title: Sex differences and the effects of ovariectomy on the β-adrenergic contractile response.
abstract: 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 β(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 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 A(1) adenosine receptor (A(1)AR) in antagonizing the β-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 β-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 β-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.
authors.affiliation: Department of Physiology and the Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: McIntosh
authors.forename: P Charukeshi
authors.initials: PC
authors.lastname: Chandrasekera
authors.forename: Robert D
authors.initials: RD
authors.lastname: Lasley
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010052:Ovariectomy; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D020536:Enzyme Activators; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D007545:Isoproterenol