Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness (original) (raw)
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Role of cytochrome P450 epoxygenase in regulating renal membrane transport and hypertension
Current Opinion in Nephrology and Hypertension, 2013
Purpose of review-CYP-epoxygenase metabolism of arachidonic acid (AA) plays important roles in regulating renal Na transport and afferent arterioles vasoactivity. In the past several years, progress has been made in characterizing the specific CYP-epoxygenases responsible for the regulation of renal Na transport and in exploring the mechanism by which they modulate tubular sodium(Na) transport, preglomerular arteriole blood flow, and blood pressures. This review summarizes and updates recent progress in this area of research. Recent Finding-CYP-epoxygenase metabolites of AA inhibited epithelial Na channel (ENaC) in the cortical collecting duct (CCD) and 11,12-epoxyeicosatrienoic acid (11,12-EET) was mainly responsible for mediating the inhibitory effect on ENaC. Down-regulation of CYP2C44 abolished AA-mediated inhibition of ENaC and increased ENaC activity. Additionally, 11,12-EET stimulated Ca 2+-activated big-conductance K channels (BK) in the CCD and afferent arterioles smooth muscles. Furthermore, in preglomerular arterioles, inhibition of PP2A attenuated the stimulatory effect of 11,12-EET on BK. Summary-CYP-epoxygenase-mediated suppression of renal Na transport is partially achieved by inhibition of ENaC activity in the CCD by CYP2C44 derived EETs. Stimulation of PP2A contributes to the EET-mediated vasodilation and activation of BK channels in preglomerular arterioles.
Hypertension, 2000
Arachidonic acid metabolites contribute to the endothelin-1 (ET-1)-induced decrease in renal blood flow, but the vascular sites of action are unknown. Experiments performed in vitro used the rat juxtamedullary nephron preparation combined with videomicroscopy. The response of afferent arterioles to ET-1 was determined before and after cytochrome P450 (CYP450) or cyclooxygenase (COX) inhibition. Afferent arteriolar diameter averaged 20Ϯ1 m (nϭ17) at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.001 to 10 nmol/L ET-1 caused a graded decrease in diameter of the afferent arteriole. Vessel diameter decreased by 30Ϯ2% and 41Ϯ2% in response to 1 and 10 nmol/L ET-1, respectively. The afferent arteriolar response to ET-1 was significantly attenuated during administration of the CYP450 hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), such that afferent arteriolar diameter decreased by 19Ϯ3% and 22Ϯ3% in response to 1 and 10 nmol/L ET-1, respectively. COX inhibition also greatly attenuated the vasoconstriction elicited by ET-1, whereas the CYP450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl) hexanamide enhanced the ET-1-mediated vascular response. Additional studies were performed using freshly isolated smooth muscle cells prepared from preglomerular microvessels. Renal microvascular smooth muscle cells were loaded with the calcium-sensitive dye fura 2 and studied by use of single-cell fluorescence microscopy. Basal renal microvascular smooth muscle cell [Ca 2ϩ ] i averaged 95Ϯ3 nmol/L (nϭ42). ET-1 (10 nmol/L) increased microvascular smooth muscle cell [Ca 2ϩ ] i to a peak value of 731Ϯ75 nmol/L before stabilizing at 136Ϯ8 nmol/L. Administration of DDMS or the COX inhibitor indomethacin significantly attenuated the renal microvascular smooth muscle cell calcium response to ET-1. These data demonstrate that CYP450 hydroxylase and COX arachidonic acid metabolites contribute importantly to the afferent arteriolar diameter and renal microvascular smooth muscle cell calcium responses elicited by ET-1. (Hypertension. 2000;35[part 2]:307-312.
Actions of epoxygenase metabolites on the preglomerular vasculature
Journal of the American Society of Nephrology, 1996
Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow. This study examined the preglomerular actions of various epoxyeicosatrienoic acids (EET). By use of the in vitro blood-perfused juxtamedullary nephron preparation, interlobular and afferent arteriolar diameter responses to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diameters of interlobular and afferent arterioles preconstricted with 0.5 microM norepinephrine averaged 24 +/- 1 microns (N = 27) and 17 +/- 1 microns (N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diameters of the interlobular and afferent arterioles. At a dose of 100 nM, 11,12-EET increased the diameters of the interlobular and afferent arterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. The vasodilatory response to 11,12-EET was stereoselective because 11,12(R,S)-EE...
Microcirculation, 2001
To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 -hydroxylase would alter the enhanced vasoconstrictor response to elevated PO 2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 -hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O 2 sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6-and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O 2 and 21% O 2 before and after P-450 enzyme inhibition. Results: The P-450 -hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O 2 -induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O 2 -induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O 2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO 2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO 2 in young SHR during the early development of hypertension. Microcirculation (2001) 8, 435-443.
American Journal of Physiology-Heart and Circulatory Physiology, 2000
The present study evaluated the contribution of cytochrome P-450 ω-hydroxylase in modulating the reactivity of cremaster muscle arterioles in normotensive rats on high-salt (HS) and low-salt (LS) diet and in rats with reduced renal mass hypertension (RRM-HT). Changes in arteriolar diameter in response to ACh, sodium nitroprusside (SNP), ANG II, and elevated O2 were measured via television microscopy under control conditions and following cytochrome P-450 ω-hydroxylase inhibition with 17-octadecynoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on either LS or HS diet, resting tone was unaffected and arteriolar reactivity to ACh or SNP was minimally affected by cytochrome P-450 ω-hydroxylase inhibition. In RRM-HT rats, cytochrome P-450 ω-hydroxylase inhibition reduced resting tone and significantly enhanced arteriolar dilation to ACh and SNP. Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and O2 in all the g...
