The proposed studies will evaluate the control of vasopressin and ACTH secretion using a well-established conscious canine model. The first project will evaluate the hypothesis that neurohypophyseal vasopressin is important in the generation of an ACTH response to those stimuli which activate neurohypophyseal vasopressin secretion into the short portal and systemic circulations. Insulin hypoglycemia without or with concomitant mild nitroprusside hypotension, which differentially activate vasopressin secretion, will be performed before and several weeks after neurohypophysectomy. In addition, intrasellar and intracarotid vasopressin infusion will determine if the effect is exerted directly at the pituitary. Finally, intravenous vasopressin infusion before and after superdiaphragmatic vagotomy will determine if vasopressin normalizes ACTH secretion in neurohypophysectomized dogs via a peripheral, possible visceral, effect. The second project will evaluate the possibility that ACTH infusion augments the subsequent ACTH response to hypertonic_ saline by increasing circulating adrenal steroids or via a non-adrenal effect. Non-glucocorticoid (aldosterone) will be evaluated as will the effect of ACTH Infusion on subsequent ACTH secretion in adrenalectomized, steroid-replaced dogs. The third project will determine if long term (7 day) physiological infusions of cortisol is effective as an inhibitor of the vasopressin response to hypertonic saline. The fourth project will determine if intravenous CRF infusion increases vasopressin secretion via a central, circulatory, or visceral effect by studying dogs after the administration of CRF antagonist into the third ventricle, after low pressure baroreceptor denervation, or after superdiaphragmatic vagotomy, respectively. It is clear that there are multiple interactions between the vasopressin and CRF-ACTH-adrenocortical control systems. These include (1) the involvement of neurohypophyseal vasopressin in ACTH secretion, (2) the negative feedback effects of adrenal steroids on vasopressin secretion, and (3) the putative role of circulatory and/or central CRF in the control of vasopressin secretion. These interactions can only be fully appreciated in terms of human health and disease if they are evaluated in a well-defined conscious animal model which allows invasive and non- invasive open and closed-loop techniques.
| Papanek, P E; Bovee, K C; Skelton, M M et al. (1993) Chronic pressure-natriuresis relationship in dogs with inherited essential hypertension. Am J Hypertens 6:960-7 |
