The aim of the current proposal is to continue our investigation on nitric oxide, NO, in control of normal kidney function and vascular tone. We will use a range of NO synthesis inhibitors and agonists to define regional differences in NO activity in the vasculature and the role of various NO synthases in control of BP and renal function. We will investigate the susceptibility of the kidney to the vasodilatory actions of administered L-arginine and the relationship between BP and tone in the renal vasculature. We will continue our investigations into interactions between NO and other vasoactive control systems, specifically studying the role of the sympathetic nervous system/renal nerves in NO blockade induced hypertension and renal vasoconstriction; the relationship between NO and angiotensin II, NO and endothelin and NO and the eicosinoids in control of renal vascular tone and mesangial cell growth and matrix production. We will also continue our investigations into the relationship between surgery/anesthesia and the NO system; specifically we will determine the mechanism by which prior surgery protects against the lethal effects of acute NO blockade in anesthetized animals and the mechanism(s) by which surgery/anesthesia increase NO/cGMP. We will conduct extensive further studies on the chronic NO blockade model of systemic and glomerular hypertension with reference to the role of the SNS and the possible activation of an inducible NO synthase during partial NO blockade. We will also investigate the role of NO during the development of hypertension in the SHR, DOCA/salt, Dahl salt sensitive and 5/6th ablation models of hypertension. Finally, we will investigate the role of NO in control of short and long term sodium balance, with particular reference to NO derived from inducible NO synthase. We will employ a range of techniques including the conscious chronically catheterized rat and the glomerular micropuncture preparation; measurement of proliferation and collagen matrix production in cultured rat glomerular mesangial cells; isolated rat glomerulus and vascular segments, cultured under cell culture conditions to assess NO production; Northern blot analysis, in situ hybridization (possibly RT-PCR) to assess mRNA levels of the NO synthases and arginine biosynthetic enzymes.
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