GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II‐mediated pressor responses in Sprague–Dawley rats

Background and purpose: Liver X receptors (LXRs) activate genes that regulate lipid and cholesterol metabolism. LXR agonists were shown recently to also increase murine renin gene expression in vivo . To further examine a link between lipid metabolism, the renin‐angiotensin‐aldosterone‐system and blood pressure regulation, we investigated the effect of a LXR agonist (GW3965) on angiotensin II (Ang II)‐mediated vasoreactivity and vascular angiotensin II receptor (ATR) gene expression. Experimental approach: Arterial blood pressure (BP) was measured during Ang II infusions (1.5 min duration; 0.001–3 μg kg −1 ) in pentobarbital‐anesthetized male Sprague–Dawley rats (n = 6‐9) after oral administration of GW3965 (10 mg kg −1 , q.d.) or vehicle for 7 – 15 days. Mesenteric arteries and plasma were collected to analyze ATR gene expression and to measure plasma renin activity (PRA) and lipid profile, respectively. Key results: Basal mean arterial pressure (MAP) was similar between groups. GW3965 dosing blunted the vasopressor effect of Ang II, which was significantly different with the 0.3 and 3 μg kg −1 doses. No difference in heart rate, PRA or lipid profile was observed between groups. A time‐course indicated that ATR type 1 and 2 gene expression of GW3965‐treated vs. vehicle‐treated rats decreased by 50%, reaching significance for ATR type 2, but not for ATR type 1, at time‐points coinciding with BP measurements. Conclusions and implications: GW3965 decreased Ang II‐mediated vasopressor responses coincident with a trend toward reduced ATR gene expression, suggesting that LXR agonists could affect vascular reactivity. British Journal of Pharmacology (2007) 151 , 450–456; doi: 10.1038/sj.bjp.0707241