- Email: [email protected]
F094 improved nitric oxide synthesis in postmenopausal women treated with 17β-estradiol valerate-evidence for responders and non-responders
F094
F093 (cent)
In the E2 group NO concentrations on day 2 were significantly higher than on day 1 (37.3 + 7.6 vs 21.4 2 7.7 umol/l); moreover, NO levels in the E2 group resulted significantly higher than in the placebo group on day 2 (37.3 + 7.6 vs 22 F 4.3 ~moi/l), day 3 (47.5 2 17.8 vs 18.2 4 3.9 pmolil), day 5 (40.7 5 17.1 vs 19.2 5 6.0 umolil), day 6 (38.1 2 18.3 vs 20.0 t 4.9 umol/l) and day 7 (33.4 + 5.2 vs 22.5 k 5.7 pmol/l); the area under the curve of NO metabolites concentrations in the E2 group between day I and 8 was about 50% greater that in the placebo group. In conclusion, shortterm transdermal E2 administration increases NO production in postmenopausal women; although long-term effects should be evaluated, our data suggest that a NO-mechanism could contribute to explain the cardiovascular protective effect of ERT in postmenopausal women.
F095
IMPROVED NITRIC OXIDE SYNTHESIS IN POSTMENOPAUSAL WOMEN TREATED WITH 178ESTRADIOL VALERATE - EVIDENCE FOR RESPONDERS AND NON-RESPONDERS
B Imthurn, M Rosselli,A WJig&‘, R K Dubey*, P J Keller. Clin. Endo~rinolo8y,Dep. of Obstet.andGynecol., Univ. Hospitai, Zurich; #Schering (Schweiz) AG, Zurich, Switzerland; *CIin. Pharm.Univ. PittsburghMed. Center,PittsburghPA, USA. Increasedincidenceof cardiovasculardiseasein postmenopausal women(PMW) is related to ovarian dysfunction while hormone replacementtherapy (HRT) has cardioprotectiveeffects. Since atherosclerosis andhype~ensionis associated with impairedrelease of endothelium-derived nitric oxide (NO), we investigatedwhether HRT augmentsthe levelsof circulatingNO.- Twenty-sevenPMW received2mgestradiolvalerateper day orally for 21 days. Serum nitrite/nitrate(N02-/Nos.)levelswereassessed prior to initiation of HRT and after 12 months of treatment. Whereasthe mean NOz/NOJ. levels rised from 21612.1pmol/L at baseline to 30.0~3.7~mol/L(p=O.OOS)after 12 months, this increasewas significant(>30%; responders) in only 14 out of 27 PMW. In the remaining 13 PMW (non-responders) there was only a slight increase,no change or even a decreasein NOJNOs. levels. Furthermore,elevatedN02/N03-levelsin responders correlatedwith decreased serumLDL-C (low densitylipoprotein}levels @=0.154, p=O.O38).- Our datasuggest,that a considerabie number,but not all PMW fully profit from the cardioprotectiveeffectsof HRT.
F096
THE VASORELAXANT EFFECT OF A SERIES OF ESTROGENIC AGONISTS AND PARTIAL AGONISTS IS NOT CORRELATED TO THEIR AFFINITY AT THE ESTROGEN RECEPTOR
LOW-DOSE
M J Sheardown,S M Thorpe, Endocrinology, Novo Nordisk, Novo Nordisk Park, 2760-DK Maaloev, Denmark The relaxant effect of estrogenon pre~on~cted vasculartissueis well known. In this study we have investigatedthe relaxanteffects of 17-B-estradiol, estrone,estriol anda seriesof estrogenicagonists andpartial agonistsin ringsof rat thoracicaortapre-contractedwith 300 nM phenylephrine.The ECSO valuesfor 17-R-estradiol, estrone andestriolwere2 1, 250, and58 ,uM, respectively. The potenciesof the other compoundsinvestigatedwere raloxifene (61, tarnoxifen (29), diethylstilbestrol(44) and 17-a-estradiol(I 60). The relaxant effect of 17-&estradiolwas partly inhibited by the nitric oxide synthetaseinhibitor L-NAME (100 PM) andwassimilarly reduced in rings denudedof endothelium. The effects of raloxifene and tamoxifenwere greatly reducedin the presenceof L-NAME. The affinity of thesecompounds for bindingto the estrogenreceptorwas evaluatedin competitivebindingassays{competitionwith 3H-17-13estradiol)in rabbit uterinecytosolsusingthe classicaldextran-coated charcoal(DCC) assaymethod. Interestinglytherewasno significant correlationbetweenthe potency in the rat aorta and the binding afftnity (r2 = 0.001,p > 0.93) suggesting this rapidrelaxanteffect is not mediatedby the classicalestrogenreceptor. The data suggest that nitric oxide maybe at leastpartly involved.
