title: I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities.
abstract: 1. Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker I(f) current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)AR), or beta-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography. 2. Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3. Ivabradine was similarly effective in reducing HR in the beta(2)AR transgenic mice. Further, ivabradine at 10 mg kg(-1) day(-1) reduced the maximal HR increase in response to the beta-agonist isoproterenol, without modifying the response of contractile parameters. 4. These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.
authors.affiliation: Experimental Cardiology Laboratory, Baker Heart Research Institute, Commercial Road, Melbourne, Victoria 3004, Australia. xiaojun.du@baker.edu.au
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Xinheng
authors.initials: X
authors.lastname: Feng
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Tze Ping
authors.initials: TP
authors.lastname: Tan
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000077550:Ivabradine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology
chemical_list: D001552:Benzazepines; D007473:Ion Channels; D011943:Receptors, Adrenergic, beta; D000077550:Ivabradine