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 b 2 -adrenergic receptors (b 2 AR), or b-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 b 2 AR transgenic mice. Further, ivabradine at 10 mg kg À1 day À1 reduced the maximal HR increase in response to the b-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.

Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice

“…Here, we show that improvement in endothelial function and significant slowing of atherogenesis can be achieved by ivabradine, an oral treatment that is well tolerated in mice and humans. 13,14 Treating mice with ivabradine at the highest dose that did not reduce heart rate had no effect on endothelial function. Exposure of isolated aortic rings from ApoE Ϫ/Ϫ mice to ivabradine in the organ bath did not alter vasodilatation.…”

“…12,13 Ivabradine given orally to mice (10 mg/kg body weight per day) reduces heart rate without influencing left ventricular contractile function and therefore is used as a tool to study the effects of heart rate on vascular biology. 14 We hypothesized that selective heart rate reduction by ivabradine may improve vascular function. Therefore, the aim of this study was to determine the effect of ivabradine on endothelial function, atherosclerotic lesion formation, and parameters of vascular oxidative stress in cholesterol-fed apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice.…”

Bradycardic and Proarrhythmic Properties of Sinus Node Inhibitors

“…However, the induction of very striking dysrhythmias by each tested SNI has not been described before. Although the sinus node inhibitors have been studied both in vivo (Borer et al, 2003;Vilaine et al, 2003;Colin et al, 2004;DiFrancesco and Camm, 2004;Du et al, 2004;Monnet et al, 2004) and in vitro (Goethals et al, 1993;Bogaert and Pittoors, 2003;DiFrancesco and Camm, 2004), reports of a changed variability of heart rates, AP cycle lengths, or diastolic depolarization rates are missing. This lack of information is probably due to the fact that in these previous studies, the drugs had been applied in a dosage and manner to study only the bradycardic effect of the compounds.…”

“…The slowing effect on sinoatrial node depolarization has been assumed consequently to be the reason for the bradycardic action of these substances (DiFrancesco and Camm, 2004). For several years, ivabradine, a member of the newer SNIs which also include cilobradine and zatebradine, has been tested in animals (Vilaine et al, 2003;Colin et al, 2004;Du et al, 2004;Monnet et al, 2004) and humans (Borer et al, 2003). It has been found that although this substance has a depressing effect on the heart rate, neuronal side effects are limited to occasional visual symptoms.…”

Heart Rate Reduction by Ivabradine Improves Aortic Compliance in Apolipoprotein E-Deficient Mice

“…The I( f ) current inhibitor ivabradine reduces heart rate without influencing left ventricular contractile function and blood pressure and may be used as a tool to study the effects of heart rate on vascular biology [15]. This study was therefore undertaken to test the hypothesis that selective heart rate reduction (HRR) induced by ivabradine may affect aortic compliance as well as to characterize underlying molecular mechanisms.…”