72
HRT REDUCES VASCULAR RESISTANCE THE CENTRAL RETIN’AL ARTERY
IN
K M vanBaal, V. ~~atov~c, CD A ~fehouwer,J M C van Vugt, GA Dekker, HP van Ge@z,E R A Peters-Mder, G A Voetberg, M J van der Moore, P Kenemans. Prqject “Ageing Women”, Free University Hospital,De Boelelaan 1117,1007MB Amsterdam,TheNetherlands. Beneficial effects of HRT on the cardiovascularsystem in pos~enopau~ womenare not fully expiainedby changesin plasma lipoproteins.Directeffectsof oestrogens on vasculardynamicsarealso involved. Most studieshave investigatedeffects of unopposed oestrogens. Effectson thecentralretinalartery(CRA), asa parameter of circulationin smallarteries, havenot beenstudied.In aprospective study we random&d30 healthypostmenopausal women(meanage;52 years) intotwo groups.Fifteenwomenweretreatedwith orally 17Roestradioll mg daily and dydrogesterone, 5 or 10 mg daily (day 15-28),and comparedwith 15 non-treatedwomen. At baselineand atter three monthsof therapywemeasured vascular resistance (pulsatilityindex,PI) and flow of the CRA andof the uterineartery, usingColor-Doppler ultrasound,asa parameterof arterialfunction. At baseline,vascular resistanceparameterswere positively correlatedwith time since m~opause(CRA: rho=O.42;uterineartery: rho=#SO,PcO.05).After threemonths,themeanPI of theCRA decreased with 21%in the HRT groupversusa 9% increase in thecontrolgroup(P
F093 (cent)
In the E2 group NO concentrations on day 2 were significantly higher than on day 1 (37.3 + 7.6 vs 21.4 2 7.7 umol/l); moreover, NO levels in the E2 group resulted significantly higher than in the placebo group on day 2 (37.3 + 7.6 vs 22 F 4.3 ~moi/l), day 3 (47.5 2 17.8 vs 18.2 4 3.9 pmolil), day 5 (40.7 5 17.1 vs 19.2 5 6.0 umolil), day 6 (38.1 2 18.3 vs 20.0 t 4.9 umol/l) and day 7 (33.4 + 5.2 vs 22.5 k 5.7 pmol/l); the area under the curve of NO metabolites concentrations in the E2 group between day I and 8 was about 50% greater that in the placebo group. In conclusion, shortterm transdermal E2 administration increases NO production in postmenopausal women; although long-term effects should be evaluated, our data suggest that a NO-mechanism could contribute to explain the cardiovascular protective effect of ERT in postmenopausal women.
F095
IMPROVED NITRIC OXIDE SYNTHESIS IN POSTMENOPAUSAL WOMEN TREATED WITH 178ESTRADIOL VALERATE - EVIDENCE FOR RESPONDERS AND NON-RESPONDERS
B Imthurn, M Rosselli,A WJig&‘, R K Dubey*, P J Keller. Clin. Endo~rinolo8y,Dep. of Obstet.andGynecol., Univ. Hospitai, Zurich; #Schering (Schweiz) AG, Zurich, Switzerland; *CIin. Pharm.Univ. PittsburghMed. Center,PittsburghPA, USA. Increasedincidenceof cardiovasculardiseasein postmenopausal women(PMW) is related to ovarian dysfunction while hormone replacementtherapy (HRT) has cardioprotectiveeffects. Since atherosclerosis andhype~ensionis associated with impairedrelease of endothelium-derived nitric oxide (NO), we investigatedwhether HRT augmentsthe levelsof circulatingNO.- Twenty-sevenPMW received2mgestradiolvalerateper day orally for 21 days. Serum nitrite/nitrate(N02-/Nos.)levelswereassessed prior to initiation of HRT and after 12 months of treatment. Whereasthe mean NOz/NOJ. levels rised from 21612.1pmol/L at baseline to 30.0~3.7~mol/L(p=O.OOS)after 12 months, this increasewas significant(>30%; responders) in only 14 out of 27 PMW. In the remaining 13 PMW (non-responders) there was only a slight increase,no change or even a decreasein NOJNOs. levels. Furthermore,elevatedN02/N03-levelsin responders correlatedwith decreased serumLDL-C (low densitylipoprotein}levels @=0.154, p=O.O38).- Our datasuggest,that a considerabie number,but not all PMW fully profit from the cardioprotectiveeffectsof HRT.
