Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II

Abstract

.-The present study examined the effects of ANG II on the renal synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and its contribution to the renal vasoconstrictor and the acute and chronic pressor effects of ANG II in rats. ANG II (10 Ϫ11 to 10 Ϫ7 mol/l) reduced the diameter of renal interlobular arteries treated with inhibitors of nitric oxide synthase and cyclooxygenase, lipoxygenase, and epoxygenase by 81 Ϯ 8%. Subsequent blockade of the synthesis of 20-HETE with 17-octadecynoic acid (1 mol/l) increased the ED 50 for ANG II-induced constriction by a factor of 15 and diminished the maximal response by 61%. Graded intravenous 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) attenuated the pressor response to ANG II by 40%. An intravenous infusion of ANG II (50 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in rats for 5 days increased the formation of 20-HETE and epoxyeicosatrienoic acids (EETs) in renal cortical microsomes by 60 and 400%, respectively, and increased MAP by 78 mmHg. Chronic blockade of the synthesis of 20-HETE with intravenous infusion of DDMS (1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or EETs and 20-HETE with 1-aminobenzotriazole (ABT; 2.2 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) attenuated the ANG II-induced rise in MAP by 40%. Control urinary excretion of 20-HETE averaged 350 Ϯ 23 ng/day and increased to 1,020 Ϯ 105 ng/day in rats infused with ANG II (50 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) for 5 days. In contrast, urinary excretion of 20-HETE only rose to 400 Ϯ 40 and 600 Ϯ 25 ng/day in rats chronically treated with ANG II and ABT or DDMS respectively. These results suggest that acute and chronic elevations in circulating ANG II levels increase 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.cytochrome P-450; epoxyeicosatrienoic acids; hypertension; kidney PREVIOUS STUDIES INDICATE that ANG II enhances the activity of phospholipases to release arachidonic acid (AA) (39,42,43) and stimulates the formation of cyclooxygenase (15,27,28,37,38,40,41) and lipoxygenase metabolites of AA (5, 40, 48) in various tissues. These products modulate the vasoconstrictor response to ANG II in both the renal and peripheral circulation (27,30). In this regard, ANG II normally stimulates the formation of prostacyclin, which attenuates the vasoconstrictor response to ANG II (12,28,30,32,37,38,40). ANG II also promotes the formation of 12-hydroxyeicosatetraenoic acid (12-HETE), which potentiates the rise in intracellular calcium concentration and the vasoconstrictor and mitogenic response to ANG II in vascular smooth muscle (VSM) cells (5,16,31,48,53). In hypertensive animals, the balance between the formation of vasodilator and vasoconstrictor metabolites of AA shifts toward the formation of vasoconstrictor metabolites, i.e., thromboxane A 2 and endoperoxides, and these products potentiate the vasoconst...

CytochromeP-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

“…For example, ANG II and endothelin stimulate the renal formation of 20-HETE, which contributes to the renal vasoconstrictor and natriuretic actions of these hormones (11,12,35). The expression of CYP4A enzymes and the formation of 20-HETE are also elevated in the kidney of ANG II-infused hypertensive rats (1), and 20-HETE contributes to the development of hypertension and end-organ damage in this model (1,27,28). Vasopressin is another vasoconstrictor peptide that activates phospholipase A2 and releases AA (31).…”

“…Recent studies have indicated that CYP metabolites of AA play an important role as second messengers in the regulation of the tubular and vascular effects of peptide hormones and growth factors (1,3,37,40). For example, ANG II and endothelin stimulate the renal formation of 20-HETE, which contributes to the renal vasoconstrictor and natriuretic actions of these hormones (11,12,35).…”

“…Inhibition of the synthesis of 20-HETE attenuates the vasoconstrictor response of renal arterioles to elevations in transmural pressure in vitro (16, 18) and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo (8,48). At the level of the renal tubules, 20-HETE inhibits sodium reabsorption in the proximal tubule and thick ascending limb of the loop of Henle (6,32,34,39).Previous studies indicated that the renal production of EETs and/or 20-HETE is altered in diabetes and in genetic and experimental models of hypertension (1,7,21,24,25,28,41). The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3).…”

“…Previous studies indicated that the renal production of EETs and/or 20-HETE is altered in diabetes and in genetic and experimental models of hypertension (1,7,21,24,25,28,41). The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3).…”

“…The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3). There is considerable evidence that 20-HETE contributes to the vasoconstrictor responses to these hormones by modulating potassium channel activity and calcium influx (1). Arginine vasopressin (AVP), similar to ANG II and endothelin, is also a potent vasoconstrictor that activates phospholipase A2 and releases AA (10,31).…”