Cytochrome P450‐Dependent Metabolites Of Arachidonic Acid And Renal Function In The Rat

Ao, Oyekan

doi:10.1046/j.1440-1681.2000.03313.x

Cited by 8 publications

(8 citation statements)

References 29 publications

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“…Indeed, previous studies have indicated that CYP inhibitors attenuate renal response to vasoconstrictors (4,11) and that blockade of the CYP system with DBDD increases renal blood flow and GFR (36). Alternatively, C H20 could increase in BB rats in the absence of vasopressin, if the permeability of the medullary collecting duct to water was further reduced.…”

Section: Discussionmentioning

confidence: 99%

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

Sarkis¹,

Ito²,

Mori³

et al. 2005

American Journal of Physiology-Renal Physiology

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. Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus. Am J Physiol Renal Physiol 289: F1333-F1340, 2005. First published July 12, 2005 doi:10.1152/ajprenal.00188.2005.-This study compared the renal metabolism of arachidonic acid in Brattleboro (BB) (vasopressin deficient) and Long-Evans (LE) control rats and the effects of a cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) on renal function in these animals. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer medullary microsomes was significantly greater in BB than in LE rats (155 Ϯ 16 vs. 92 Ϯ 13 and 59 Ϯ 7 vs. 33 Ϯ 3 pmol ⅐ min Ϫ1 ⅐ mg protein Ϫ1 ). Renal cortical epoxygenase activity was not different in these strains. The expression of CYP4A proteins was 58 and 78% higher in the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with a vasopressin type 2 receptor agonist for 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect on renal function in LE rats. However, urine flow increased by 54% and urine osmolarity decreased by 33% in BB rats treated with ABT. Plasma levels of oxytocin fell significantly from 7.2 Ϯ 1.3 to 3.9 Ϯ 1.0 pg/ml. The effects of ABT in BB rats were attenuated by chronic infusion of oxytocin (0.7 ng ⅐ min Ϫ1 ⅐ 100 g Ϫ1 ) to maintain fixed high plasma levels of this hormone. These results indicate that the expression of CYP4A protein and the renal formation of 20-HETE are elevated in the kidney of BB rats due to a lack of vasopressin and that chronic blockade of the formation of 20-HETE and EETs with ABT promotes water excretion in vasopressin-deficient BB rats by reducing the circulating levels of oxytocin, which is a weak vasopressin agonist. Brattleboro rats; 20-hydroxyeicosatetraenoic acid; cytochrome P-450; epoxyeicosatrienoic acid; renal hemodynamics ARACHIDONIC ACID (AA) is metabolized by cytochrome P-450 (CYP) enzymes in the kidney to produce epoxyeicosatrienoic acids (EETs), 20-hydroxyeicosatetraenoic acid (20-HETE), and dihydroxyeicosatrienoic acids (DiHETEs). These compounds have been reported to play an important role in the control of both renal tubular and vascular function (26). EETs are potent endothelial-derived vasodilators in the renal circulation (17, 47). They also inhibit sodium and water reabsorption in the collecting duct (40). In contrast, 20-HETE is produced by vascular smooth muscle cells and is a potent constrictor of renal arterioles (5,19,23). 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 an...

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Section: Discussionmentioning

confidence: 99%

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

Sarkis¹,

Ito²,

Mori³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…Again, no changes in RBF were observed when MI or MS‐PPOH were administered alone. These results are in agreement with in vivo findings by Oyekan 17 in the anaesthetized rat. As with 17‐ODYA, the renal vasodilation induced by indomethacin was fully prevented by pretreatment with MI or MS‐PPOH.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Furthermore, the two CYP450 pathways were inhibited separately. To do so, the synthesis of epoxides was blocked selectively with miconazole (MI) or N -methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), [15][16][17][18] whereas the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) was inhibited with N Ј -hydroxyphenylformamidine (HET0016), a new and highly selective 20-HETE synthase inhibitor. [19][20][21][22]…”

