Published online before print November 29, 2004, doi: 10.1161/01.HYP.0000150782.28485.91
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(Hypertension. 2005;45:103.)
© 2005 American Heart Association, Inc.
Scientific Contributions |
Decreased Levels of Cytochrome P450 2E1–Derived Eicosanoids Sensitize Renal Arteries to Constrictor Agonists in Spontaneously Hypertensive Rats
From the Department of Pharmacology (F.Z., H.D., R.K., H.S., M.L.-S., A.N.), New York Medical College, Valhalla, NY; and Departments of Biochemistry and Pharmacology (V.R.G., J.R.F.), University of Texas Southwestern Medical School, Dallas.
Correspondence to Alberto Nasjletti, MD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail alberto_nasjletti{at}nymc.edu
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Abstract |
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We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 µmol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7±6.0 versus 44.9±2.8 pmol/mg) and 18-HETE (13.8±1.6 versus 7.9±0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3±9.1 versus 98.9±12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the Rmax was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28±0.07 versus 0.71±0.12 µmol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 µmol/L) than WKY (10 µmol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.
Key Words: rats, spontaneously hypertensive • vasoconstriction • kidney
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Introduction |
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The kidney expresses cytochrome P450 (CYP) oxygenases, which catalyze monohydroxylation of arachidonic acid at positions C20, C19, and C18, yielding 20-HETE, 19-HETE, and 18-HETE, respectively.1,2 In the rat kidney, 20-HETE synthesis is attributable to CYP4A isoforms,1,3 19-HETE synthesis to CYP4A isoforms,1,3 and CYP2E12 and 18-HETE synthesis to CYP2E1.2 20-HETE produced by renal preglomerular vessels4,5 sensitizes vascular smooth muscle to constrictor agonists1,6,7 and contributes to pressure-induced vasoconstriction8 and tubuloglomerular feedback.9 20-HETE promotes vasoconstriction via mechanisms involving inhibition of Ca2+-activated K+ (KCa) channels,10,11 augmentation of Ca2+ channel conductance,12 and activation of Rho-kinase.13 Interestingly, 19-HETE was reported to interfere with 20-HETE–induced constriction of renal preglomerular vessels,14 and 19-HETE and the 18(R)-HETE were shown to produce renal vasodilation.15 Hence, the possibility arises that the vasoregulatory actions of 20-HETE are counterbalanced by those of 19-HETE and 18-HETE.
Arterial vessels of spontaneously hypertensive rats (SHR) are more sensitive to constrictor agonists than corresponding vessels of Wistar-Kyoto rats (WKY).16–18 20-HETE is a critical determinant of the increased sensitivity to vasoconstrictors in SHR because interventions that decrease the expression or activity of CYP4A isoforms reduce the sensitivity of SHR vessels to constrictor agonists to a level not different from that of similarly treated WKY vessels.16,18
The present study examines the hypothesis that a deficit in vascular production of 19-HETE and 18-HETE in SHR facilitates the sensitizing action of 20-HETE on agonist-induced vasoconstriction and thus increases vascular reactivity of vascular.
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Methods |
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Chemicals and Reagents
20-HETE, 19(S)-HETE, 19(R)-HETE, 18(S)-HETE, 18(R)-HETE, and the CYP4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS)3 were synthesized as described.19 Antibodies directed against CYP2E1, CYP4A, and ß-actin were obtained from Gentest. All other chemicals were obtained from Sigma.
Animals
Protocols using 10- to 12-week-old WKY and SHR (Taconic Farms) were approved by the institutional animal care and use committee. Blood pressure, measured by tail sphygmography, was 120±1 and 176±1 mm Hg (P<0.05) in WKY and SHR, respectively. Kidneys were excised from rats anesthetized with sodium pentobarbital (60 mg/kg IP), and the interlobar arteries were dissected out for assessment of CYP4A and CYP2E1 protein, measurement of 20-HETE, 19-HETE, and 18-HETE, and evaluation of agonist-induced vascular contraction.
Assessment of CYP4A and CYP2E1 Protein
Interlobar arteries were homogenized in ice-cold potassium phosphate buffer (10 mmol/L, pH 7.4) containing 250 mmol/L sucrose, 1 mmol/L EDTA, 0.1% Nonidet P-40, and 0.1 mmol/L PMSF. Homogenates were centrifuged (1000g for 10 minutes), and the supernatant was used for protein assay and separation of proteins by 12% SDS-PAGE, followed by Western blot analysis of CYP4A, CYP2E1, and ß-actin.5 Immunocomplexed bands were quantified by densitometric analysis. Data are expressed as the CYP4A or CYP2E1/ß-actin ratio.
