4.6 Article

Sex differences and the effects of ovariectomy on the β-adrenergic contractile response

Journal

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00711.2010

Keywords

cardiac; beta-adrenergic; adenosine receptor; gender; ovariectomy

Funding

  1. National Heart, Lung, and Blood Institute [R01HL-066132]

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McIntosh VJ, Chandrasekera PC, Lasley RD. Sex differences and the effects of ovariectomy on the beta-adrenergic contractile response. Am J Physiol Heart Circ Physiol 301: H1127-H1134, 2011. First published June 17, 2011; doi:10.1152/ajpheart.00711.2010.The presence of sex differences in myocardial beta-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 beta-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the beta-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in beta(1)-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 beta-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 mu M compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A(1) adenosine receptor (A(1)AR) in antagonizing the beta-adrenergic contractile response was investigated using both the A(1)AR agonist 2-chloro-N-6-cyclopentyl-adenosine and A(1)AR knockout (KO) mice. Intact females showed an enhanced A(1)AR anti-adrenergic effect compared with males and ovariectomized females. The beta-adrenergic contractile response was potentiated in both male and female A(1)ARKO hearts, with sex differences no longer present above 1 nM ISO. The beta-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A(1)AR may contribute to these sex differences.

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