The focus of this proposal is to evaluate the mechanisms by which the L- arginine analogues and nitric oxide alter basal and pressure-dependent renin release in the rat. Original studies conducted in this laboratory recently identified the two analogues N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) as powerful inhibitors of renin release; furthermore, infusion of a nitric oxide donor, sodium nitroprusside, reversed the renin-suppressing effect of L-NAME. These arginine analogues are specific competitive inhibitors of nitric oxide synthase and block the generation of endogenous vasodilator nitric oxide to elevate arterial pressure. Subsequent studies demonstrated that L- NAME administered to normal rats completely blocked pressure-dependent control of renin release in the high pressure domain, but not in the low pressure domain. Rats treated with L-NAME for four days develop sustained arterial hypertension and their basal plasma renin levels are completely reset to normal values. Preliminary findings in this new model of hypertension suggest that the intrarenal baroreceptor mechanism for renin release provides an exaggerated response when renal perfusion pressure is reduced by means of an adjustable clamp placed on the suprarenal aorta. Based on these experimental observations, we hypothesize that: 1) nitric oxide formation normally opposes the inhibitory influence of the intrarenal baroreceptor mechanism in the high pressure domain; 2) analogues of L-arginine suppress basal release of renin in normal animals by interrupting this tonic stimulatory influence of nitric oxide, thereby allowing inhibitory input from the baroreceptor to dominate release of renin; 3) chronic blockade of nitric oxide synthesis is associated with functional resetting and increased sensitivity of the renal baroreceptor mechanism for renin release in the high pressure domain.
The specific aims are: 1) to determine and compare the pressure-response curves for plasma renin activity (PRA) during reductions of renal perfusion pressure in a) normal rats given L-NAME acutely and b) hypertensive rats given L-NAME for 4 days; 2) to determine and compare dose-response curves for PRA to infusion of sodium nitroprusside or the vasodilator papaverine in a) normal rats given L- NAME acutely and b) hypertensive rats given L-NAME for 4 days, and 3) to determine the pressure-response curve for PRA during reduction of renal perfusion pressure in normal rats given L-NAME acutely and receiving low dose infusions of the nitric oxide donor sodium nitroprusside.