Section: Introductionmentioning

confidence: 99%

Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid‐dependent epoxygenases^‡

Caron

Hassani

Declèves

et al. 2004

Clin Exp Pharma Physio

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A significant renal vasodilation was observed previously after an acute cyclo-oxygenase (COX) inhibition induced with indomethacin. Because this effect could be due to COX-dependent intrarenal metabolization of arachidonic acid through cytochrome P450 (CYP450) pathways, the aim of the present study was to investigate, in vivo, possible interactions between COX and CYP450 mono-oxygenases. Mean arterial pressure (MAP) and renal blood flow (RBF), using an electromagnetic flow transducer for RBF evaluation, were measured continuously in 71 anaesthetized euvolaemic rats. Appropriate solvents (vehicle), 3 mg/kg indomethacin, 17-octadecynoic acid (17-ODYA; 2 mmol/L), either miconazole (MI; 1.5 mmol/L) or N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 5 mg/kg) and N'-hydroxyphenylformamidine (HET0016; 5 or 10 mg/kg) were administered to inhibit either COX, CYP450 mono-oxygenases, epoxygenases or hydroxylase, respectively. The CYP450 and COX inhibitors were also combined as follows: 17-ODYA/indomethacin, MI (or MS-PPOH)/indomethacin, HET0016/indomethacin and indomethacin/HET0016. Mean arterial pressure and RBF were not modified by vehicle, 17-ODYA or MI (or MS-PPOH). However, MAP decreased slightly (P < 0.05; paired t-test, 5 d.f.) and RBF increased transiently (P < 0.05; anova, 5 d.f.) after HET0016. In contrast, MAP decreased by 10 mmHg (P < 0.05) and RBF increased by 10% (P < 0.05) after indomethacin. This enhancement was prevented by 17-ODYA or MI (or MS-PPOH), but not by HET0016. Moreover, RBF increased step-wise to 21% in the indomethacin/HET0016 experiment (P < 0.05). Consequently, changes from baseline in renal vascular resistance differed among treatments, averaging -2 +/- 3 (vehicle), -13 +/- 3 (indomethacin; P < 0.05 vs vehicle), -4 +/- 3 (17-ODYA/indomethacin), -3 +/- 4 (MI or MS-PPOH/indomethacin), -15 +/- 3 (HET0016/indomethacin; P < 0.05) and -22 +/- 4% (indomethacin/HET0016; P < 0.05). In conclusion, these results demonstrate that the renal vasodilation induced by indomethacin can be prevented by prior inhibition of CYP450 mono-oxygenases and further suggest that the CYP450 epoxygenases pathway may prevail.

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“…20-HETE plays a significant role in the myogenic response of renal, cerebral, mesenteric, and skeletal muscle arterioles to elevations in transmural pressure (131,140,156,195,197,202,225,478) and autoregulation of renal and cerebral blood flow in rats in vivo (140,349,527). Some of the evidence supporting this view is presented in Figure 10.…”

Section: E Myogenic Responsementioning

confidence: 99%

P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

Roman

2002

Physiological Reviews

1,248

1,485

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Recent studies have indicated that arachidonic acid is primarily metabolized by cytochrome P-450 (CYP) enzymes in the brain, lung, kidney, and peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) and that these compounds play critical roles in the regulation of renal, pulmonary, and cardiac function and vascular tone. EETs are endothelium-derived vasodilators that hyperpolarize vascular smooth muscle (VSM) cells by activating K(+) channels. 20-HETE is a vasoconstrictor produced in VSM cells that reduces the open-state probability of Ca(2+)-activated K(+) channels. Inhibitors of the formation of 20-HETE block the myogenic response of renal, cerebral, and skeletal muscle arterioles in vitro and autoregulation of renal and cerebral blood flow in vivo. They also block tubuloglomerular feedback responses in vivo and the vasoconstrictor response to elevations in tissue PO(2) both in vivo and in vitro. The formation of 20-HETE in VSM is stimulated by angiotensin II and endothelin and is inhibited by nitric oxide (NO) and carbon monoxide (CO). Blockade of the formation of 20-HETE attenuates the vascular responses to angiotensin II, endothelin, norepinephrine, NO, and CO. In the kidney, EETs and 20-HETE are produced in the proximal tubule and the thick ascending loop of Henle. They regulate Na(+) transport in these nephron segments. 20-HETE also contributes to the mitogenic effects of a variety of growth factors in VSM, renal epithelial, and mesangial cells. The production of EETs and 20-HETE is altered in experimental and genetic models of hypertension, diabetes, uremia, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of this pathway in the control of cardiovascular function, it is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits.

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Cytochrome P450‐Dependent Metabolites Of Arachidonic Acid And Renal Function In The Rat

Cited by 8 publications

References 29 publications

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

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

Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid‐dependent epoxygenases^‡

P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

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Cytochrome P450‐Dependent Metabolites Of Arachidonic Acid And Renal Function In The Rat

Cited by 8 publications

References 29 publications

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

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

Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid‐dependent epoxygenases‡

P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

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Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid‐dependent epoxygenases^‡