Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We have demonstrated that CGAP expression in dosal root ganglia (DRG), the sites of neuronal cell bodies that send CGRP-containing nerves to blood vessels, is decreased in the spontaneously hypertensive rat (SHR) which could contribute to the high blood pressure, and increased in the mineralocorticoid-salt (DOC-salt) hypertensive rat, which could attenuate the high blood pressure. Importantly, we have shown that the administration of a CGRP receptor antagonist, (CGRP 8-37), to DOC-salt rats significantly increases blood pressure. This is the first conclusive evidence that endogenous CGRP plays a role in hypertension. In addition, using primary cultures of adult DRG neurons, we have shown that factors, known to be altered in hypertension, such as nerve growth factor (NGF) and bradykinin/prostaglandins (BK/PG), stimulate, and the sympotheses: 1) Alternations in neuronal CGRP expression in the SHR and DOC-salt rats directly modulate changes in systemic and regional hemodynamics, and 2) The regulation of neuronal CGRP expression in both normal rats and the hypertension models involves the direct actions of NGF, the SNS, the BK/PG system, and glucocorticoids. Theses hypotheses will be tested by combining in vivo studies, in normal and hypertensive (SHR and DOC-salt) rats with in vitro studies in primary cultures of DRG neurons. First, NGF treatment of SHR will be used to markedly increase neuronal CGRP expression which, in turn, will decrease blood pressure (BP) and/or increase regional organ blood flows, as measured by the radioactive microsphere technique. To determine that these hemodynamic changes are mediated by CGRP we will administer (CGRP 8-37) to these NGR treated rats. Second, in DOC-salt hypertension, which displays enhanced CGRP expression, it will be determined whether (CGRP 8-37) selectively decreases region organ blood flows. Additional in vivo studies will be performed in normal rats and the two hypertensive models to evaluate the effects of NGF, the SNS, BK/PG, and glucocorticoids on DRG CGRP mRNA, determined by a ribonuclease protection assay, and immunoreactive CGRP (iCGRP) content and serum iCGRP levels, determined by a specific RIA. In vitro studies in primary cultures of DRG neurons will be performed to assess the interations of these CGRP regulatory factors and the mechanism(s) by which they regulate CGRP synthesis and release. These studies will provide a crucial step in elucidating the factors and mechanisms that regulate the expression of this neuropeptide and its role in hypertension.
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