The objectives of our program are (a) to elucidate the mechanisms of regulation of the renal kallikrein-kinin and the arachidonate-prostaglandin systems, (b) to characterize the interactions of kinins and prostaglandins with systems that promote vasoconstriction, antidiuresis, and antinatriuresis, and (c) to define the significance of such interactions to the regulation of vascular and renal functions. The following specific objectives will be addressed. 1. Characterization of the action of vasopressin to increase renal kinins with regard to dose response and temporal relationships, the type of vasopressin receptor that is involved, and the specificity of vasopressin as a stimulus. We will investigate the effect of vasopressin agonistic and antagonistic analogs on various components of the renal kallikrein-kinin system. 2. Examination of relationships between the level of vasopressin and renal kinin excretion during experimental conditions that stimulate vasopressin secretion, and evaluation of the effects of vasopressin antagonists on the renal kallikrein-kinin system. These studies will be conducted in conscious rats with and withouts stimulation of vasopressin secretion by hypovolemia, water deprivation, or by an osmotic stimuli. 3. Investigation of the mechanism whereby vasopressin increases renal kinins: effects of vasopressin on cell-bound kininogenase. 4. Examination of the role of kinins in the action of vasopressin to increase renal prostaglandins. We will compare the action of vasopressin to increase renal prostaglandins in rats with and without pretreatment with an inhibitor of kinin generation. 5. Investigation of the functional significane of the vasopressin-renal kinin interaction. We will study the effects of kallikrein inhibitors on renal function in rats with varying levels of vasopressin. 6. Characterization of the alterations in the renal arachidonate-prostaglandin system which are associated with excess and with deficiency of glucocorticoids. 7. Evaluation of the contribution of prostaglandins to renal function during excess and deficiency of glucocorticoids.
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