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Postmenopausal hypertension: role of 20-HETE

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Postmenopausal hypertension: role of 20-HETE
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  Postmenopausal hypertension: role of 20-HETE Licy L. Yanes, 1,4 Roberta Lima, 1,4 Mohadetheh Moulana, 1,4 Damian G. Romero, 2 Kuichang Yuan, 1,4 Michael J. Ryan, 1,4 Rodney Baker, 3 Huimin Zhang, 1 Fan Fan, 3 Deborah D. Davis, 1 Richard J. Roman, 3 and Jane F. Reckelhoff  1,4 1  Departments of Physiology and Biophysics,  2  Biochemistry and   3 Pharmacology and   4 Women’s Health Research Center,University of Mississippi Medical Center, Jackson, Mississippi Submitted 14 June 2010; accepted in final form 2 April 2011 Yanes LL,Lima R, Moulana M, Romero DG, Yuan K, RyanMJ, Baker R, Zhang H, Fan F, Davis DD, Roman RJ, Reckelhoff JF.  Postmenopausal hypertension: role of 20-HETE.  Am J Physiol Regul Integr Comp Physiol  300: R1543–R1548, 2011. First publishedApril 6, 2011; doi:10.1152/ajpregu.00387.2010.—Blood pressure(BP) increases after menopause. However, the mechanisms responsi-ble have not been elucidated. In this study we tested the hypothesisthat 20-hydroxyeicosatetraenoic acids (20-HETE), produced by cyto-chrome  P -450 (CYP450)  -hydroxylase, contributes to the hyperten-sion in a model of postmenopausal hypertension, aged female spon-taneously hypertensive rats (PMR). 1-Aminobenzotriazole, a nonse-lective inhibitor of arachidonic acid metabolism, for 7 days, reducedBP in PMR but had no effect in young females. Acute intravenousinfusion of HET-0016, a specific inhibitor of 20-HETE, over 3 h, alsoreduced BP in PMR. CYP4A isoform mRNA expression showed nodifference in renal CYP4A1 or CYP4A3 but increases in CYP4A2and decreases in CYP4A8. CYP4A protein expression was decreasedin kidney of PMR compared with young females. Endogenous 20-HETE was significantly higher in cerebral vessels of PMR than youngfemales (YF) but was significantly lower in renal vessels of PMR.Omega-hydroxylase activity in cerebral vessels was also higher inPMR but was similar in kidney vessels in both groups. In renalmicrosomal preparations, endogenous 20-HETE was not different inPMR and young females, but  -hydroxylase activity was significantlylower in PMR than YF. The data with blockers suggest that 20-HETEcontributes to postmenopausal hypertension in SHR. The data alsosuggest that cerebral production of 20-HETE may be increased andrenal tubular production may be decreased in PMR, thus both con-tributing to their elevated BP.arachidonic acid metabolite; female; blood pressure BLOOD PRESSURE (BP) INCREASES  in women following menopause.Hypertension is a major risk factor for cardiovascular disease,which is the leading cause of death in postmenopausal women.BP in aging women is also less well controlled than in men(15). Therefore, a better understanding of prohypertensivemechanisms in postmenopausal women may lead to bettertherapeutic options.Arachidonic acid (AA) can be metabolized via cytochrome P -450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs)and 20-hydroxyeicosatetraenoic acids (20-HETE) (13). 20-HETE is a potent vasoconstrictor, while EETs are vasodilators.Blockade of vascular 20-HETE has been reported to lowerblood pressure in young male (SHR) (13). On the other hand,20-HETE also inhibits Na  -K  -ATPase activity in the proxi-mal tubule and thick ascending limb of Henle (TALH), andimpaired renal production of 20-HETE is associated with Naretention and the development of hypertension in Dahl salt-sensitive rats (8, 13). Therefore, two mechanisms by which BPcould increase after menopause is via a decrease in the intrare-nal tubular production of 20-HETE or an increase in thevascular production of 20-HETE. The role that 20-HETE playsin mediating hypertension in females in general, and specifi-cally in postmenopausal