Effect of losartan on angiotensin II-mediated endothelin and prostanoid excretion in humans.
Angiotensin II (Ang II) stimulates renal prostanoid and vascular endothelin-1 (ET-1) release. Most known Ang II effects are mediated by AT1 receptors. Our aim was to determine whether AT1 receptor activation mediates Ang II-evoked renal prostanoid and ET-1 release. Eleven healthy men were randomized in a crossover, double-blind fashion to receive 100 mg/day of losartan or matching placebo, for 8 days. Blood and urine were sampled before and after a 2-h infusion of Ang II at a rate previously determined to increase mean arterial pressure (MAP) by 25 to 30 mm Hg in each subject. After a 14-day washout, subjects received the alternate treatment. Pretreatment with losartan had little effect on baseline MAP, but increased plasma renin activity, and virtually eliminated the pressor response to Ang II infusion. Angiotensin II significantly increased prostanoid excretion after placebo; the prostanoid response to Ang II was even greater after losartan. Plasma ET-1 was not altered by Ang II infusion, with or without losartan. In contrast, urine ET-1 excretion rate decreased to 40% of baseline after Ang II but not after losartan pretreatment; losartan alone had no effect. We conclude that Ang II decreases renal ET-1 synthesis and release through the AT1 receptor. In contrast, Angiotensin II-mediated renal prostanoid synthesis does not require activation of AT1 receptors. These findings indicate that AT1 receptor antagonists could provide renal protection through indirect mechanisms.
Quest
D W
DW
Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada. questd@uke.usask.ca
Gopalakrishnan
V
V
McNeill
J R
JR
Wilson
T W
TW
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000652:urine*; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011453:Prostaglandins / Q000652:urine*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood
D057911:Angiotensin Receptor Antagonists; D019332:Endothelin-1; D010919:Placebos; D011453:Prostaglandins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D012083:Renin; D019808:Losartan