH-releasing factor. This peptide has been shown to develop multiple large ovarian follicles in the cow, a species that normally only develops one large follicle during its estrous cycle. Therefore, l-GnRH-III holds promise for control of reproduction in species from fish to human. Supported by a Merit Award from the National Institutes of Health.

Recent Publications:

A PubMed listing of research publications for Samuel M. McCann, M.D.