The overall goal of this project is to achieve an understanding of the relationship between nitric oxide (NO) release from endothelial NO synthase (eNOS), the circulating levels of angiotensin II (Angll), and the regulation of arterial blood pressure. This goal will be addressed by combining newly developed methodology to measure fluid and electrolyte homeostasis and blood pressure in conscious mice with a variety of unique cellular, molecular, and physiological techniques. We will test the hypothesis that NO produced from eNOS in endothelial cells is the primary buffering mechanism against the prohypertensive actions of Angll. As a corollary to this primary hypothesis, we further theorize that selective inhibition, or elimination, of NO production in endothelial cells will lead to hypertension that is independent of NaCI intake while inhibition of NOS in renal tubular structures will lead to sodium-sensitive hypertension.
Aim 1 will utilize unique cellular and molecular techniques to characterize the distribution of NOS isoforms and NOS enzymatic activity in microdissected renal tubular and vascular segments of wild-type (WT) and eNOS null mutant (-/-) mice and to determine the changes in NOS expression in these segments during alterations in circulating Angll and/or sodium chloride intake.
Aim 2 will employ novel techniques to perform in vivo microdialysis in anesthetized mice and sample arterial blood from conscious mice to characterize the interaction between circulating Angll, dietary sodium intake, and renal NO production in WT and eNOS(-/-)mice.
Aim 3 will determine the functional effects of changes in circulating Angll and/or dietary sodium intake in WT and eNOS(-/-) mice using methodology which permits long-term monitoring of cardiovascular/renal variables in conscious mice. Together, this novel combination of experimental methods will be used to determine the important role of NO derived from eNOS in the modulation of the vasoconstrictor and prohypertensive effects of Angll in the conscious mouse. Results of these studies in conscious mice should provide new understanding of the role of eNOS-derived NO in the control of renal function and arterial blood pressure. Moreover, the results of these studies may also provide important insight into the causes of hypertension and hypertension-related complications that are a leading cause of death and morbidity in the US.
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