HETE Assessment
Interlobar arteries were transferred into vials containing 1 mL of Krebs buffer saturated with 95% O2-5% CO2 and complemented with NADPH (1 mmol/L). Samples were incubated at 37° for 60 minutes; in some experiments, DDMS (30 µmol/L) or the CYP2E1 inhibitor diethyldithiocarbamate (DETC; 500 µmol/L)20 were included in the buffer. Because DETC inhibits Cu/Zn superoxide dismutase (SOD) and extracellular SOD,21 the effect of DETC on vascular HETEs also was examined in vessels incubated in buffer containing the superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron; 1 mmol/L). At the end of the incubation, media and vessels were extracted with acidified (pH 4.0) ethyl acetate, and the organic phase was processed for quantification of HETEs by negative chemical ionization mass spectroscopy.22
Assessment of Agonist-Induced Vascular Contraction
Interlobar arteries were cut into rings (2 mm in length) and mounted on 25-µm stainless-steel wires in the chambers of a myograph (J.P. Trading) for measurement of isometric tension.6 Rings were bathed in Krebs buffer and gassed with 95% O2-5% CO2. After a 30-minute equilibration interval, vessels were challenged with 80 mmol/L KCl, and after washing, concentration-response curves to phenylephrine (10–9 to 5x10–5 mol/L) or vasopressin (10–11 to 10–7 mol/L) were constructed in the absence and presence of test agents by cumulatively increasing the concentration of agonist every 2 to 3 minutes. Isometric tension is expressed in millinewtons per millimeter of vessel length (mN/mm).
Data Analysis
Data are expressed as means±SEM. Concentration-response data were fitted to a logistic function by nonlinear regression, and the maximum asymptote of the curves (Rmax) and concentration of phenylephrine producing 50% of the maximal response (EC50) were calculated as described.16 Concentration-response data were analyzed by 2-way ANOVA, followed by a Duncan multiple range test. All other data were analyzed by 1-way ANOVA or Student t test. The null hypothesis was rejected at P<0.05.
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Results |
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Vascular Expression of CYP4A and CYP2E1 and Levels of 20-HETE, 19-HETE, and 18-HETE
The expression of CYP4A protein was comparable in interlobar arteries of WKY and SHR, whereas that of CYP2E1 protein was decreased (P<0.05) in arteries of SHR (Figure 1). Relative to data in interlobar arteries of WKY bathed in buffer without added drugs, arteries of SHR displayed similar levels of 20-HETE, whereas estimates of 19-HETE and 18-HETE were decreased (P<0.05; Figure 1). Values of 20-HETE in arteries of WKY and SHR were decreased (P<0.05) by DDMS (30 µmol/L) but were unaffected by DETC (500 µmol/L; Figure 1). 19-HETE estimates were reduced (P<0.05) by DDMS in arteries of SHR and by DETC in arteries of WKY and SHR (Figure 1). Estimates of vascular 18-HETE in WKY and SHR were unaffected by DDMS but were decreased (P<0.05) by DETC (Figure 1). In vessels incubated in buffer containing Tiron (1 mmol/L), to prevent superoxide accumulation, DETC also reduced (P<0.05) estimates of 19-HETE and 18-HETE, respectively, by 40.7±7.4% and 44.5±14.6% in WKY and by 49.1±5.9% and 58.3±9.3% in SHR, whereas estimates of 20-HETE were not affected significantly in WKY (–1.8±5.8%) or SHR (–7.7±9.4%).
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P<0.05 relative to corresponding value in WKY; *P<0.05 relative to corresponding value in untreated vessels.
Effect of DDMS on Constrictor Responsiveness to Phenylephrine
Figure 2 illustrates the effect of phenylephrine on isometric tension in interlobar arteries of WKY and SHR, bathed in Krebs buffer containing and not containing DDMS (30 µmol/L). Phenylephrine elicited concentration-dependent isometric tension development in all experimental groups. The Rmax for phenylephrine was similar in vessels of WKY and SHR, in the absence and presence of DDMS. In preparations not exposed to the CYP4A inhibitor, the EC50 of phenylephrine in vessels of SHR was exceeded (P<0.05) by that in vessels of WKY (0.28±0.07 versus 0.71±0.12 µmol/L), implying enhanced sensitivity to the agonist. DDMS decreased the sensitivity of the vessels to phenylephrine, more so in SHR than in WKY, causing a rightward shift in the concentration-response curve and increasing (P<0.05) the EC50 for the constrictor agonist by 
54% and 475% in arteries of WKY and SHR, respectively. After treatment with DDMS, the EC50 for phenylephrine in vessels of WKY and SHR was comparable.
