Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium

Abstract

Objectives: This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.

Background: Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine.

Methods: The effects of dobutamine (2, 5 and 10 micrograms/kg body weight per min) alone and in combination with zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis.

Results: A 50% reduction in left circumflex coronary artery blood flow (58 +/- 4 to 29 +/- 2 ml/min [mean value +/- SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 micrograms/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 micrograms/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 +/- 0.06 to 0.48 +/- 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 +/- 0.05 to 0.78 +/- 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 +/- 41% (0.39 +/- 0.09 to 0.71 +/- 0.12 ml/100 g per beat). Atrial pacing abolished the effects of zatebradine.

Conclusions: The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function.