rats, has not been previously studied.In the kidney, 20-HETE is produced in vascular smoothmuscle cells by CYP  -hydroxylase enzymes, mainly isoformsCYP4A1, CYP4A2, and CYP4A8, and to a lesser extentCYP4A3 (10, 13). All four isoforms have been found in maleand female rat kidneys, but CYP4A2 is thought to be the majorenzyme producing 20-HETE in the preglomerular vasculaturein adult male rats (10). The isoform responsible for 20-HETEsynthesis in the tubules is not clear since CYP4A2, CYP4A3,and CYP4A8 were all found in nephron segments of normo-tensive male and female rats by Ito et al. (10). Whetherhypertensive females exhibit similar expression of the isoformsof CYP4A has not been determined.We have previously characterized aged (18 mo) femalespontaneously hypertensive rats (PMR) as a model of post-menopausal hypertension (5). In PMR, estrous cycling stops by12 mo of age, and by 16 mo of age, BP is significantly higherthan in young cycling female SHR (5). Recently, we showedthat some, but not all, of the increases in BP in this model aremediated by activation of the endothelin and renin-angiotensinsystems (RAS) (16, 17). However, blockade of each systemindividually does not normalize the BP in PMR, suggestingthat other mechanisms may also contribute to postmenopausalhypertension in this model. 20-HETE has previously beenshown to contribute to the vasoconstrictor actions of bothendothelin and ANG II (2, 13).Thus, the present study was performed to determine the roleof 20-HETE in mediating the hypertension in a unique animalmodel of postmenopausal hypertension, the PMR. We hypoth-esized that 20-HETE would contribute to the elevated BP inPMR, either via an increase in vascular 20-HETE productionor due to a reduction in renal tubular 20-HETE. METHODS  Rats Retired breeder PMRs, were received from the vendor (TaconicFarms; Germantown, NY) at 4–9 mo of age and were aged in theLaboratory Animal Facility of the University of Mississippi MedicalCenter. PMR were studied at 18 mo of age. Controls were youngfemale SHR obtained at 2 mo of age and studied at 3 mo. All rats weremaintained on standard rat chow (Teklad, Harlan Sprague Dawley,Indianapolis, IN) and tap water in an environment with 12:12-hlight-dark cycles. All protocols were reviewed and approved by theInstitutional Animal Care and Use Committee of the University of  Address for reprint requests and other correspondence: J. F. Reckelhoff, Dept.of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 N. StateSt., Jackson, MS 39216-4505 (e-mail: jreckelhoff@umc.edu).  Am J Physiol Regul Integr Comp Physiol  300: R1543–R1548, 2011.First published April 6, 2011; doi:10.1152/ajpregu.00387.2010.0363-6119/11 Copyright  ©  2011 the American Physiological Societyhttp://www.ajpregu.org R1543  Mississippi Medical Center, and studies were performed in accor-dance with the  Guide for the Care and Use of Laboratory Animals ,National Institutes of Health.  Experimental Protocols Effects of 1-aminobenzotriazole.  Radiotelemetry BP was moni-tored, as we have previously reported (18). Briefly, telemetry probeswere implanted below the renal arteries using aseptic technique usinginhaled anesthesia (isoflurane), and rats were allowed to recover for 2wk. After that, mean arterial pressure (MAP) was recorded 24 h a dayduring a 3-day baseline period and then for 7 days while the ratsreceived daily intraperitoneal injection of the nonspecific CYP 450enzyme inhibitor, 1-aminobenzotriazole (1-ABT; Sigma, St. Louis,MO) in a dose of 50 mg·kg  1 ·day  1 or vehicle (0.9% NaCl). Theeffects of vehicle or ABT on MAP were compared in PMR ( n  6 or7/group) and young female SHR ( n    5–6/group). This dose of 1-ABT has been previously shown to inhibit renal production of 20-HETE and EETs (3, 14).  Effects of HET-0016 on BP.  