PT  - JOURNAL ARTICLE
AU  - Patrice Colin
AU  - Bijan Ghaleh
AU  - Xavier Monnet
AU  - Luc Hittinger
AU  - Alain Berdeaux
TI  - Effect of Graded Heart Rate Reduction with Ivabradine on Myocardial Oxygen Consumption and Diastolic Time in Exercising Dogs
AID  - 10.1124/jpet.103.059717
DP  - 2004 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 236--240
VI  - 308
IP  - 1
4099  - http://jpet.aspetjournals.org/content/308/1/236.short
4100  - http://jpet.aspetjournals.org/content/308/1/236.full
SO  - J Pharmacol Exp Ther2004 Jan 01; 308
AB  - 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 (If 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. The American Society for Pharmacology and Experimental Therapeutics