Losartan inhibition of angiotensin-related drinking and Fos immunoreactivity in hypertensive and hypotensive contexts

We assessed the ability of acute peripheral administration of the AT-1 receptor antagonist, losartan, to reverse both the water intake and Fos-immunoreactivity (Fos-ir) induced in rats by either peripheral or cerebroventricular (i.c.v.) administration of angiotensin (Ang) II. We compared this with endogenous generation of Ang II during either hypovolemia or hypotension. Relatively low doses of losartan blocked the dipsogenic effect of peripherally administered exogenous Ang II, but a higher dose (20 mg/kg) was needed to block the dipsogenic effect of i.c.v.-administered Ang II. Fos-ir induced by i.c.v. Ang II was attenuated in SFO and SON by 10-20 mg losartan/kg given peripherally, but Fos-ir in the MnPO and PVN was unaffected. These findings suggest that losartan has limited permeability into the brain. We used peripheral losartan to assess the contribution of Ang II to water intake and Fos-ir responses to peripheral injection of either polyethylene glycol (PEG; a colloid that produces non-hypotensive hypovolemia) or isoproterenol (hypotensive agent). Water intakes were unaffected by the higher dose of losartan given s.c. Intraperitoneal injection of EXP 3174, the active metabolite of losartan that may more readily penetrate the blood-brain barrier, inhibited isoproterenol-, but not PEG-induced water intakes. Fos-ir was induced by PEG and isoproterenol in several regions of the brain also activated by Ang II. Fos-ir was greatly attenuated in the SFO by losartan following administration of PEG, but not isoproterenol, and was either unaffected or increased in SON and PVN after either agent. These data suggest that the increased circulating Ang II following PEG or isoproterenol acts at the SFO and is more readily reversible by losartan in normotensive (PEG) than in hypotensive (isoproterenol) states. Non-Ang neural input to the SON and PVN, presumably from baroreceptors, appears to be sufficient to produce strong Fos-ir in these regions, as well as to engage drinking.