The endothelium is a rich source of vasoactive factors which influence organ perfusion (blood flow), organ function, and blood pressure. We hypothesize that under normal conditions, endothelium-derived relaxing factor (EDRF) serves as a buffer against the effects of endogenous vasoconstrictors, especially angiotensin II (AII), or the endothelium- dependent constricting factor (EDCF), endoperoxide/thromboxane. We hypothesize further that under conditions resulting in increased AII, such as during sodium restriction or the development of hypertension, EDRF increases in response to elevated AII and/or increased blood pressure and counteracts vasoconstriction. Since the kidney is rich in AII, its perfusion is particularly influenced by EDRF. We will use a competitive substrate antagonist, NW-nitro-L-arginine (N-Arg), to inhibit EDRF. This will allow us to determine the influence of EDRF on the control of blood pressure and organ perfusion in normotensive rats as well as in various models of hypertension, particularly as it relates to endogenous AII.
In specific aim #1 we hypothesize that the contribution of EDRF to vascular resistance is proportional to the basal blood pressure and/or the level of endogenous vasoconstrictors such as AII. We will examine the effect of blood pressure on the pressor response to N-Arg in normal rats. We will determine the influence of basal blood pressure on the pressor response to EDRF inhibition with N-Arg, whether EDRF increases with blood pressure, and whether inhibition of EDRF increases the pressor response to exogenous vasoconstrictors. We will determine whether chronic L-arginine administration, the substrate for EDRF, alters pressor responses, and whether inhibiting endogenous vasoconstrictors alters the systemic and renal response to N-Arg.
In specific aim #2, we hypothesize that the renal circulation is particularly responsive to EDRF inhibition. To show this, we will compare the response of the renal and mesenteric vasculatures to EDRF inhibition and determine the relative changes in resistance, particularly those influenced by AII.
In specific aim #3 we hypothesize that EDRF is increased in hypertension, particularly in AII-dependent models. We will determine whether EDRF is antihypertensive and buffers against increases in blood pressure, especially in renin-angiotensin dependent models of hypertension. We will determine whether systemic pressor and renal responses to EDRF inhibition are greater in hypertension, and whether this is a function of the dependence of different models of hypertension on AII. We will also examine whether chronic EDRF inhibition accelerates the onset of hypertension, and whether supplemental L-arginine administration retards its onset.
In specific aim #4 we will study whether agents which transiently decrease renal function, such as diagnostic contrast materials, act by poisoning endothelial cells and consequently inhibiting EDRF production. We will examine whether contrast agents added directly to isolated vessels, or given to rats decreases endothelium- dependent vasodilation or renal function. The results of these studies will help us understand how the endothelium regulates blood pressure and modulates renal perfusion and function, particularly in opposition to constrictor influences such as AII and EDCF.
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