Progestins oppose the effects of estradiol on the endothelin-1 receptor type B in coronary arteries from ovariectomized hyperlipidemic rabbits

Objective: Progestins may be associated with the adverse cardiovascular outcomes observed with estrogen plus progestogen therapy, but the mechanism is not resolved. In this study we examined the effect of 17 beta-estradiol (E-2) alone and in combination with two progestins on the endothelin-1 (ET-1) system in coronary arteries. Design: Watanabe heritable hyperlipidemic rabbits were treated orally with either E-2 (4 mg/d), medroxyprogesterone acetate (MPA) (10 rng/d), norethisterone acetate (NETA) (2 mg/d), E-2 + MPA, E-2 + NETA, or placebo for 16 weeks (n = 10 in each group). Coronary arteries were used for mRNA and myograph analyses. Results: E-2 alone but not in combination with MPA or NETA increased ETB mRNA expression in coronary arteries. Accordingly, E-2 alone but not in combination with MPA or NETA reduced the maximal contraction to ET-1, and the reduction was sustained after ETA but not after ETB blockade. E-2 reduced preproendothelin-1 mRNA expression; however, this effect was not blunted by MPA or NETA. ETA and ET-converting enzyme-1 mRNA expression was unaffected by treatment. Conclusions: The data suggest that long-term E-2 treatment selectively attenuates ET-1-induced vasoconstriction, possibly by increasing ETB gene expression in rabbit coronary arteries and that this effect is abolished by the two progestins investigated. This observation may help to explain how progestins oppose the supposed beneficial effects of estrogen on the arterial wall.