The working hypothesis of this proposal is that neuropeptide Y (NPY) and the cholinergic system of the posterior hypothalamic nucleus (PHN) plays a role in the regulation of the cardiovascular system by affecting autonomic nervous and endocrine systems. The intent of this project is to elucidate, through the completion of its specific aims, the mechanism by which NPY and the cholinergic systems of the PHN affect the cardiovascular system in the conscious rat. The goal of Specific Aim 1 is to determine the contribution of the autonomic nervous system to the cardiovascular changes elicited by posterior hypothalamic administration of NPY or carbachol (CCH). To determine if changes in heart rate and blood pressure following administration of NPY or CCH into the PHN are due to alterations in sympathetic and/or parasympathetic nerve activity, the effect of pretreatment of animals with propranolol, prazosin, and/or methylatropine on the NPY- and CCH-induced changes in the cardiovascular system will be evaluated. The animals used in these experiments will be instrumented so that cardiac output can be simultaneously measured in order to determine the effect of sympathetic and/or parasympathetic activity on cardiac output, stroke volume and total peripheral resistance. The goal of Specific Aim 2 is to determine the contribution of the adrenal medulla to the cardiovascular changes induced by NPY or CCH. This will be determined by use of guanethidine (to deplete norepinephrine from the sympathetic nerve terminals) and adrenal demedullation (to remove epinephrine). The goal of Specific Aim 3 is to determine the effect of injection of NPY or CCH into the PHN on the sensitivity of the baroreceptor reflex, and to determine the role of plasma vasopressin (AVP) in the observed changes in baroreflex sensitivity. This will be done by correlating changes and heart rates to rapid changes in blood pressure induced by a vasoconstrictor (phenylephrine) and a vasodilator (nitroprusside) before and during the pressor response to NPY or CCH. The role of AVP will be assessed by the use of a selective V-1 AVP receptor antagonist. The goal of Specific Aim 4 is to determine the effect of the baroreceptor reflex on the pressor response induced by NPY or CCH. This will be done by sinoaortic denervation of animals prior to NPY or CCH. The goal of Specific Aim 5 is to determine the plasma levels of catecholamines and AVP prior to and during the pressor response to NPY or CCH. This will be done using HPLC-EC to measure the catecholamines and radioimmunoassay to measure AVP. The results of these studies will increase our understanding of the mechanisms by which central NPY and cholinergic systems affect the cardiovascular system and provide evidence for a possible role of central NPY in regulation of the cardiovascular system. This understanding is necessary for future studies on neuronal pathways involved and the possible role of NPY on cholinergic neuronal systems in the development and/or maintenance of essential hypertension.
