VASOPRESSIN IN PATHOGENESIS OF DOCA/SALT HYPERTENSION

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Increasing evidence suggests that vasopressin (VP) may play a role in the development of DOCA/salt hypertension. Of great importance is the finding that VP-deficient Brattleboro rats (DI rats) fail to develop hypertension with DOCA/salt treatment but do so when replaced with VP. Little is known of the mechanism of action of VP in hypertension. The present research plan proposes to identify the mechanism(s) of action of VP in DOCA/salt hypertension. VP may function as a direct vasoconstrictor/pressor agent. We will study the direct vasoconstrictor/pressor effect of VP in light concomitent activity of the sympathetic nervous system and the baroreceptor reflex. Vascular reactivity to VP will be assessed in the unanesthetized DOCA/salt treated rats instrumented with chronic catheters and pulsed-Doppler flow probes at various stages of hypertension before and after blockade of the sympathetic nervous system or sinoaortic deafferentation. VP may act as an antidiuretic agent. This will be tested by assessing changes in body fluid volumes, renal function and water and electrolyte metabolism over the course of development of hypertension. VP may act indirectly to modulate the responsiveness of vascular smooth muscle to other vasoconstrictors particularly catecholamines. This will be tested by assessing vascular reactivity in isolated, perfused vascular beds. Finally, VP may modulate the function of central neural target areas controlling the baroreflex and sympathetic outflow. This will be tested by 1) determining the interaction of VP with the locus coeruleus, nucleus tractus solitarii, and posterior hypothalamus using microinjection, push-pull perfusion and brain punch techniques 2) determining the effects of stimulation of the paraventricular and supraoptic nuclei on the baroreflex function. 3) determining the interaction of VP with central catecholaminergic neurons. The results of these experiments should provide fundamental information on the role of VP in normal cardiovascular regulation as well as in the pathogenesis of hypertension.