Hypotensive Response to Losartan in Normal Rats

Abstract

Abstract We have reported that the angiotensin II (Ang II) AT 1 receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg·kg −1 ·d −1 ) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9±0.4 ng Ang I·mL −1 ·h −1 ) compared with NNa rats (4.0±0.3 ng Ang I·mL −1 ·h −1 ), control arterial pressure was not different between NNa (113±4 mm Hg) and HNa (113±2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (−12±2 mm Hg) but had no effect on arterial pressure in HNa rats (+4±4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (−32±2 mm Hg) but remained unchanged compared with control in HNa rats (+5±6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II, is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema–lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95±3 mm Hg) and APx (96±2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1±1.5 versus APx, 5.3±1.6 ng Ang I·mL −1 ·h −1 ). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80±2 mm Hg) compared with APx (90±3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72±2 mm Hg) was significantly lower than in APx rats (83±4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72±2 mm Hg; APx, 84±2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.