Effects of the glucocorticoid II receptor antagonist mifepristone on hypertension in the obese Zucker rat.
We have investigated the possible involvement of endogenous corticosteroids in the maintenance of hypertension in aged lean and obese Zucker rats using the type II corticosteroid antagonist mifepristone. At 8 mo of age, the start of the study, obese Zuckers had been hypertensive for at least 2 mo (systolic blood pressure; 153 +/- 4 vs. 136 +/- 5 mmHg; n = 8-9; P < .05) and were hyperinsulinemic (756 +/- 98 vs. 193 +/- 61 microU x ml(-1)) and hypercorticosteronemic (524 +/- 83 vs. 260 +/- 97 ng x ml(-1)) compared to their lean littermates. There were no differences in plasma renin activity between lean and obese animals and plasma renin activity was unaffected by any treatment. Oral treatment of obese rats with mifepristone (40.0 mg x kg(-1) day(-1) for 9 days) resulted in a gradual reduction in SBP to lean levels by day 9. Mifepristone treatment did not affect plasma insulin or corticosterone levels but resulted in a significant reduction in plasma aldosterone concentration. Mifepristone was without significant effect on systolic blood pressure in lean rats. Oral treatment of lean rats with corticosterone-21-acetate (3.0 mg x kg(-1) day(-1) for 9 days) resulted in a rise in systolic blood pressure to levels similar to obese Zuckers after 9 days. Plasma insulin levels were unchanged but corticosterone immunoreactivity was significantly reduced. Plasma aldosterone levels were increased from 564 +/- 3 to 802 +/- 68 pg x ml(-1). Our data suggest that raised glucocorticoids and aldosterone may be factors contributing to hypertension in obesity.
Clapham
J C
JC
Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, U.K.
Turner
N C
NC
D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D009765:Obesity / Q000150:complications*; D051381:Rats; D011924:Rats, Zucker; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*
D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000450:Aldosterone; C029939:corticosterone acetate; D003345:Corticosterone