Compensatory responses to dehydration include increases in plasma vasopressin (AVP), plasma renin activity (PRA) (and thus angiotensin II) and peripheral vascular resistance. AVP and angiotensin II (AII) are potent vasoconstrictors, and both act in the central nervous system to modulate control of the sympathetic nervous system (SNS). The CNS effects of both are mediated at least in part at the area postrema. AVP acts at the area postrema to augment reflex inhibition of the SNS, while AII exerts sympathoexcitatory effects at the area postrema. The integrated effects of concomitant elevations of both of these peptides at the area postrema is not known. This is especially thus od chronic increases in both AVP and AII, as occurs during dehydration. The proposed studies will address the central concept that the area postrema modulates arterial and cardiopulmonary baroreflexes during dehydration, and thus influences the regulation of the circulation in the dehydrated state. The specific hypotheses which we will test are: 1) the area postrema modulates the reflexly mediated changes in plasma AVP, AII and catecholamines in response to 48 hours of water deprivation; 2) the dehydration-induced increases in AVP and AII modulate arterial and cardiopulmonary baroreflex control of the SNS via an action at the area postrema; and 3) the area postrema modulates reflex compensation to the vasoconstrictor effects of AVP, AII and the SNS during dehydration. The role of the area postrema in neurohumoral responses to dehydration, and in mediating effects of AVP and/or AII on baroreflex function during dehydration, will be evaluated by comparing responses in conscious, area postrema lesioned and sham lesioned animals. Area postrema modulation of the vasoconstrictor effects of AVP, AII and the SNS during dehydration will be evaluated by measuring regional vascular resistance responses to blockade of AVP, AII or the SNS in area postrema lesioned animals. Experiments will examine the effects of direct activation of the area postrema, and effects of microinjection of AVP and/or AII into the area postrema on baroreflex function during dehydration. Little is known about integrative cardiovascular responses to simultaneous elevations in AVP and AII, especially when both are increased chronically. Hypovolemic states, as well as pathophysiologic conditions such as congestive heart failure and certain forms of hypertension are characterized by longterm changes in these neurohumoral factors. Therefore, it is important to obtain a clear understanding of their interactions in regulation of the circulation in order to assess their role in pathophysiological states.
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