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Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats
ORALS: Vasoactive Factors and Vascular Biology
A]H-APRIL 1997-VOL. 10, NO. 4, PART 2
EFFECT OF PROLONC3ED L-ARGININETREATMENTON VASCULARACTIONSINDUCEDBY LOSARTANIN SHR R Macso, E Redrigo,R Mufioz-Gamia, J Navarrn-Cid, LM Ruilop#, V Cachofeim,V I-ahem.Dpto Fisiologfa,Facultad Mcdicina, UCM & UnidadHiperte.nsifm,Hospital12 deOctubre, Madrid,,Spain. Wepcevio.sly repted that nitric oxide (NO) participstea in the antihypsrtesiveeffect oflosartan in SHR. The administration of the precuraorof NO, L-arginine, hea shown kseficial effmts on bloodpressure and endotbelial function in Dahl salt-semitive rats. In the present study We have evahtatad tfte effects of prelongcd L-arginine administration on artihypcrtcnsive and vascular actions induced by Iosartattin SHR. Male SHR 2Qwceka
old receivedone of the followingtreatments in drinking water for 12 weeks: h+rginine (660 mg/Kg/day), Iosartan (10 mg/Kg/chiy) and L-arginine+loanttan. A controlgroup with no treatment wua run in parallel. Systolic blood pressure (SBP) and relaxing and contractingrespmaes in aorric rings were evsluatcd in all groups. Chronic oral administrationof Iosai-tansignificantlyreduced SBP (158 t 3 w 189 + 4 mmHg; p< O.05) compared to controls. Oose-relatedrcspcmaeato acetylcholine(Ach; l@-lO+mol/l) were enbaccdby Ip$urtanadministration(maximalresponse: 83 + 8 vs W * 3 % of prccontraction to phenylephrine). However, responses to supcroxide-dismutuse(SOD; O.I-IGO HJ/ml) and sodium nitropcwside(sNP; 10’0-10’mol/1)were not affected by Iosastan. L-arginine treatment, did not modify either SBP or vssctdar reactivity. By contrast, L-arginine attenuated the antihypertensive effect of Iosattan, as well M the etiand relaxation co Ach induced by losartan. Maximal constrictor
respmscs to phenylephrine,endotbelin-1and the thrombexane AZ analogue, U46619, were.not affectedby any of the trcatmenta. In conclusion: 1) the antihypa-leoaiveeffect of losartanis associated
withan improvement
of Ach-induoed
relaxation in sertic rings
2) prolonged treatment with elevated doses of L. arginine exei?s deleterious effecta’of the vascular actions of Iosatmnin SHR. Kay Words: Nitric oxide, L-arginine, AT,-antagoctist, vascular function, blood pressure from SHR,
—.
EFFECTOFCHRONIC ETA-SELECTIVE ENDOTHELIN RECEPTOR ANTAGONISM ONBLOODPRESSUREfN EXPEfU~NTAL AND GENETIC HYPERTENSIONR4 RATS. A Turgeon, ELS$lWh*. Clinical Research Institute, University of Montr4al, MontWal, Qc, Canada.
Treabnent with an ET.133TBendotbelbt receptor wdagonist reducedbloodpressurein rat modelsof hypertensionwbich ovcrexprcss endothelin-1in the vasculacwall, particularlyin small arteries,but not in those mndcls of hypertensionwhich do not overexptasssndotbelin-1. Sincefailureto respondto the 13T.lET,antagonistcouldbe due in partto blockadeofvasorelaxantendotbelialETBreceptors, the effect of selective ETA antagonism(with A-127722.5or LU13S252)was investigated. Bloodpressureof deoxycorticesterone acetate(DOCA)-sabhypertensive rats (which overcxprcssVUSCUIW endotbelin-1and respond with blocd pressureloweringto ET./ET, antagonism),was Iowercdby a meanof24 and of 27 mmHg(p
convetiingenzymeinhibitorcilazapril(whichmightsensitizeresponsesto endotbelinantagonism)resultedin similarloweringof bloodpressure in A-127722 .5-traated anduntreated SHR.One-kidney1clip Gcddblatt(l-K lC) hypertensiverats (whichpresentmild overexprsssionof endotbelin-1 antagonism) but do not respondwithbloodPressure lowering to ETA/ETB treated with LU135252at tbs dose which Iow.wadblood preaaurcin DGCA-sabrats did not exhibitbloodpressurereduction.Thus,treatment witheidmrdow of A-127722.5orwitb the doseusedLU135252resultsin blood ptcssure lowering sintilat to that obtsbted with an ET,@TLI andothelinantagonist.Bloodprcssumwas Iowemdonly in h~mnsivc rats known to overexprcss vitseuhu endothelin-1 (DOCA-sab bypmcnsiverats)but not in thosewbichdo not @fR) or onlyhave mild vasoulacovet’expression ofertdothelin-1gene(l-K lC bypmtensiverats). interruptionof the renin-mgiotansinayscatnin SHR did net sensitize blood prassura to potential hypotcnsiveeffects of m ET.-selective receptorantagonist. Key Words: Endothelin raceptorsubws, antagonists,DOCA,renal and genetichypertension,SHR, attgiotensinconverting enzymeinhibitor