The effects of a more selectiveinhibitor of 20-HETE,  N  -hydroxy-  N  -(4-butyl-2 methylphenyl)forma-midine (HET-0016; Cayman Chemical, Ann Arbor, MI) (12), onMAP was also determined in PMRs. A group of PMRs were anes-thetized by isoflurane, and a catheter was placed in the femoral arteryand vein. The catheters were exteriorized at the back of the neck, andafter 4 days of recovery, MAP was recorded in conscious freelymoving rats using Power LAB software, as we have previouslyreported (18). Following 30 min baseline MAP, PMR were giveneither HET-0016 ( n  10; 10 mg/kg bolus and then 1 mg·kg  1 ·h  1 )or vehicle ( n    6; captisol 30% in saline) intravenously, and MAPwas recorded over a 3-h period. Preparation of renal microsomes.  Microsomal preparations weremade from kidneys removed from young female rats and PMR ( n  6/group). Kidney tissue (0.5 g) was homogenized in 3 ml 100 mMpotassium phosphate buffer (pH 7.4), with 250 mM sucrose andprotease inhibitor cocktail (Sigma, St. Louis, MO). Following differ-ential centrifugation, the supernatant fraction was discarded, and thepellet was resuspended in 500  l 100 mM potassium phosphate buffer(pH 7.4), with 10 mM MgCl 2 , 33% glycerol, 500 mM EDTA, and 1  M DTT. Protein concentration was determined by Bradford assayusing a commercially available reagent (Bio-Rad, Richmond, CA)with BSA 2% as a standard.  Measurement of 20-HETE and     -hydroxylase activity in cerebraland preglomerular blood vessels and renal microsomes of PMR and YF SHR.  Endogenous 20-HETE and   -hydroxylase activity in cere-bral and renal vessels and renal microsomes were assessed by HPLC-mass spectroscopy in tissues from young female SHR and PMR ( n  6/group). In our experience, the preglomerular microvasculature canbe easily contaminated with tubular segments that have very highlevels of 20-HETE synthesis. Thus, we also isolated cerebral mi-crovessels to obtain an additional indication of microvascular 20-HETE production that was extrarenal. Both renal and cerebral vesselswere isolated using 3% Evans blue and sieving methods, as describedpreviously (4, 9). Endogenous 20-HETE levels were measured invessels that were homogenized in 1 ml of ice-cold physiological saltsolution. To determine   -hydroxylase activity, isolated vessels wereincubated for 30 min at 37°C in 1 ml of 100 mM potassium phosphatebuffer (pH 7.4), containing 10 mM MgCl 2  and 500 mM EDTA, 1 mMreduced NADPH, 40  M cold arachidonic acid, and 2  M indometh-acin in a shaking bath, with 100% O 2  superfusion. Reactions wereterminated by acidification to pH 3.5 with formic acid, and the vesselswere homogenized. Tissue samples were extracted twice with 3 ml of ethyl acetate, and organic layer dried under nitrogen. Samples werereconstituted in acetonitrile and analyzed using LC/MS/MS, as pre-viously described (4), using an ABI Sciex 4000 Q TRAP system.  Measurement of mRNA expression of CYP4A isoforms with real-time RT-PCR in kidney of PMR and YF SHR.  Kidney cortical andmedullary mRNA ( n    8 rats/group) was extracted with TRIzolReagent (Molecular Research Center, Cincinnati, OH), resuspended inDEPC-H 2 O, DNase treated with DNA-free kit (Ambion, Austin, TX),and quantified by spectrophotometry, as we previously reported (17).Five micrograms of RNA were reverse transcribed with 0.5  g T 12 VNprimer and Superscript III (Invitrogen, Carlsbad, CA) in a finalvolume of 20  l. The reaction was carried out for 60 min at 50°C andterminated by incubating at 75°C for 15 min. Primers for CYP4A1,CYP4A2, CYP4A3, and CYP4A8 have been previously described(11). Elongation factor I (EF-1) primers were used as controls.Real-time RT-PCR reactions contained 1  l RT product, 0.1  M eachprimer, 0.2 mM dNTPs, SYBR Green I (1:20,000 final concentration;Molecular Probes, Eugene, OR) and 1   l Titanium Taq DNA poly-merase (Clontech, Palo Alto, CA). Amplifications were performed inan iCycler real-time thermal cycler (Bio-Rad). Cycling conditionswere 1 min at 95°C, followed by 50 cycles of 15 s at 95°C, 15 s at60.0°C, and 60 s at 72°C. Fluorescence data were collected during theelongation step. After PCR amplification, the specificity of the PCRreaction was confirmed by melting temperature determination of thePCR products and electrophoretic analysis in 2% agarose gels. Stan-dard curves were made with serial dilutions of pooled RT samples.Results are expressed as arbitrary units and standardized against EF-1mRNA expression. Western blot analysis of CYP4A in kidney microsomes.  