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.