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Angiotensin Type 1 Receptors in the Subfornical Organ Mediate the Drinking and Hypothalamic-Pituitary-Adrenal Response to Systemic Isoproterenol

University of Cincinnati, Department of Psychiatry (E.G.K., S.J.M., J.F.D., K.A.S., L.Y.M., A.D.d.K., S.C.B., S.C.W., R.R.S.), Program in Neuroscience (S.J.M., K.A.S., A.D.d.K.), and Genome Research Institute, Cincinnati, Ohio 45237

Address all correspondence and requests for reprints to: Eric G. Krause, Ph.D., University of Cincinnati, GRI-E, Lab 209, 2170 East Galbraith Road, Cincinnati, Ohio 45237. E-mail: krauseeg{at}ucmail.uc.edu.

Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT₁Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT₁Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT₁R [AT₁R antisense (AT₁R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT₁R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT₁R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a β-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT₁R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT₁R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT₁R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.