Proteinlevels of CYP4A were determined in renal microsomal preparationsfrom young female SHR and PMR ( n    6/group) by Western blotanalysis, as we have previously described (17), using goat anti-CYP4A antibody (1:3,000; Daiichi, Tokyo, Japan) and donkey anti- Fig. 1.  A : Mean artierial pressure (MAP) during baseline period in femalespontaneously hypertensive rats (PMR) and young female spontaneouslyhypertensive rats (YF SHR).  B : effect of chronic 1- aminobenzotriazole (ABT)administration on MAP in PMR and young female SHR. Data are expressed asdelta change  SE. * P  0.05 compared with young female SHR. # P  0.05compared with PMR controls. R1544  HYPERTENSION, MENOPAUSE AND 20-HETE  AJP-Regul Integr Comp Physiol  •  VOL 300  •  JUNE 2011  •  www.ajpregu.org  goat secondary antibodies (1:15,000; Santa Cruz Biotechnology,Santa Cruz, CA). Mouse beta-actin antibody served as a loadingcontrol (1:10,000; Santa Cruz) with goat anti-mouse as secondaryantibody (1:20,000; Santa Cruz). Statistics.  Data are presented as means    SE. Statistical analyseswere performed with SigmaPlot v11 (Systat Software, San Jose, CA).MAP changes between young and old PMR with and without 1-ABTover 7 days were analyzed using a repeated-measures ANOVAfollowed by Student-Newman-Keuls post hoc comparisons. Differ-ences in MAP with HET-0016 in PMR were analyzed by Student’s t  -test. Student’s  t  -test was also used for comparison between youngfemales and PMR in molecular studies and measurement of 20-HETEand omega-hydroxylase activities. A value of   P    0.05 was consid-ered statistically significant. RESULTS  Effects of 1-ABT on MAP in PMR and YF SHR.  TelemetricMAP was significantly higher in PMR than young femalesduring the 3-day baseline period (Fig. 1  A ) (166  1 vs. 138  1 mmHg,  P    0.05). Chronic treatment with 1-ABT reducedMAP significantly in PMR (average over 7 days   18    3mmHg), but had no effect on MAP in young female SHR(Fig. 1  B ).  Effect of HET-0016 infusion on MAP of PMR.  MAP in PMRcontrols and untreated PMR was 203    3 mm and 200    3mmHg, respectively. Acute infusion of HET-0016, the spe-cific inhibitor of 20-HETE synthesis, over 3 h, reducedMAP by 21    3 mmHg in conscious, freely moving PMR(Fig. 2). Vehicle had no effect on MAP in PMR.  Expression (mRNA) of CYP 4A isoforms in kidney cortex and medulla in PMR and YF SHR.  The results of theseexperiments are presented in Fig. 3. Expression of renalCYP4A1 and CYP4A3 mRNA was similar in cortex and Fig. 2. Effect of HET-0016 administration on MAP in PMR. Data areexpressed as delta change in MAP compared with the baseline period. # P   0.05 compared with untreated rats.Fig. 3. mRNA levels of renal CYP 450 isoforms from PMR and young females by real-time RT-PCR.  A  and  C  : CYP4A1 and CYP4A3 mRNA expression weresimilar in PMR compared with YF SHR.  B : CYP4A2 mRNA expression was significantly upregualted in PMR compared with YF SHR.  D : CYP4A8 mRNAexpression was significantly downregulated in PMR compared with YFSHR. Data are expressed as means  SE. * P  0.05 compared with young females. R1545 HYPERTENSION, MENOPAUSE AND 20-HETE  AJP-Regul Integr Comp Physiol  •  VOL 300  •  JUNE 2011  •  www.ajpregu.org  medulla of PMR and young females (Figs. 3,  A  and  C  ,respectively). Expression of CYP4A2 mRNA was significantlyelevated in the renal cortex in PMR compared with youngfemales and was in very low abundance and not different inmedulla between the groups (Fig. 3  B ). In contrast, CYP4A8mRNA expression was significantly decreased in the renalcortex of PMR compared with young female counterparts andwas not different in the medulla between the groups (Fig. 3  D ).  