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) DDMS. Results are the mean±SEM. n=No. of experiments. *P<0.05 relative to data in vessels not exposed to DDMS.
Effect of 20-HETE, 19-HETE, and 18-HETE on Vascular Reactivity to Phenylephrine
Figure 3 shows data on the effect of 20-HETE on phenylephrine-induced contraction of interlobar arteries bathed in buffer containing DDMS (30 µmol/L). Exogenous 20-HETE increased the sensitivity of WKY and SHR vessels to the constrictor agonist, decreasing the EC50 without altering the Rmax. But the minimal concentration of exogenous 20-HETE that decreased the EC50 for phenylephrine was much smaller in vessels of SHR (0.1 µmol/L) than of WKY (10 µmol/L). Hence, vessels of SHR are more sensitive than vessels of WKY to 20-HETE–induced reduction of phenylephrine EC50. In contrast, arteries of WKY and SHR, bathed in buffer containing DDMS (30 µmol/L), did not differ from each other in terms of the effect of KCa channel blockade with tetraethylammonium (TEA) on phenylephrine-induced contractions. Exposure of WKY vessels to TEA at 10, 50, 100, 500, and 1000 µmol/L, respectively, decreased (P<0.05) the EC50 for phenylephrine from 1.12±0.03 (n=5) to 0.90±0.18, 0.63±0.13, 0.62±0.08, 0.65±0.07, and 0.40±0.09 µmol/L (n=5 at all concentrations of TEA). TEA also decreased (P<0.05) the EC50 for the constrictor agonist in SHR vessels, from 1.18±0.07 (n=5) to 0.87±0.11, 0.84±0.12, 0.64±0.18, 0.55±0.06, and 0.44±0.05 µmol/L (n=5 at all concentrations of TEA). TEA did not affect the Rmax for phenylephrine in vessels of WKY or SHR (data not shown).
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The ability of 20-HETE to increase the sensitivity of DDMS-treated vessels to phenylephrine does not extend to 19(R)-HETE and 19(S)-HETE. We found that the EC50 for the constrictor agonist in DDMS-treated arteries of WKY (1.16±0.04 µmol/L; n=6) was not affected by 10 µmol/L 19(R)-HETE (1.22±0.09 µmol/L; n=6) or 19(S)-HETE (1.62±0.47 µmol/L; n=4). Neither was the EC50 for phenylephrine in DDMS-treated arteries of SHR (1.59±0.63 µmol/L; n=6) affected by 10 µmol/L 19(R)-HETE (1.70±0.34 µmol/L; n=6) or 19(S)-HETE (1.67±0.52 µmol/L; n=6). The Rmax for the constrictor agonist in DDMS-treated arteries of WKY was similar in the absence (4.47±0.18 mN/mm; n=6) and presence of 10 µmol/L 19(R)-HETE (4.81±0.40 mN/mm; n=5) or 19(S)-HETE (4.33±0.68 mN/mm; n=4). The Rmax for phenylephrine in DDMS-treated vessels of SHR also was similar in the absence (3.53±0.36 mN/mm; n=6) and presence of 10 µmol/L 19(R)-HETE (4.04±0.22 mN/mm; n=6) or 19(S)-HETE (3.48±0.43 mN/mm; n=6). Notably, as illustrated in Figure 4, in arteries of SHR bathed in buffer containing DDMS (30 µmol/L), the ability of exogenous 20-HETE to decrease the EC50 for phenylephrine was virtually blunted in preparations exposed to 19(R)-HETE or 18(R)-HETE but not to 19(S)-HETE or 18(S)-HETE (all at 1 µmol/L). The EC50 for phenylephrine in vessels of SHR (0.12±0.01 µmol/L; n=8), bathed in buffer containing DDMS (30 µmol/L) and 20-HETE (10 µmol/L), was increased (P<0.05), respectively, 541% (0.77±0.19 µmol/L); n=8) and 650% (0.90±0.10 µmol/L; n=8) by 0.1 and 1.0 µmol/L 19(R)-HETE and 366% (0.56±0.05 µmol/L; n=8) and 850% (1.14±0.24 µmol/L; n=8) by 0.1 and 1.0 µmol/L 18(R)-HETE. The EC50 for phenylephrine was not affected by 0.01 µmol/L 19(R)-HETE or 18(R)-HETE (0.17±0.02 and 0.13±0.04 µmol/L, respectively; n=8).
