Sustained-release preparations composed of
verapamil-polymeric controlled-release matrices were characterized in vitro and utilized as epicardial implants in dogs with ischemic ventricular arrhythmias. Anesthetized open-chest dogs were subjected to 5 hourly, 10-min complete occlusions of the left anterior descending coronary artery followed by reperfusion. A controlled-release matrix preparation (20%
verapamil, 80%
polyurethane), placed on the left ventricular epicardium prior to the third occlusion, resulted in successful inhibition of
ventricular tachycardia (VT) during acute
ischemia in a dose-dependent manner. The largest matrix size used, 300 mg (20%
verapamil), provided a net systemic dose of 0.52 +/- 0.18 mg/kg over 140 min and significantly reduced VT episodes during acute
ischemia (fifth occlusion) compared to untreated controls (0.16 +/- 0.04 vs. 1.01 +/- 0.35 episodes/min, respectively; t = 2.62, p = 0.01). In controls, by the fifth occlusion
ventricular fibrillation (VF) occurred after 5.41 +/- 0.78 min in 89% of animals. However, after a 300-mg
verapamil matrix was placed on the left ventricular ischemic zone, VF occurred in only 45% (chi-squared = 4.1, p = 0.04, vs. controls) of the animals after 7.87 +/- 0.92 min (fifth occlusion). Systemic venous plasma
verapamil levels during the 2 h following the 300-mg matrix ischemic zone implantation ranged from 8.4-22.0 ng/ml, while simultaneous regional coronary venous levels were 125.0-387.0 ng/ml. Sonomicrometry studies of left ventricular wall thickening carried out with a series of 300-mg
verapamil matrix cardiac implants did not demonstrate any significant myocardial dysfunction. It is concluded that controlled-release
verapamil, administered directly to the heart, was effective for preventing VT and VF associated with acute coronary
ischemia, and that this route of administration was not associated with any significant deterioration of cardiac function.