F096
THE VASORELAXANT EFFECT OF A SERIES OF ESTROGENIC AGONISTS AND PARTIAL AGONISTS IS NOT CORRELATED TO THEIR AFFINITY AT THE ESTROGEN RECEPTOR
LOW-DOSE
M J Sheardown,S M Thorpe, Endocrinology, Novo Nordisk, Novo Nordisk Park, 2760-DK Maaloev, Denmark The relaxant effect of estrogenon pre~on~cted vasculartissueis well known. In this study we have investigatedthe relaxanteffects of 17-B-estradiol, estrone,estriol anda seriesof estrogenicagonists andpartial agonistsin ringsof rat thoracicaortapre-contractedwith 300 nM phenylephrine.The ECSO valuesfor 17-R-estradiol, estrone andestriolwere2 1, 250, and58 ,uM, respectively. The potenciesof the other compoundsinvestigatedwere raloxifene (61, tarnoxifen (29), diethylstilbestrol(44) and 17-a-estradiol(I 60). The relaxant effect of 17-&estradiolwas partly inhibited by the nitric oxide synthetaseinhibitor L-NAME (100 PM) andwassimilarly reduced in rings denudedof endothelium. The effects of raloxifene and tamoxifenwere greatly reducedin the presenceof L-NAME. The affinity of thesecompounds for bindingto the estrogenreceptorwas evaluatedin competitivebindingassays{competitionwith 3H-17-13estradiol)in rabbit uterinecytosolsusingthe classicaldextran-coated charcoal(DCC) assaymethod. Interestinglytherewasno significant correlationbetweenthe potency in the rat aorta and the binding afftnity (r2 = 0.001,p > 0.93) suggesting this rapidrelaxanteffect is not mediatedby the classicalestrogenreceptor. The data suggest that nitric oxide maybe at leastpartly involved.
72
HRT REDUCES VASCULAR RESISTANCE THE CENTRAL RETIN’AL ARTERY
IN
K M vanBaal, V. ~~atov~c, CD A ~fehouwer,J M C van Vugt, GA Dekker, HP van Ge@z,E R A Peters-Mder, G A Voetberg, M J van der Moore, P Kenemans. Prqject “Ageing Women”, Free University Hospital,De Boelelaan 1117,1007MB Amsterdam,TheNetherlands. Beneficial effects of HRT on the cardiovascularsystem in pos~enopau~ womenare not fully expiainedby changesin plasma lipoproteins.Directeffectsof oestrogens on vasculardynamicsarealso involved. Most studieshave investigatedeffects of unopposed oestrogens. Effectson thecentralretinalartery(CRA), asa parameter of circulationin smallarteries, havenot beenstudied.In aprospective study we random&d30 healthypostmenopausal women(meanage;52 years) intotwo groups.Fifteenwomenweretreatedwith orally 17Roestradioll mg daily and dydrogesterone, 5 or 10 mg daily (day 15-28),and comparedwith 15 non-treatedwomen. At baselineand atter three monthsof therapywemeasured vascular resistance (pulsatilityindex,PI) and flow of the CRA andof the uterineartery, usingColor-Doppler ultrasound,asa parameterof arterialfunction. At baseline,vascular resistanceparameterswere positively correlatedwith time since m~opause(CRA: rho=O.42;uterineartery: rho=#SO,PcO.05).After threemonths,themeanPI of theCRA decreased with 21%in the HRT groupversusa 9% increase in thecontrolgroup(P