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19(R)-HETE and 18(R)-HETE also decrease the sensitivity to phenylephrine in settings in which 20-HETE synthesis is not impaired because both eicosanoids increased (P<0.05) the EC50 for phenylephrine in arteries of WKY and SHR not exposed to DDMS (Figure 5). On the other hand, neither the EC50 nor the Rmax for phenylephrine in arteries of WKY were affected by 10 µmol/L 19(S)-HETE (EC50 0.66±0.20 versus 0.65±0.26 µmol/L; Rmax 4.07±0.53 versus 4.22±0.69 mN/mm; n=6) or by 10 µmol/L 18(S)-HETE (EC50 0.30± 0.03 versus 0.37±0.09 µmol/L; Rmax 4.59±0.41 versus 3.74±0.43 mN/mm; n=4). Also, neither the EC50 nor the Rmax for phenylephrine in arteries of SHR was affected by 10 µmol/L 19(S)-HETE (EC50 0.22±0.03 versus 0.26±0.04 µmol/L; Rmax 3.90±0.40 versus 3.97±0.35 mN/mm; n=6) or by 10 µmol/L 18(S)-HETE (EC50 0.17±0.03 versus 0.11±0.02 µmol/L; Rmax 4.23±0.28 versus 4.33±0.10 mN/mm; n=4).
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Constrictor Responsiveness to Vasopressin as Affected by DDMS and HETEs
Shown in Figure 6, in interlobar arteries not treated with DDMS (30 µmol/L), the EC50 for vasopressin-induced isometric tension development was smaller (P<0.05) in SHR compared with WKY, but the Rmax value did not differ significantly. DDMS caused a rightward shift in the concentration-response curve to vasopressin, increasing the (P<0.05) the EC50 by 191% and 1264% in renal arteries of WKY and SHR, respectively. In vessels exposed to DDMS, 20-HETE (10 µmol/L) caused a leftward shift in the concentration-response curve to vasopressin, decreasing the EC50 without altering the Rmax; the sensitizing effect of 20-HETE was blunted in vessels concurrently exposed to 19(R)-HETE or 18(R)-HETE (both at 1 µmol/L).
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Discussion |
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The salient conclusion derived from this study is that a vasoregulatory imbalance created by diminished production of CYP2E1-derived eicosanoids in arteries of SHR amplifies the sensitizing action of CYP4A-derived 20-HETE on agonist-induced vasoconstriction. The various components of this conclusion are discussed below.
Our study documents that 19-HETE and 18-HETE are lower in interlobar arteries of SHR than of WKY, in contrast to 20-HETE estimates, which are comparable in both strains. That DDMS decreases vascular 20-HETE is in line with reports that CYP4A isoforms are a primary determinant of the level and rate of production of 20-HETE in preglomerular vessels.5 On the other hand, the level of 18-HETE, unaffected by DDMS, was greatly decreased by an inhibitor of CYP2E1 (DETC) implying that vascular 18-HETE is a product of CYP2E1 activity. Levels of 19-HETE fell prominently in vessels treated with DETC and less so with DDMS, suggesting that synthesis of this eicosanoid proceeds through CYP2E1- and CYP4A-catalyzed reactions. Participation of CYP2E1 in the synthesis of 19-HETE and 18-HETE in the kidney was documented previously.2 It was reported that 70% and 30% of the 19-HETE synthesized by CYP2E1 corresponds to the (S) and (R) stereoisomers, respectively, whereas virtually all the 18-HETE corresponds to the (R) stereoisomer.2
According to this study, interlobar artery expression of CYP4A proteins is comparable in SHR and WKY, whereas CYP2E1 expression is diminished in SHR. Hence, reduction of 19-HETE and 18-HETE levels in renal arteries of SHR may be a consequence of diminished vascular expression of CYP2E1. Our study offers no information on the mechanism underlying downregulation of CYP2E1 in interlobar arteries of SHR.
