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 to 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, IBMX, and CPT-cAMP. Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 uM as compared to females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1 adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist CCPA and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared to 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.
- Adenosine Receptor
- Beta-adrenergic Receptor
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology