This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.High blood pressure (HBP) is known to be one of the leading causes of cardiovascular disorders in the US and occurs at disproportionately high rates in ethnic minorities. While salt sensitivity has been established as an important factor in the prevalence and severity of hypertension in humans, the underlying pathophysiology is not well identified. In addition, salt sensitivity is more prevalent among African Americans and has been postulated to contribute to both hypertension and hypertensive nephropathy.Animal models provide excellent opportunities for examining specific regulatory systems that can then be translated into clinical trials.Studies by the investigator's previous group have shown that Gamma Melanocyte Stimulating Hormone (yMSH), a potent natriuretic peptide, plays a role in normal sodium homeostasis in rats. They demonstrated that Sprague Dawley (SD) rats have increased pituitary prohormone proopiomelanocortin (POMC) and protease convertases (PC1 and PC2 that process the POMC into []MSH) mRNA expressions along with an increase in plasma _MSH level at 3 weeks of chronic salt loading, suggesting a possible role of this system (_,MSH system) in sodium homeostasis. Our lab has recently demonstrated an increase in both POMC message expression and plasma _,MSH levels in Wistar Kyoto (WKY) rats fed with high salt diet (HSD; 8% NaCI) compared to WKY rats fed with low salt diet (LSD; 0.3% NaCI) diet. This result is consistent with that of SD rats from previous studies. By contrast, we observed blunting of POMC mRNA expression along with inappropriately high levels of plasma ,/MSH in SHR fed with HSD compared to SHR fed LSD. Based on these findings we postulate that the increase of plasma yMSH level with decreased POMC message expression in SHR HSD rats is due to melanocortin receptor (MCR) resistance to _/MSH in the kidneys induced by HSD. This resistance subsequently leads to high levels of plasma _,MSH and feedback suppression of POMC mRNA expression. Thus, the specific aims of this study are: 1) To examine the effect of dietary salt on renal MC3 receptor mRNA expression in the kidneys of SHR rats.2) To examine the response of blood pressure, MC3 mRNA expression and rate of sodium (Na) excretion to exogenous _,MSH in SHR rats when fed a high salt diet.3) To examine the changes in blood pressure, MC3 receptor mRNA expression and rate of Na excretion following administration of MC3 receptor antagonist and agonist in SHR rats receiving high salt diet.
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