Renal microsomal CYP4A protein expression.  CYP4A pro-tein expression in microsomal fractions was significantly lowerin PMR than young females (Fig. 4).  Renal and cerebral vascular 20-HETE levels and    -hydrox- ylase activity.  The results of these experiments are presented inTable 1. Endogenous 20-HETE levels in cerebral vessels weresix-fold higher in PMR than young females. In contrast, en-dogenous 20-HETE in renal microvessels were 4-fold lower inPMR than young females. Omega-hydroxylase activity wasalso higher in cerebral vessels of PMR compared with youngfemales but was not different in intrarenal microvessels be-tween young and old females. Levels of endogenous 20-HETEin intrarenal microsomal fractions were not different betweenPMR and young females. However,   -hydroxylase activitywas significantly lower in microsomal fractions of PMR thanyoung females. DISCUSSION BP increases after menopause in women, and hypertensionis a major cardiovascular disease risk factor. The leading causeof death in postmenopausal women is cardiovascular disease(1, 7). The baseline study from the Women’s Health Initiativeshowed that  60% of hypertensive postmenopausal women inthe United States are currently treated with conventional phar-macological drugs, such as calcium channel blockers anddiuretics, yet the hypertension was poorly controlled (15).These data suggest that more research is needed to elucidatethe mechanisms that mediate postmenopausal hypertension todevelop specific treatment protocols.Previous studies have shown that the production of 20-HETE is altered in experimental and genetic models of hyper-tension, diabetes, pregnancy, and uremia (13). However, therole of 20-HETE in altering BP in an animal model of post-menopausal hypertension has not been studied previously. Inthe present study, we found that chronic infusion of 1-ABT,which inhibits the synthesis of both 20-HETE and EETs,lowered BP in PMR. It had no significant effect in youngfemales. Similarly, acute administration of a specific inhibitorof 20-HETE, HET-0016, reduced MAP by about the sameamount in PMR. These results are consistent with the view thatan elevated vascular production of the vasoconstrictor 20-HETE contributes to the elevation in blood pressure in PMR.To test this hypothesis, we measured endogenous 20-HETEand  -hydroxylase activity in renal and cerebral arterioles, aswell as in renal cortical microsomes. In addition, we measuredthe mRNA expression of CYP4A isoforms and the proteinexpression of CYP4A in kidney tissue. We found differentlevels of 20-HETE in cerebral and kidney vessels in PMRcompared with young females. In cerebral microvessels, wefound that endogenous 20-HETE levels were significantlyhigher in PMR than young females. But in kidney microves-sels, 20-HETE levels were significantly lower in PMR thanyoung females. One caveat to this finding is that renal mi-crovessels can be contaminated with tubular segments thatmake much higher levels of 20-HETE, whereas 20-HETE isnot thought to be made in other extra cerebral tissues thancerebral microvessels. On the basis of this, we measuredcerebral 20-HETE and  -hydroxylase activity levels to verifyour findings of endogenous 20-HETE in kidney microvessels.It is possible that the renal microvessels of young females were Fig. 4. CYP4A protein expression in young femaleSHR and PMR. Representative Western blot, andanalyses of bands. Data are expressed at arbitraryunits (AU) for each group and are presented asmeans    SE. * P    0.05 compared with youngfemales. Table 1.  