Impact of Mineralocorticoid Receptor and Angiotensin II Type 1 Receptor Antagonism on Blood Pressure Regulation in Obese Zucker Rats: Role of Sex Differences

Abstract

Abstract Background Previous studies suggest that obesity-induced hypertension in females, but not males, is due to leptin-mediated stimulation of aldosterone secretion and subsequent activation of the mineralocorticoid receptor (MR). Although angiotensin II type 1 receptor (AT1R) antagonism lowers blood pressure (BP) in male obese Zucker rats (OZR), which have defective leptin signaling, the potential role of sex differences in BP responses to renin–angiotensin–aldosterone system blockade, including MR antagonism, in obesity is still unclear. We tested the cardiovascular effects of MR antagonism, alone or in combination with AT1R blockade in male and female OZR (n = 5/sex) and lean Zucker rats (n = 7/sex). Methods BP and heart rate (HR) were measured by telemetry 24 hour/day. After a 6-day control period, spironolactone (40 mg/kg/day) was given for 10 days followed by a 7-day combined treatment with losartan (20 mg/kg/day), and followed by 6-day post-treatment recovery period. Results Compared with lean rats, OZR were hypertensive (mean arterial pressure: 115 ± 4 vs. 104 ± 2 and 111 ± 1 vs. 100 ± 3 mm Hg for males and females) and had lower HR (355 ± 9 vs. 393 ± 7 and 367 ± 10 vs. 412 ± 13 bpm). MR blockade alone did not alter BP or HR in lean or obese male and female Zucker rats, whereas combined treatment reduced BP in obese and lean rats by 31 ± 3 vs. 21 ± 1 and 8 ± 1 vs. 5 ± 1 mm Hg in males and females, respectively. No changes were observed in HR. Conclusions These results suggest that there are important sex differences in BP responses to chronic AT1R blockade but no major involvement of MR activation in BP regulation in OZR.