COMPARISON OF THE POTASSIUM CHANNEL BLOCKER TEDISAMIL WITH THE BETA-ADRENOCEPTOR BLOCKER ESMOLOL AND THE CALCIUM-ANTAGONIST GALLOPAMIL IN PATIENTS WITH CORONARY-ARTERY DISEASE

Background: Tedisamil is a new bradycardic agent proven to exert anti- ischemic and antiarrhythmic effects by blockade of the different cardi ac and vascular K+ currents. Hypothesis: It was the aim of the present study to compare the favorable anti-ischemic effects of tedisamil, wi th two long established representatives in the treatment of coronary a rtery disease (CAD), namely, the beta(1) blocker esmolol and the Ca-2 antagonist gallopamil. Methods: The hemodynamic and neurohumoral effec ts of the new potassium channel blocker tedisamil, an agent with negat ive chronotropic and class III antiarrhythmic properties, were compare d with the ultra-short-acting beta(1)-selective adrenoceptor blocker e smolol and the calcium antagonist gallopamil. A total of 22 patients w ith angiographically proven CAD and reproducible ST-segment depression in the exercise electrocardiogram was included in two studies with an almost identical design and inclusion criteria. The investigation was carried out using right heart catheterization and bicycle ergometry. A subgroup of 8 patients receiving 0.3 mg/kg body weight tedisamil int ravenously (TV) in an open dose-finding study was compared with a grou p of 14 patients who had received esmolol (IV bolus of 500 mu g/kg, ma intenance dose 200 mu g/kg/min) and gallopamil (initial dose 0.025 mg/ kg, maintenance dose 0.0005 mg/kg/h) in a second intraindividual compa rison. Results: Tedisamil and esmolol reduced heart rate at rest by 13 % (p < 0.001), and 6% (p < 0.05), and at maximum working levels by 8% (p < 0.01) and 9% (p < 0.05), respectively. Gallopamil increased heart rate at rest by 7% (p < 0.05), with only slight changes occurring dur ing exercise. Corresponding findings for each drug were observed for c ardiac output both at rest and during exercise [tedisamil: at rest -10 % (NS), max. exercise -8%; esmolol: at rest -14% (NS), max. exercise - 18% (NS); gallopamil: no significant changes]. Compared with tedisamil , stroke volume was reduced by esmolol [at rest and max, workload: -9% (NS)] and gallopamil [rest: -6% (NS), max, exercise: -2% (NS)]. Of th e indirect parameters of ventricular function, that is, mean capillary wedge pressure (PCWPm) and right ventricular ejection fraction, only PCWPm demonstrated significant differences between tedisamil and gallo pamil (+18% and -6% at rest, +17% and -21% during exercise, respective ly; p < 0.001). Compared with gallopamil, both tedisamil and esmolol w ere superior in their effects on rate-pressure product, myocardial oxy gen consumption, and ST-segment depression, whereas plasma lactate con centration was more reduced by tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular. Conclusion: Tedisam il and esmolol showed almost equipotent anti-ischemic effects at the d oses administered. Tedisamil acts mainly by reductions in heart rate, and esmolol, though to a lesser degree, also by reductions in systolic blood pressure. The mechanism of gallopamil is to reduce afterload an d to improve coronary perfusion. At the doses applied, however it has lower antianginal potency compared with tedisamil and esmolol.