Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand White rabbit.
OBJECTIVE
The lack of a cardioprotective effect of hormone replacement therapy (HRT), as suggested by the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI) may in part be explained by the progestin used. The aim of this study was to elucidate the effect of different progestins on cerebrovascular reactivity in an animal model.


METHODS
Fifty-six ovariectomized New Zealand White rabbits were randomized into seven groups receiving hormone treatment for 4 weeks: medroxyprogesterone acetate (MPA) (10 mg/day); norethisterone acetate (NETA) (3 mg/day); conjugated equine estrogens (CEE) (1.25 mg/day); 17beta-estradiol (E2) (4 mg/day); MPA + CEE (10 mg/day + 1.25 mg/day); NETA + E2 (3 mg/day + 4 mg/day); or placebo. Segments from the basilar and posterior cerebral arteries were mounted in myographs for tension recordings. Concentration-response curves to potassium, acetylcholine, sodium nitroprusside, L-NAME (N(omega)-nitro-L-arginine methyl ester), calcium and endothelin-1 were established.


RESULTS
Treatment with MPA caused a significant increase in vasoconstriction, expressed as E(max) (mN/mm, mean +/- SEM; p < 0.05), in response to potassium (3.18 +/- 0.19 vs. 2.47 +/- 0.19) and calcium (4.00 +/- 0.22 vs. 3.34 +/- 0.14) in the posterior cerebral artery, and to endothelin-1 (6.88 +/- 0.69 vs. 5.22 +/- 0.30) in the basilar artery, when compared with NETA. This difference was neutralized in the groups receiving the combined treatment of MPA + CEE and NETA + E2. No overall differences were seen between CEE and E2.


CONCLUSIONS
In rabbit cerebral arteries, MPA treatment causes a higher development in arterial tension compared with NETA, indicating that different progestins may display different cerebrovascular effects. However, when accompanied by estrogens, as in the case of HRT, this difference is eliminated.
Pedersen
S H
SH
Clinical Research Unit and Department of Obstetrics and Gynecology, Hvidovre University Hospital, Copenhagen, Denmark.
Pedersen
N G
NG
Dalsgaard
T
T
Lund
C O
CO
Nilas
L
L
Ottesen
B
B
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000473:pathology; D003251:Constriction, Pathologic / Q000139:chemically induced; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology; D005260:Female; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D023421:Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077563:Norethindrone Acetate; D010052:Ovariectomy; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D011897:Random Allocation; D014665:Vasodilator Agents / Q000494:pharmacology
D003271:Contraceptive Agents, Female; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D004958:Estradiol; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium; D009640:Norethindrone; D019331:NG-Nitroarginine Methyl Ester