F041 Relaxant effects of progesterone and synthetic progestins in rat aorta in comparison to 17β-estradiol

F041

F041 (cant)

RELAXANT EFFECTS OF PROGESTERONE AND SYNTHETIC PROGESTINS IN RAT AORTA IN COMPARISON TO 17l3-ESTRADIOL E Glusa’, S Wagner’,

T Gr&er, M Oettel,

JenapharmGmbH D-07745 Jena and University Jena,Center for VascularBiology andMedicine’, D-99089Erfurt, Germany

When endothelium-denuded vesselswere pretreated with the hormonesfor 60 or 90 mitt, the concentrationresponse curvesfor PE were shifted to the night in comparisonto the curves for PE in vesselswith intact endothelium. The maximumcontractileeffects werereducedby 15-30%. In calcium-freemediumwith 60 mM KC1 contractions were induced by cumulative addition of CaC12. Progesterone, NETA and CMA (10 pM each) as well as 17B-E causeda parallel shift to the right of the concentrationresponse curve for CaC12with a suppression of the maximumresponse (1530%). 178-E was the most potent inhibitor. In all experiments dienogesthad no effect. Estrogen ‘or progesteronereceptor antagonistsdid not interfere with the relaxant responseto progesteroneor 178-E. Indomethacin(3 FM) and glibenclamide (1uM) did not impair the effects of the hormones. Thesestudies suggestthat besides178-E the progestinsprogesterone,CMA and NETA causeda reductionof vasculartoneprobablydueto blockade of voltage-dependent calciumchannels.

Hormonereplacementtherapy (HRT) in postmenopausal womenis associated with a decreased incidenceof ischemicheartdisease that is partly explainedby the relaxant action of estrogenson arteries. However,the effect of progestinsasconstituentsof HRT is scarcely investigated. In the presentpaperthe influenceof progesterone, chlormadinoneacetate(CMA), norethisteroneacetate(NETA) and dienogest(DNG) in comparison to 17l3-estradiol (17B-E)on vascular toneof rat aortawasstudied.Ringsfrom therat aortawereplacedin an organbath for isometrictensionrecording. Contractionswere inducedby KC1 (30 mM), phenylephrine(PE, 1pM or IOnM-10 PM) or CaCl* (0.3-20 mM). The integrity of endotheliumwas assessed by the relaxant responseto acetylcholine(10 nM-1OyM) whichwasdiminishedafter pretreatment with NG-nitro-L-arginineor mechanicalremovalof the endothelium.The concentrationsof the steroid hormoneswere 0.1-10 pM In PE-precontractedvessels progesterone (10 pM) caused an endothelium-independent relaxation of about 25 % with a maximumwithin 30 min, the responseof CMA and NETA amountedto 15 % while a 30 % relaxationwas found in responseto 17R-E. In KCI-precontracted vesselsthe relaxant effect was somewhatmore pronounced. Combinationof progesteroneand 178-E indicated an additive relaxanteffect. Continued

F042 (cant)

F042 RALOXIFENE INHIBITS AORTIC ACCUMULATION OF CHOLESTEROL IN OVARIECTOMIZED, CHOLESTEROLFED RABBITS. NH Biarnason’, Christiansen’.

J Haarbo’,

I Byrjalsed,

R Kauffman’,

C

1: Centerfor Clinical & BasicResearch,BallerupByvej 222, 2750 Ballerup, Denmark. 2: Eli Lilly Research Laboratories, Indianapolis,Indiana46265,US The protective effect of long-term hormonereplacementtherapy against cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstratedskeletalantiresorptiveand hypolipedemicproperties without stimulatingthe endometrium. To study the effect on atherogenesis 100rabbits(75 ovx.) weretreatedandcholesterol-fed for 45 weeks(Table). Blood samplingwasperformedrepeatedlyto determineserumlipids and lipoproteins,estradioland raloxifene. After sacrificethe cholesterolcontent of aorta (aortic chol.) was measuredand normalizedfor aortic protein content. Uteruswas weighed and taken. I----- endometrialspecimens i sham ovx 3.5/35 mg 4mg178 Pmplac. plac. raloxifene estradiol Aver. serum 17.3 18.9 16.1 15.0 NS *1.12 chol.(mmoliI)41.45+I.42 fl .Ol Aortic chol. 473 577 397 177 < (nmol/mgprot)&59.6k55.1 *53.6 Continued

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Comparedto placebo. aortic chol. \vas significantly reduced in raloxifene(p=O.O2)andestrogen(p