Progestins used in hormonal replacement therapy display different effects in coronary arteries from New Zealand white rabbits.
OBJECTIVE
The aim of this study was in an animal model to assess the vascular effects of different progestins commonly used in hormonal replacement treatment.


METHODS
Fifty-six non-atherosclerotic, ovariectomized New Zealand white rabbits were randomized into seven groups: (1) medroxyprogesterone acetate (MPA), (2) norethisterone acetate (NETA), (3) conjugated equine estrogens (CEE), (4) 17-beta-estradiol (E2), (5) MPA+CEE , (6) NETA+E2 , (7) or placebo (n=8) and given hormonal treatment through the diet for 4 weeks. Ring segments from the left proximal coronary artery and from the distal part of the left anterior descending coronary artery were microdissected and mounted for isometric tension recordings in a myograph. The vasoconstrictory responses induced by potassium, endothelin-1, calcium and Nw-nitro-L-arginine methyl ester, and the vasodilatory response induced by acetylcholine and sodiumnitroprusside were investigated. The maximum contraction/relaxation (Emax) and the concentration required to induce half the maximum response (EC50) were determined. EC50 values were expressed as the negative logarithm to the molar concentration, pD2=-log EC50.


RESULTS
Treatment with MPA alone caused when compared to treatment with NETA an increase in tension development in the distal coronary artery after the addition of potassium ( 6.36+/-0.36 versus 4.31+/-0.42 P<0.005) (single dose response, mN/mm, mean+/-S.E.M.) and endothelin-1 (9.41+/-0.82 versus 6.43+/-0.73 P<0.05) (Emax, mN/mm, mean+/-S.E.M.). Treatment with MPA compared to placebo caused an endothelin-1 induced increase of Emax in the distal coronary artery (9.21+/-0.87 versus 6.51+/-0.65 P<0.05) and a calcium induced increase of pD2 in both coronary arteries (2.98+/-0.19 versus 2.42+/-0.12 P<0.05, proximal coronary artery) (3.26+/-0.09 versus 2.9+/-0.1 P<0.05, distal coronary artery) (pD2, mean+/-S.E.M.). Treatment with NETA compared to placebo in the proximal coronary artery, after the addition of sodiumnitroprusside caused a decrease of pD2 (5.33+/-0.19 versus 5.94+/-0.13 P<0.05). Treatment with E2 compared to treatment with CEE in the proximal coronary artery caused a decrease of pD2 after the addition of sodiumnitroprusside (5.00+/-0.16 versus 5.77+/-0.28 P<0.05). No significant differences were found between MPA+CEE and NETA+E2.


CONCLUSIONS
Treatment with MPA alone seems to enhance the contractile response to potassium and endothelin-1 in the distal coronary artery compared to NETA, indicating that different progestins used in hormonal replacement treatment may display different effects on contractile functions of coronary arteries.
Pedersen
Nina G
NG
Department of Obstetrics and Gynaecology, Clinical Research Unit, Hvidovre University Hospital, Copenhagen, Denmark.
Pedersen
Susan H
SH
Dalsgaard
Tórur
T
Lund
Claus O
CO
Nilas
Lisbeth
L
Ottesen
Bent
B
D000109:Acetylcholine; D000818:Animals; D001158:Arteries / Q000187:drug effects; D002118:Calcium; D003331:Coronary Vessels / Q000187:drug effects*; D004195:Disease Models, Animal; D019332:Endothelin-1; D004958:Estradiol / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology; D005260:Female; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008593:Menopause; D019331:NG-Nitroarginine Methyl Ester; D009599:Nitroprusside; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077563:Norethindrone Acetate; D010052:Ovariectomy; D011188:Potassium; D011372:Progestins / Q000494:pharmacology*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D019332:Endothelin-1; D004966:Estrogens, Conjugated (USP); D011372:Progestins; D009599:Nitroprusside; D004958:Estradiol; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium; D009640:Norethindrone; D019331:NG-Nitroarginine Methyl Ester