Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists.
Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar 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 intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to the betablocker esmolol and atenolol in patients with coronary artery disease. Tedisamil induced a dose-dependent decrease in both heart rate and the index of myocardial oxygen consumption associated with an improvement in ST segment depression. Tedisamil as well as esmolol and atenolol showed almost equipotent antiischemic effects at the doses administered. Compared with gallopamil, both tedisamil and esmolol were superior in their effects on myocardial oxygen consumption and ST segment depression, whereas plasma lactate concentrations were more reduced by tedisamil and gallopamil.
Mitrovic
V
V
Max Planck Institute for Physiological and Clinical Research, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany. veselin.mitrovic@kerckhoff.med.uni-giessen.de
Oehm
E
E
Thormann
J
J
Pitschner
H
H
Hamm
C
C
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000787:Angina Pectoris / Q000188:drug therapy; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001262:Atenolol / Q000008:administration & dosage / Q000627:therapeutic use; D001578:Benzopyrans / Q000008:administration & dosage / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D003521:Cyclopropanes / Q000008:administration & dosage / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D004562:Electrocardiography; D005080:Exercise Test; D005711:Gallopamil / Q000008:administration & dosage / Q000627:therapeutic use; D006439:Hemodynamics; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists*; D011412:Propanolamines / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D003521:Cyclopropanes; D004095:Dihydropyridines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011412:Propanolamines; D014665:Vasodilator Agents; D005711:Gallopamil; C061050:bimakalim; D001262:Atenolol; C059921:tedisamil; C036604:esmolol