Key result
Long-term 17beta-estradiol treatment selectively attenuated ET-1-induced vasoconstriction by increasing ETB gene expression in rabbit coronary arteries, an effect abolished by MPA and NETA.
Why the study?
Does the addition of progestins to estradiol alter the endothelin-1 system and vasoconstriction in coronary arteries of hyperlipidemic rabbits?
Does the addition of progestins to estradiol alter the endothelin-1 system and vasoconstriction in coronary arteries of hyperlipidemic rabbits?
Progestins abolish the beneficial vasodilatory effects of estradiol on the endothelin-1 system in coronary arteries, providing a potential mechanism for adverse cardiovascular outcomes with combined hormone therapy.
Progestins may abolish estradiol's coronary vasodilatory effects in this rabbit model; leaves open relevance to combined hormone therapy risks in women.
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 17beta-estradiol (E2) 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 E2 (4 mg/d), medroxyprogesterone acetate (MPA) (10 mg/d), norethisterone acetate (NETA) (2 mg/d), E2 + MPA, E2 + NETA, or placebo for 16 weeks (n=10 in each group). Coronary arteries were used for mRNA and myograph analyses. RESULTS: E2 alone but not in combination with MPA or NETA increased ETB mRNA expression in coronary arteries. Accordingly, E2 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. E2 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 E2 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.
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Pedersen et al. (2008) studied Hyperlipidemia (n=60). 17beta-estradiol (E2) alone and in combination with medroxyprogesterone acetate (MPA) or norethisterone acetate (NETA) vs. Placebo was evaluated on ETB mRNA expression and maximal contraction to ET-1 in coronary arteries. Long-term 17beta-estradiol treatment selectively attenuated ET-1-induced vasoconstriction by increasing ETB gene expression in rabbit coronary arteries, an effect abolished by MPA and NETA.
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