REDUCTION OF EXERCISE-INDUCED REGIONAL CONTRACTILE DYSFUNCTION IN DOGS USING A NOVEL CALCIUM-CHANNEL BLOCKER (RO-40-5967)

Ro 40-5967 is a calcium channel blocker with a novel chemical structure. The purpose of this study was to evaluate the effects of Ro 40-5967 on systemic hemodynamics and regional contractile function in a canine model of chronic coronary artery stenosis in which no contractile dysfunction is observed at rest, but dynamic exercise elicits regional myocardial ischemia and contractile dysfunction. Thirteen dogs were chronically instrumented with sonomicrometers for the measurement of wall thickness in the anterior and posterior left ventricular walls, a micromanometer for measuring left ventricular pressure (LVP) and its first derivative (dP/dt), and a catheter in the aorta for measuring systemic arterial pressure. An ameroid constrictor on the left circumflex coronary artery produced gradual constriction of the vessel such that treadmill exercise elicited regional contractile dysfunction. Runs were repeated 3 hours later after the administration of Ro 40-5967 (0.3 mg/kg, IV). During the control run, regional systolic wall thickening in the posterior wall fell from 25.5 +/- 6.3% (SD) to 15.9 +/- 5.1% (p < 0.05). Ro 40-5967 did not change resting function in the poststenotic myocardium (26.9 +/- 8.4%) but improved regional function during the run to 18.2 +/- 6.2% (p < 0.05). This improvement was associated with a slight decrease in the exercise heart rate (213 +/- 18 vs. 200 +/- 16 bpm, NS), no change in peak ventricular pressure (156 +/- 22 vs. 157 +/- 20 mmHg), mean aortic pressure (123 +/- 19 vs. 118 +/- 20 mmHg), dP/dt (5129 +/- 1143 vs. 5288 +/- 1120 mm Hg/sec), or systolic wall thickening in a distant control region. Thus, in the exercising dog with fixed coronary stenosis, Ro 40-5967 had an antiischemic effect with no detectable negative inotropic effect.