Inhibitors of cytochrome P-450 attenuate the myogenic response of dog renal arcuate arteries
Circulation Research, 1991
The role of cytochrome P-450 in the myogenic response of isolated, perfused renal arcuate arteries of dogs to elevations in transmural pressure was examined. The phospholipase A2 inhibitor oleyloxyethylphosphorylcholine (1 and 10 microM) inhibited the greater than threefold increase in active wall tension in these arteries after an elevation in perfusion pressure from 80 to 160 mm Hg. Inhibition of cyclooxygenase activity with indomethacin (1 or 10 microM) had no effect on this response. The cytochrome P-450 inhibitors ketoconazole (10 and 100 microM) and beta-diethyl-aminoethyldiphenylpropylacetate (SKF 525A, 10 and 100 microM) also inhibited the myogenic response. At a pressure of 160 mm Hg, SKF 525A (10 microM) and ketoconazole (100 microM) reduced active wall tension in renal arteries by approximately 70%. Partial inhibition of the myogenic response was obtained after perfusion of the vessels with mechanism-based inhibitors of P-450, 1-aminobenzotriazole (75 microM) and 12-hydro...
Elevated renovascular tone in young spontaneously hypertensive rats. Role of cytochrome P-450
Hypertension, 1993
The present study examined the role of cytochrome P-450 metabolites of arachidonic acid in elevating renal vascular resistance in young spontaneously hypertensive rats (SHR). Differences in vascular tone were assessed in the preglomerular vasculature of 3-to 4-week-old prehypertensive SHR (n = l l) and normotensive Wistar-Kyoto (WKY, n=10) and Wistar-Lewis (n=10) rats. Pressure-diameter relations to changes in renal perfusion pressure were compared using the juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution. At a pressure of 60 mm Hg, the basal diameters of the interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 43±2, 17±0.3, and 11 ±0.4 /u,m, respectively. The diameters of the interlobular arteries and afferent arterioles were 9% to 14% smaller than those of corresponding vessels in WKY and Wistar-Lewis rats. Addition of P-450 inhibitors, ketoconazole (100 /imol/L) or 7-ethoxyresorufin (1 /imol/L), to the perfusate dilated the afferent arteriole of SHR by 7% to 12%, whereas it increased the diameter by only 0% to 6% in control rats and significantly reduced the differences in the pressure-diameter relation in the preglomerular vasculature of SHR and control rats. Inhibitors of P-450 eliminated the contractile response of afferent arterioles to increases in renal perfusion pressure in all three groups. Removal of calcium from the perfusate eliminated differences in the diameters of the preglomerular vasculature in SHR and normotensive rats. Renal P-450 activities in SHR and normotensive rats were compared by incubating cortical microsomes with [ I4 C] arachidonic acid, and the products were separated by reversed-phase high-performance liquid chromatography. The production of the primary metabolite, 20-hydroxyeicosatetraenoic acid, was significantly greater in SHR than in WKY rats, whereas the production of 11,12-epoxyeicosatrienoic acid was greater in WKY rats than in SHR and Wistar-Lewis rats. These observations indicate that cytochrome P-450 metabolites of arachidonic acid enhance preglomerular vascular tone in juxtamedullary nephrons of young SHR, which may contribute to the resetting of the pressure-natriuretic relation.
Journal of Vascular Research, 2001
This study determined the contribution of prostanoids, cytochrome P450 (CP450) 4A enzyme metabolites of arachidonic acid, and other potential mediators of hypoxic dilation of isolated rat skeletal muscle resistance arteries. Gracilis arteries (GA) were viewed via television microscopy and dilator responses to hypoxia (reduction in superfusate and perfusate PO2 from ∼145 to ∼40 mm Hg) were measured with a video micrometer. Hypoxic dilation of gracilis arteries was severely impaired by either endothelium removal or cyclooxygenase inhibition with indomethacin, but not by nitric oxide synthase inhibition with L-NAME. Treatment of GA with 17-octadecynoic acid (17-ODYA) alone to inhibit CP450 4A enzymes significantly reduced hypoxic dilation from control levels. Treatment of vessels with N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (MS-PPOH) to inhibit the production of epoxyeicosatrienoic acids (EETs) did not alter hypoxic dilation, although treatment with dibromo-dodecenyl-met...
American journal of physiology. Renal physiology, 2014
Cytochrome P-450, family 2, subfamily c, polypeptide 44 (Cyp2c44) epoxygenase metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) in kidney and vascular tissues. In the present study, we used real-time quantitative PCR techniques to examine the effect of high salt or high K(+) (HK) intake on the expression of Cyp2c44, a major Cyp2c epoxygenase in the mouse kidney. We detected Cyp2c44 in the proximal convoluted tubule, thick ascending limb, distal convoluted tubule (DCT)/connecting tubule (CNT), and collecting duct (CD). A high-salt diet increased the expression of Cyp2c44 in the thick ascending limb and DCT/CNT but not in the proximal convoluted tubule and CD. In contrast, an increase in dietary K(+) intake augmented Cyp2c44 expression only in the DCT/CNT and CD. Neither high salt nor HK intake had a significant effect on the blood pressure (BP) of wild-type mice. However, HK but not high salt intake increased BP in CD-specific, Cyp2c44 conditional knockout (KO) mi...