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Articles in PresS, published online ahead of print March 7, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00664.2001
Submitted on November 7, 2001
Accepted on February 26, 2002
1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: magdalena_alonsogalicia{at}merck.com.
The present study examined the effects of angiotensin II (Ang II) on the renal synthesis of 20-HETE and its contribution to the renal vasoconstrictor and the acute and chronic pressor effects of Ang II in rats. Ang II (10-11 to 10-7 mol/L) reduced the diameter of renal interlobular arteries treated with inhibitors of nitric oxide synthase and cyclooxygenase, lipoxygenase and epoxygenase by 81 ± 8%. Subsequent blockade of the synthesis of 20-HETE with 17-octadecynoic acid (17-ODYA, 1 µmol/l) increased the ED50 for Ang II-induced constriction by a factor of 15, and diminished the maximal response by 61%. Graded IV infusion of Ang II (5-200 ng/min) dose-dependently increased mean arterial pressure (MAP) in thiobutylbarbitol anesthetized rats by 35 mmHg. Acute blockade of the formation of 20-HETE with dibromododecenyl methylsulfimide (DDMS, 10 mg.kg-1) attenuated the pressor response to Ang II by 40%. An IV infusion of Ang II (50 ng.kg-1.min-1) in rats for five days increased the formation of 20-HETE and EETs in renal cortical microsomes by 60 and 400%, respectively, and increased MAP by 78 mm Hg. Chronic blockade of the synthesis of 20-HETE with intravenous infusion of DDMS (1 mg.kg-1.hr-1) or EETs and 20-HETE with 1-aminobenzotriazole (ABT, 2.2 mg.kg-1.hr-1) attenuated the Ang II-induced rise in MAP by 40%. Control urinary excretion of 20-HETE averaged 350 ± 23 ng/day and increased to 1020 ± 105 ng/day in rats infused with Ang II (50 ng.kg-1.min-1) for 5 days. In contrast, urinary excretion of 20-HETE only rose to 400 ± 40 and 600 ± 25 ng/day in rats chronically treated with Ang II and ABT or DDMS. These results suggest that acute and chronic elevations in circulating Ang II levels increases the formation of 20-HETE in the kidney and peripheral vasculature and that 20-HETE contributes to the acute and chronic pressor effects of Ang II.
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