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 cardiac and vascular K+ currents.


OBJECTIVE
It was the aim of the present study to compare the favorable anti-ischemic effects of tedisamil, with two long established representatives in the treatment of coronary artery disease (CAD), namely, the beta1 blocker esmolol and the Ca2 antagonist gallopamil.


METHODS
The hemodynamic and neurohumoral effects of the new potassium channel blocker tedisamil, an agent with negative chronotropic and class III antiarrhythmic properties, were compared with the ultra-short-acting beta1-selective adrenoceptor blocker esmolol and the calcium antagonist gallopamil. A total of 22 patients with 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 intravenously (i.v.) in an open dose-finding study was compared with a group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intraindividual comparison.


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 during exercise. Corresponding findings for each drug were observed for cardiac 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 the 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 gallopamil (+18% and -6% at rest, +17% and -21% during exercise, respectively; p < 0.001). Compared with gallopamil, both tedisamil and esmolol were superior in their effects on rate-pressure product, myocardial oxygen consumption, and ST-segment depression, whereas plasma lactate concentration was more reduced by tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular.


CONCLUSIONS
Tedisamil and esmolol showed almost equipotent anti-ischemic effects at the doses 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 and to improve coronary perfusion. At the doses applied, however, it has lower antianginal potency compared with tedisamil and esmolol.
Mitrovic
V
V
Max Planck Institute for Clinical and Physiological Research, Kerckhoff-Klinik, Bad Nauheim, Germany.
Oehm
E
E
Thormann
J
J
Pitschner
H
H
Haberbosch
W
W
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D001784:Blood Gas Analysis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D002395:Catecholamines / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003521:Cyclopropanes / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005711:Gallopamil / Q000008:administration & dosage / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008875:Middle Aged; D026902:Potassium Channel Blockers; D011412:Propanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D002395:Catecholamines; D003521:Cyclopropanes; D026902:Potassium Channel Blockers; D011412:Propanolamines; D019344:Lactic Acid; D005711:Gallopamil; C059921:tedisamil; C036604:esmolol