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Modulatory effects of progestins on long-term estrogen treatment in coronary arteries from hyperlipidemic rabbits

Susan Helene Pedersen Laursen

Summary

In contrast to numerous epidemiological and experimental studies, randomized clinical trials have refuted a beneficial cardiovascular effect of long-term combined hormone replacement treatment (HRT) in post-menopausal women. It has been proposed that the progestin component in HRT may oppose the potentially beneficial effects of estrogen on vascular function and that different combinations of estrogen and progestin may affect vascular function differently.

This thesis elucidates possible mechanisms of actions of long-term 17Ŗ-estradiol (E2) treatment alone or in combination with two commonly applied progestin compounds i.e. medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) in an animal model of human menopause. It is hypothesized that the progestin component modulates the effect of estrogen and that different progestins exert differential effects on coronary vascular function. The first study examined the effect of long-term E2 treatment alone and in combination with MPA or NETA on the endothelin-1 (ET-1) system, and the second study examined the effect of treatment on nitric oxide, K+ and Ca2+-mediated mechanisms.

Watanabe Heritable Hyperlipidemic rabbits were treated orally with either E2 (4mg/day), medroxyprogesterone acetate (MPA) (10mg/day), norethisterone acetate (NETA) (2mg/day), E2+MPA, E2 + NETA, or placebo for 16 weeks (n=10 in each group). Intramural distal coronary arteries were used for mRNA and myograph analyses.

The results of the first study demonstrate a reduction in the vasoconstrictor response to ET-1 with E2 treatment. This reduction was sustained with ETB but not ETA receptor stimulation and ETB mRNA was increased with E2 treatment, which suggests that the vascular response was mediated through regulation of the ETB receptor. The alteration in coronary responsiveness and gene expression was opposed by the addition of MPA and NETA. Furthermore, E2 decreased the production of ET-1 and this was not opposed by the two progestins. ETA receptor and endothelinconverting- enzyme mRNA was unaffected by treatment.

The second study found that E2 treatment increased vasodilatation induced by sodium nitroprusside and decreased vasocontraction induced by potassium. The first but not the latter response was opposed by MPA. The combination of MPA and E2, but neither compound alone enhanced nimodipine induced vasodilatation and increased the expression of voltage-gated Ca2+ Summary vii channel mRNA. NETA had no opposing effects. Hormone treatment did not affect largeconductance Ca2+ -activated K+-channel, ATP-sensitive K+-channels or cGMP-dependent protein kinase mRNA expression. Hyperlipidemia had no effect on vascular reactivity in either study.

The results of the studies show that long-term E2 treatment exerts beneficial vascular effects in coronary arteries from hyperlipidemic rabbits, and that the progestin component may modulate the effects of estrogen. A differential effect of MPA and NETA is observed when evaluating calciummediated mechanisms but not the ET-1 system. The results may contribute some understanding to the effects of HRT on coronary vascular function.