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Background-Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17␤-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ER␣ and ER␤. However, which ER is critically involved in the modulation of LVH is poorly understood. We therefore used ER␣-deficient (ER␣ Ϫ / Ϫ ) and ER␤-deficient (ER␤ Ϫ / Ϫ ) mice to analyze the respective ER-mediated effects. Methods and Results-Respective ER-deficient female mice were ovariectomized and were given E2 or placebo subcutaneously using 60-day release pellets. After 2 weeks, they underwent transverse aortic constriction (TAC) or sham operation. In ER␣ Ϫ / Ϫ animals, TAC led to a significant increase in ventricular mass compared with sham operation. E2 treatment reduced TAC induced cardiac hypertrophy significantly in wild-type (WT) and ER␣ Ϫ / Ϫ mice but not in ER␤ Ϫ/Ϫ mice. Biochemical analysis showed that E2 blocked the increased phosphorylation of p38 -mitogen-activated protein kinase observed in TAC-treated ER␣ Ϫ / Ϫ mice. Moreover, E2 led to an increase of ventricular atrial natriuretic factor expression in WT and ER␣ Ϫ / Ϫ mice. Conclusions-These findings demonstrate that E2, through ER␤-mediated mechanisms, protects the murine heart against LVH. Key Words: hypertrophy Ⅲ hormones Ⅲ myocardium Ⅲ gender T he increase of left ventricular mass represents a structural mechanism of compensation of the heart in response to pressure overload. The resulting left ventricular hypertrophy (LVH) is an important, independent negative predictor of cardiac morbidity and mortality. 1 LVH displays significant gender-based differences. Premenopausal women have a lower prevalence of LVH than men. 2 The Coronary Artery Risk Development In young Adults (CARDIA) study demonstrated a higher prevalence of LVH in men, even after correction for a large number of risk factors. It further demonstrated that the difference in left ventricular size begins early in life (ie, before menopause), suggesting that intrinsic factors are involved in the induction of LVH. 2 Sex hormones such as estrogen have been attributed to play an important role in the pathogenesis of cardiovascular disease. The recent clinical trials with respect to the therapeutic role of 17␤-estradiol (E2) vascular disease are controversial. 3 However, the potential of E2 as a therapeutic option in the modulation of cardiac disease remains poorly understood. It has been demonstrated that estrogens are able to attenuate hypertrophic responses. 4,5 E2 appears to act as a cardioprotective steroid hormone. However, the underlying mechanisms of E2 protection of the myocardium are not fully understood. Myocytes and fibroblasts contain functional estrogen receptors (ERs) ER␣ and ER␤. Via these receptors, E2 modulates the activity of the mitogen-activated protein kinase (MAPK) pathways in cardiac myocytes. 6 The MAPK signaling pathways consist of a sequence of successively acting kinases that ultimately result in the dual...

Effect of catecholamine-receptor stimulating agents on blood pressure after local application in the nucleus tractus solitarii of the medulla oblongata, European J. Pharmacol. 55 (1979) 43--56.The effect of various catecholamines and a-mimetics, given by microinjection in the A2-region of the nucleus tractus solitarii (NTS), on blood pressure was investigated in anesthetized male rats. A dose-dependent decrease of blood pressure and heart rate was induced by adrenaline as the most effective drug, followed by noradrenaline, dopamine, a-methylnoradrenaline and octopamine. Ablation of the rostral or caudal part of the NTS, or removal of the area postrema did not diminish the effect of a-methylnoradrenaline. Higher doses of noradrenaline and a-methylnoradrenaline caused an initial rise of blood pressure, while the blood pressure lowering effect of noradrenaline was diminished, and that of a-methylnoradrenaline and dopamine delayed. Isoprenaline and the (+)-stereoisomers of noradrenaline and a-methylnoradrenaline were ineffective. The hypotensive effect of dopamine was not prevented by systemic injection of the dopamine ~-hydroxylase inhibitor FLA 63. Prior application of haloperidol, yohimbine and phentolamine antagonized the hypotensive response to dopamine and a-methylnoradrenaline. Application of peripherally effective a-mimetics into the A2-region had no or little effect, while high doses increased blood pressure. Tyramine and clonidine caused some decrease of blood pressure. Clonidine also decreased blood pressure when it was applied in the area of the locus coeruleus. Application of isoprenaline in the locus coeruleus also decreased blood pressure while in contrast adrenaline, noradrenaline, dopamine and 0l-methylnoradrenaline increased blood pressure. The present data suggest that the catecholaminergic receptors in the A2-region of the NTS differ from the classic vascular a-receptor and that the NTS also may contain structures which can antagonize the decrease in blood pressure. Catecholamines a-Mimetics Locus coeruleusDecrease of blood pressure Nucleus tractus solitarii

Although E2 modulates the infarct size in ERalpha(-/-), it also appears to be responsible for the higher mortality following MI. ERbeta appears to be the receptor involved in the modulating effects of E2 in the infarcted heart.

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