20-HETE and     -hydroxylase activities in cerebral and renal vessels and renal microsomes of YF and PMR 20-HETE Levels, pmol/mg   -Hydroxylase Activity, pmol 20-HETE  min  1  mg  1 Rats Cerebral Vessels Renal Vessels Renal Microsomes Cerebral Vessels Renal Vessels Renal Microsomes YF ( n  6) 0.138  0.013 5.32  1.20 6.40  0.90 0.075  0.007 0.905  0.205 101.5  5.2PMR ( n  6) 0.821  0.263 0.902  0.064 6.20  0.61 0.133  0.020 1.28  0.24 44.4  2.8 P  value   0.05   0.01 NS 0.05 NS   0.001Values are expressed as means  SE. YF, young females; PMR, female spontaneously hypertensive rats; NS, not significant. R1546  HYPERTENSION, MENOPAUSE AND 20-HETE  AJP-Regul Integr Comp Physiol  •  VOL 300  •  JUNE 2011  •  www.ajpregu.org  contaminated with tubular segments. However, we doubt this isthe case because the data were consistent between the groups,i.e., endogenous 20-HETE was much higher in all renal vas-cular samples from young females compared with PMR.Therefore, we believe that the renal microvascular 20-HETElevels are lower in PMR than young females. In support of higher 20-HETE in cerebral microvessels,   -hydroxylase ac-tivity, the capacity to produce 20-HETE, was also higher inPMR than young females. In contrast, along with lower en-dogenous 20-HETE levels in renal microvessels of PMR,  -hydroxylase activity was not different in renal microvesselsof PMR and young females. These data suggest that themechanism for the fall in BP with the 1-ABT and HET-0016blockers, was due to a reduction in extrarenal 20-HETE vas-cular production.In contrast to the renal vasculature, in renal cortical micro-somes, mainly a tubular preparation, endogenous 20-HETElevels were similar, but the capacity to produce 20-HETE asmeasured by   -hydroxylase activity was twofold lower inPMR than young females. These data support a role forreductions in 20-HETE synthesis in the renal tubules to con-tribute to the elevated BP in PMR compared with youngfemales. The lower levels of CYP4A protein in the microsomesand the reduction in CYP4A8 in the cortex of PMR supportthese data. Since 20-HETE in renal tubules is antihypertensivedue to its inhibitory effect on sodium reabsorption, a decreasein 20-HETE synthesis in renal tubules would be prohyperten-sive. In response to HET-0016 or 1-ABT, a further decrease in20-HETE should cause an increase in BP. The reduction in BPwith both blockers was   20 mmHg, leaving PMR with BPsstill above normotensive levels. It is possible that with theblockers, the prohypertensive effect of reduced renal tubular20-HETE was offset by the antihypertensive effect of increasedextrarenal vascular 20-HETE.In any case, the studies with the 20-HETE synthesis blockersdo support a role for 20-HETE in contributing to the elevatedBP in PMR. In previous studies, we have found that blockadeof the RAS with losartan or the endothelin system with ET A receptor antagonists also does not normalize the BP in PMR(16, 17). Given the present data, we can hypothesize thatmultiple pathways contribute to the hypertension in PMR.Additional studies will be necessary to determine whethertreatment with multiple blockers will reduce the BP in PMR tonormotensive levels. Furthermore, the use of multiple blockerswill also allow us to determine whether a component of theendothelin- or ANG II-mediated hypertension in PMR is me-diated by 20-HETE, since both endothelin and ANG II canstimulate 20-HETE synthesis (13).The expression of CYP4A isoforms has not been studied infemale SHR previously. Studies by Ito and colleagues showedthat there were sex differences in the expression of some of theCYP4A isoforms along the nephron (10). However, thosestudies were performed in Sprague-Dawley rats and the iso-forms that were different between young and old female SHR,the 4A2 and 4A8, were found in similar areas of the nephronin both males and females.Finally, because 1-ABT can also inhibit synthesis of EETs,it is possible that any effect to inhibit vasodilator EETs wouldoffset the effect on BP. However, in preliminary studies, wehave infused EET