We have demonstrated that gamma (Gamma) MSH peptides have dose-dependent natriuretic and hypertensive activity. The major source of circulating Gamma MSH, the pars intermedia, has been implicated in sodium metabolism. In addition, dopamine agonists, which inhibit pars intermedia secretion, have antihypertensive effects. These data suggest a possible role for the pars intermedia, specifically Gamma MSH, in renal and cardiovascular physiology. This proposal is to investigate the mechanism of Gamma MSH, induced hypertension, and to begin to discern the role of Gamma MSH and the pars intermedia in volume and cardiovascular regulation. Gamma MSH hypertension will be investigated by using chronic intra-arterial or intracerebroventricular infusions in rats. This will allow us to compare central vs. peripheral effects. Possible mechanisms for investigation include; sympathetic nervous system activation, direct vascular effects, resetting of baroreceptors, potentiation of endogenous vasoconstrictors, and secretion of adrenocorticoids. The physiological role of Gamma MSH and the pars intermedia will be examined in saline-expanded and DOC-salt hypertensive rats. These experiments will include; measurement of circulating Gamma MSH, inhibition of hypophyseal Gamma MSH secretion by dexamethasone and/or bromocryptine treatment, selective removal of the neurointermediate lobe, and injection of Gamma MSH antibodies. We will correlate these measurements or interventions to blood pressure and sodium excretion. The renal effects of bolus injections and infusions of Gamma MSH in rate will be examined by measuring renal blood flow, glomerular filtration rate, and fractional sodium excretion. Sympathetic nervous system contributions will be determined by selective pharmacological blockage of adrenergic receptors and the use of denervated kidneys. The successful implementation of this proposal could help define a previously unrecognized class of renal and cardiovascular system regulating hormones, and provide a possible role for the pars intermedia in mammalian physiology.
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