The lont-term objectives of this research are to define the roles of the cirvumventricular organs (CVOs) in the neural and hormonal control of the circulation. The CVOs are brain sites wherein circulating, hypertension-related peptides can influences the brain without the restriction of the blood-brain barrier. In the rat, two of these roles (organum vasculosum of the lamina terminalis [OVLT] and subfornical organ [SFO] have beem implicated in the centrally-mediated component of the cardiovascular responses to antiotensin II (AII); other evidence suggests that they have roles in high-rehin models of hypertension. This proposal will examine the roles of these two CVOs in the control of cardiac output, total peripheral resistance, regional blood flow, and vasopressin secretion. Using miniaturized pulsed Doppler flow probes, experiments proposed herein will examine whether electrical stimulation of SFO or OVLT in anesthetized or conscious rats will produce changes in cardiac output, arterial pressure, or total peripheral resistance. The functional vasoconstrictor pathways activated by electrical stimulation of OVLT or SFO will be examined using knife-cuts of the patyways and electrolytic lesions of efferent relay acetycholine, serotonin, or vasopressin (AVP) will be determined. Effects of electrical stimulation of SFO or OVLT on AVP secretion will be examined in normal and sinoaortic baroreceptor-denervated rats. Finally, the effects of two neurotoxins which block AII effects and prevent experimental hypertensions will be examined. This will be done by in vivo analysis of the neurotoxins' effects on peptide bindings to the CVOs. The proposed experiments will provide specific knowledge of the roles of two angiotensin-sensitive CVOs in the control of arterial pressure, cardiac output, total peripheral resistances, regional blood flow, and AVP secretion. Insight into the basic mechanisms anti-angiotensin, antihypertnesive action of two neurotoxins will be gained. Since these blood-brain barrier-free CVOs may be involved in experimental hypertensions, the proposed research will provide valuable information on possible mechanisms by which they could influence the operation of the cardiovascular system in hypertensive, as well as in normotensive, states.
