Effect of Graded Heart Rate Reduction with Ivabradine on Myocardial Oxygen Consumption and Diastolic Time in Exercising Dogs

Abstract

Lowering heart rate reduces myocardial oxygen consumption (MVO₂) and produces potent anti-ischemic effects. The development of selective heart rate-reducing agents represents an alternative approach to the use of β-blockers. Therefore, our goal was to establish the dose-response curve of the effects of ivabradine (I_f channel inhibitor) on MVO₂ and diastolic time. Seven conscious and chronically instrumented dogs were investigated during exercise at spontaneous and paced heart rate (250 beats/min) after administration of increasing doses of ivabradine (0.25, 0.5, and 1 mg/kg i.v.). During exercise, ivabradine dose dependently and significantly reduced the exercise-induced tachycardia (-17, -21, and -32% at 0.25, 0.5, and 1 mg/kg, respectively, versus saline) without altering myocardial contractility nor mean ejection wall stress. A linear relationship between heart rate (HR) and MVO₂ was demonstrated (MVO₂ = 0.044 × HR - 1.4; r = 0.987). These effects of ivabradine on MVO₂ were abolished by atrial pacing. Similarly, ivabradine dose dependently increased diastolic time without altering the inverse and non linear relationship between diastolic time and heart rate observed with saline. In conclusion, selective heart rate reduction with ivabradine dose dependently increases diastolic time and reduces MVO₂ with a linear relationship between heart rate and MVO₂. The lack of “on-off” pharmacological profile will predict the possibility of using a wide range of dose regimen.