Sex differences and the effects of ovariectomy on the β-adrenergic contractile response.
Sex differences and the effects of ovariectomy on the β-adrenergic contractile response.
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性别差异和卵巢切除术对β-肾上腺素能收缩反应的影响。
DOI：
10.1152/ajpheart.00711.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Lasley,RobertD
中科院分区：
文献类型：
--
作者：
McIntosh,VictoriaJ;Chandrasekera,PCharukeshi;Lasley,RobertD
心肌β-肾上腺素能反应性存在性别差异是有争议的，有限的研究已经解决了这些差异的机制。使用雄性、完整雌性和卵巢切除雌性小鼠的离体灌注心脏进行研究，以研究性别差异和卵巢激素戒断对β-肾上腺素能受体功能的影响。与雄性动物相比，雌性动物心脏对β-肾上腺素能受体激动剂异丙肾上腺素（ISO）的收缩反应减弱，但卵巢切除雌性动物的收缩反应未减弱。β1肾上腺素能受体基因和蛋白表达无性别差异。为了研究腺苷酸环化酶、磷酸二酯酶和cAMP信号级联在β-肾上腺素能收缩反应中产生性别差异的作用，在离体灌注的雄性和雌性心脏中使用毛喉素、3-异丁基-1-甲基黄嘌呤（IBMX）和8-（4-氯苯硫基）腺苷3′，5 ′-环磷酸（CPT-cAMP）进行剂量反应研究。与雌性动物相比，雄性动物对300 nM和5 μM毛喉素的收缩反应适度增强，但对IBMX或CPT-cAMP的反应无性别差异。用腺苷A1受体激动剂2-氯-N6-环戊基-腺苷和A1受体敲除（KO）小鼠研究了A1受体（A1 AR）在拮抗β-肾上腺素能收缩反应中的作用。与雄性和卵巢切除雌性相比，完整雌性显示出增强的A1 AR抗肾上腺素能效应。在雄性和雌性A1 ARKO心脏中，β-肾上腺素能收缩反应均增强，高于1 nM ISO时不再存在性别差异。男性心脏的β-肾上腺素能收缩反应大于女性，腺苷酸环化酶或A1 AR作用的微小差异可能导致这些性别差异。
The presence of sex differences in myocardial β-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on β-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the β-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in β1-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the β-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1-methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 μM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist 2-chloro-N6-cyclopentyl-adenosine and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared with males and ovariectomized females. The β-adrenergic contractile response was potentiated in both male and female A1ARKO hearts, with sex differences no longer present above 1 nM ISO. The β-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A1AR may contribute to these sex differences.