inhibitor, miconazole, in PMR and found noeffect on BP (K. Yuan and J. F. Reckelhoff, unpublishedobservations). However, it is possible the EET levels could bealready reduced in PMR. Further studies will be necessary tomeasure EET levels to determine whether they are, indeed,changed compared with young females. Perspectives and Significance The mechanisms responsible for postmenopausal increasesin BP are not clear. However, women are at greatest risk forcardiovascular disease after menopause. An increase in BP is asignificant risk factor for promoting cardiovascular disease,which is the leading cause of death and morbidity in agingwomen (1, 7). Our present data suggest that an increase inextrarenal vascular 20-HETE and a reduction in renal tubular20-HETE, in part, contribute to the elevated BP in our modelof postmenopausal hypertension. Identification of therapeutictargets specifically mediating hypertension in postmenopausalwomen may allow for specific treatment regimens that willimprove their care and quality of life as they age. ACKNOWLEDGMENTS These studies were supported by National Institutes of Health GrantsHL66072, HL51971, and HL69194 to J. F. Reckelhoff; HL085907,HL085907S1, and HL092284 to M. J. Ryan, and American Heart AssociationScientist Development Grant 0830239N to LLY. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. REFERENCES 1.  Bentley-Lewis R, Koruda K, Seely EW.  The metabolic syndrome inwomen.  Nat Clin Pract Endocrinol Metab  3: 696–704, 2007.2.  Croft KD, McGiff JC, Sanchez-Mendoza A, Carroll MA.  AngiotensinII releases 20-HETE from rat renal microvessels.  Am J Physiol RenalPhysiol  279: F544–F551, 2000.3.  Dos Santos EA, Dahly-Vernon AJ, Hoagland KM, Roman RJ.  Inhibi-tion of the formation of EETs and 20-HETE with 1-aminobenzotriazoleattenuates pressure natriuresis.  Am J Physiol Regul Integr Comp Physiol 287: R58–R68, 2004.4.  Dunn KM, Renic M, Flasch AK, Harder DR, Falck JR, Roman RJ. Elevated production of 20-HETE in the cerebral vasculature contributes toseverity of ischemic stroke and oxidative stress in spontaneously hyper-tensive rats.  Am J Physiol Heart Circ Physiol  295: H2455–H2465, 2008.5.  Fortepiani LA, Zhang H, Racusen L, Roberts LJ, 2nd, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension inspontaneously hypertensive rats.  Hypertension  41: 640–645, 2003.6.  Fortepiani LA, Reckelhoff JF.  Role of oxidative stress in the sexdifferences in blood pressure in SHR.  J Hypertension  23: 801–805, 2005.7.  He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, Wang J, Chen CS,Chen J, Wildman RP, Klag MJ, Whelton PK.  Major causes of deathamong men and women in China.  N Engl J Med   353: 1124–1134, 2005.8.  Hoagland KM, Maier KG, Roman RJ.  Contributions of 20-HETE to theantihypertensive effects of Tempol in Dahl salt-sensitive rats.  Hyperten-sion  41: 697–702, 2003.9.  Imig JD, Zou AP, Stec DE, Harder DR, Falck JR, Roman RJ. Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renalarterioles.  Am J Physiol  39: 217–227, 1996.10.  Ito O, Alonso-Galicia M, Hopp KA, Roman RJ.  Localization of cyto-chrome  P -450 4A isoforms along the rat nephron.  Am J Physiol RenalPhysiol  274: F395–F404, 1998.11.  Marji JS, Wang MH, Laniado-Schwartzman M.  Cytochrome  P -450 4Aisoform expression and 20-HETE synthesis in renal preglomerular arter-ies.  Am J Physiol Renal Physiol  283: F60–F67, 2002.12.  Miyata N, Taniguchi K, Seki T, Ishimoto T, Sato-Watanabe M,Yasuda Y, Doi M, Kametani S, Tomishima Y, Ueki T, Sato M, KameoK.  HET0016, a potent and selective inhibitor of 20-HETE synthesizingenzyme.  Br J Pharmacol  133: 325–329, 2001.13.  Roman RJ.  P -450 metabolites of arachidonic acid in the control of cardiovascular function.  Physiol Rev  82: 131–185, 2002. R1547 HYPERTENSION, MENOPAUSE AND 20-HETE  AJP-Regul Integr Comp Physiol  •  VOL 300  •  JUNE 2011  •  www.ajpregu.org
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