The overall goal of the proposed studies is to define the physiological relationship between salt loading and endothelin (ET)-1 actions in the kidney in an effort to elucidate the mechanisms of salt-dependent hypertension. The general hypothesis being addressed is that ET-1 is important for promoting sodium excretion, particularly in hypertension produced by high salt intake. Specific mechanisms by which ET-1 influences kidney function under these conditions as well as factors that modulate ET-1 production during high salt intake will be addressed.
The specific aims are: ET-1 increases medullary blood flow during salt loading ET-1 participates in pressure natriuresis via ETB receptor activation. TGFbeta and ET-1 in the renal medullar during chronic salt loading.
The first aim will elucidate the mechanism for how ET-1 stimulates sodium excretion in normotensive rats given high salt and rats made hypertensive by DOCA-salt treatment. It is predicted that specific ETB receptor blockade will prevent increases in medullary blood flow associated with DOCA-salt treatment and thus exacerbate the associated hypertension.
The second aim will answer the question of whether ET-1 also enhances sodium excretion through its effects on renal perfusion pressure. The relationship between sodium excretion and acute changes in arterial pressure before and after treatment with an ETB receptor antagonist will be determined.
The third aim will address the possibility that shear stress with in the renal tubular system during salt loading triggers release of TGFbeta which in turn stimulates ET-1 production. The results of these studies will provide specific information regarding the role of the ET system in salt-dependent forms of hypertension and could lead to the development of new therapeutic strategies or a better rationale for treating patients with salt-dependent hypertension.
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