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A]H-APRIL 1997-VOL. 10, NO. 4, PART 2
EFFECT OF PROLONC3ED L-ARGININETREATMENTON VASCULARACTIONSINDUCEDBY LOSARTANIN SHR R Macso, E Redrigo,R Mufioz-Gamia, J Navarrn-Cid, LM Ruilop#, V Cachofeim,V I-ahem.Dpto Fisiologfa,Facultad Mcdicina, UCM & UnidadHiperte.nsifm,Hospital12 deOctubre, Madrid,,Spain. Wepcevio.sly repted that nitric oxide (NO) participstea in the antihypsrtesiveeffect oflosartan in SHR. The administration of the precuraorof NO, L-arginine, hea shown kseficial effmts on bloodpressure and endotbelial function in Dahl salt-semitive rats. In the present study We have evahtatad tfte effects of prelongcd L-arginine administration on artihypcrtcnsive and vascular actions induced by Iosartattin SHR. Male SHR 2Qwceka
old receivedone of the followingtreatments in drinking water for 12 weeks: h+rginine (660 mg/Kg/day), Iosartan (10 mg/Kg/chiy) and L-arginine+loanttan. A controlgroup with no treatment wua run in parallel. Systolic blood pressure (SBP) and relaxing and contractingrespmaes in aorric rings were evsluatcd in all groups. Chronic oral administrationof Iosai-tansignificantlyreduced SBP (158 t 3 w 189 + 4 mmHg; p< O.05) compared to controls. Oose-relatedrcspcmaeato acetylcholine(Ach; l@-lO+mol/l) were enbaccdby Ip$urtanadministration(maximalresponse: 83 + 8 vs W * 3 % of prccontraction to phenylephrine). However, responses to supcroxide-dismutuse(SOD; O.I-IGO HJ/ml) and sodium nitropcwside(sNP; 10’0-10’mol/1)were not affected by Iosastan. L-arginine treatment, did not modify either SBP or vssctdar reactivity. By contrast, L-arginine attenuated the antihypertensive effect of Iosattan, as well M the etiand relaxation co Ach induced by losartan. Maximal constrictor
respmscs to phenylephrine,endotbelin-1and the thrombexane AZ analogue, U46619, were.not affectedby any of the trcatmenta. In conclusion: 1) the antihypa-leoaiveeffect of losartanis associated
withan improvement
of Ach-induoed
relaxation in sertic rings
2) prolonged treatment with elevated doses of L. arginine exei?s deleterious effecta’of the vascular actions of Iosatmnin SHR. Kay Words: Nitric oxide, L-arginine, AT,-antagoctist, vascular function, blood pressure from SHR,
—.
EFFECTOFCHRONIC ETA-SELECTIVE ENDOTHELIN RECEPTOR ANTAGONISM ONBLOODPRESSUREfN EXPEfU~NTAL AND GENETIC HYPERTENSIONR4 RATS. A Turgeon, ELS$lWh*. Clinical Research Institute, University of Montr4al, MontWal, Qc, Canada.
Treabnent with an ET.133TBendotbelbt receptor wdagonist reducedbloodpressurein rat modelsof hypertensionwbich ovcrexprcss endothelin-1in the vasculacwall, particularlyin small arteries,but not in those mndcls of hypertensionwhich do not overexptasssndotbelin-1. Sincefailureto respondto the 13T.lET,antagonistcouldbe due in partto blockadeofvasorelaxantendotbelialETBreceptors, the effect of selective ETA antagonism(with A-127722.5or LU13S252)was investigated. Bloodpressureof deoxycorticesterone acetate(DOCA)-sabhypertensive rats (which overcxprcssVUSCUIW endotbelin-1and respond with blocd pressureloweringto ET./ET, antagonism),was Iowercdby a meanof24 and of 27 mmHg(p
convetiingenzymeinhibitorcilazapril(whichmightsensitizeresponsesto endotbelinantagonism)resultedin similarloweringof bloodpressure in A-127722 .5-traated anduntreated SHR.One-kidney1clip Gcddblatt(l-K lC) hypertensiverats (whichpresentmild overexprsssionof endotbelin-1 antagonism) but do not respondwithbloodPressure lowering to ETA/ETB treated with LU135252at tbs dose which Iow.wadblood preaaurcin DGCA-sabrats did not exhibitbloodpressurereduction.Thus,treatment witheidmrdow of A-127722.5orwitb the doseusedLU135252resultsin blood ptcssure lowering sintilat to that obtsbted with an ET,@TLI andothelinantagonist.Bloodprcssumwas Iowemdonly in h~mnsivc rats known to overexprcss vitseuhu endothelin-1 (DOCA-sab bypmcnsiverats)but not in thosewbichdo not @fR) or onlyhave mild vasoulacovet’expression ofertdothelin-1gene(l-K lC bypmtensiverats). interruptionof the renin-mgiotansinayscatnin SHR did net sensitize blood prassura to potential hypotcnsiveeffects of m ET.-selective receptorantagonist. Key Words: Endothelin raceptorsubws, antagonists,DOCA,renal and genetichypertension,SHR, attgiotensinconverting enzymeinhibitor
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