In agreement with reports that the vasculature of SHR is hypersensitive to constrictor agonists,16–18 we found that interlobar arteries of SHR are more sensitive to phenylephrine- and vasopressin-induced contraction than corresponding arteries of WKY. That DDMS decreases the sensitivity or renal arteries to phenylephrine and vasopressin is in keeping with the notion that a CYP4A-derived eicosanoid of vascular origin sensitizes vascular smooth muscle to constrictor stimuli.16 The eicosanoid in question is likely 20-HETE because in contrast to 19(S)-HETE and 19(R)-HETE, it increases the sensitivity of DDMS-treated vessels to phenylephrine, offsetting the desensitizing effect of the CYP4A inhibitor. Notably, the loss of sensitivity to phenylephrine and vasopressin caused by DDMS in arteries of SHR greatly exceeds that in arteries of WKY, implying that the sensitizing mechanism mediated by 20-HETE is expressed more prominently in SHR than WKY. This conclusion concurs with the results of a previous study in mesenteric arteries of SHR and WKY.16
According to the present study, interlobar arteries of SHR do not display augmented CYP4A expression or 20-HETE levels. These observations prevent attribution of the increased expression of CYP4A-dependent sensitization to vasoconstrictors in SHR vessels to a mere elevation of vascular 20-HETE. Rather, it may be caused by facilitation of the vasoregulatory action of 20-HETE because the minimal concentration of 20-HETE that decreases the EC50 for phenylephrine is much smaller in vessels of SHR than of WKY. It is unlikely that facilitated responsiveness to 20-HETE in vessels of SHR relates to greater abundance of KCa channels,23 the putative cellular target of 20-HETE,1 because TEA was equally effective in sensitizing arteries of SHR and WKY to phenylephrine-induced contraction.
In our study, 19(R)-HETE and 18(R)-HETE prevented exogenous 20-HETE from sensitizing DDMS-treated arteries of SHR to phenylephrine and vasopressin. These eicosanoids also may interfere with the sensitizing action of endogenous 20-HETE because they rendered vessels not exposed to DDMS less sensitive to phenylephrine. It is unlikely that 19(R)-HETE and 18(R)-HETE desensitize vessels via a mechanism unrelated to 20-HETE because neither eicosanoid affected responsiveness to phenylephrine in DDMS-treated vessels not exposed to exogenous 20-HETE. That 19(S)-HETE and 18(S)-HETE do not share with corresponding (R) stereoisomers the ability to interfere with 20-HETE–induced vascular sensitization to phenylephrine suggests a high degree of specificity in the action of 19(R)-HETE and 18(R)-HETE. A priori, specific interference by these eicosanoids with the sensitizing action of 20-HETE may result from interactions at the level of a putative 20-HETE receptor or signaling pathway.1,14
That 19(R)-HETE and 18(R)-HETE interfere with the ability of 20-HETE to sensitize vascular smooth muscle to vasoconstrictors casts a special significance on the finding that interlobar arteries of SHR feature diminished CYP2E1 expression and levels of 19-HETE and 18-HETE. A deficit in vascular production of CYP2E1-derived 19(R)-HETE and 18(R)-HETE in SHR is expected to create a vasoregulatory imbalance that, as documented in the present study, sensitizes interlobar arteries to constrictor stimuli by facilitating the action of endogenous 20-HETE.
Perspectives
20-HETE was reported to promote renal and extrarenal vasoconstriction via amplification of constrictor mechanisms involving myogenic and neurohormonal stimuli.1 Accordingly, the vasoregulatory imbalance caused by a deficit in vascular generation of CYP2E1-derived eicosanoids in SHR may have far-reaching consequences on renal hemodynamics and blood pressure. In this regard, reports that interventions that decrease the expression or activity of CYP4A produce renal vasodilation and reduce blood pressure in SHR suggest involvement of 20-HETE in the implementation of renal vasoconstrictor and hypertensive mechanisms in this experimental model.24,25 The current study in SHR supports the notion that a deficit in vascular generation of CYP2E1-derived eicosanoids contributes to the hypertension by amplifying the vascular actions of 20-HETE.
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Acknowledgments |
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This work was supported by US public health grants HL-34300, HL-18579, DK-38226, and a grant from the Robert A. Welch Foundation. We thank Ms Jennifer Brown for secretarial assistance.
Received August 4, 2004; first decision August 20, 2004; accepted November 4, 2004.
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