RT Journal Article
SR Electronic
T1 Effect of Graded Heart Rate Reduction with Ivabradine on Myocardial Oxygen Consumption and Diastolic Time in Exercising Dogs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 236
OP 240
DO 10.1124/jpet.103.059717
VO 308
IS 1
A1 Patrice Colin
A1 Bijan Ghaleh
A1 Xavier Monnet
A1 Luc Hittinger
A1 Alain Berdeaux
YR 2004
UL http://jpet.aspetjournals.org/content/308/1/236.abstract
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