Potassium channel blockade: A mechanism for suppressing ventricular fibrillation.

1Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2 The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3 Tedisamil (1-4mgkg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4 Tedisamil dose-dependently lengthened the effective refractory period and prevented electricallyinduced VF. In vivo, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5 Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K⁺ current blocker

Beatch

Abraham

MacLeod

et al. 1991

“…For instance, bretylium or bethanidine prolong the myocardial action potential by this mechanism (Bacaner et al, 1986), which results in a prolongation of the effective refractory period. Compounds of this class (class III according to Vaughan Williams, 1975) are effective in the treatment and/or prevention of ventricular fibrillation.…”

Section: Introductionmentioning

confidence: 99%

9‐Amino‐1,2,3,4‐tetrahydroacridine (THA) is a potent blocker of cardiac potassium channels

Osterrieder

1987

1 9-Amino-1,2,3,4-tetrahydroacridine (THA) is a compound with structural similarity to the K+ channel blocker 4-aminopyridine. It was investigated for its effects on myocardial membrane currents in guinea-pig isolated ventricular myocytes. 2 THA prolonged the transmembrane action potential and decreased the amplitude ofits plateau in a reversible manner. 3 Voltage-clamp experiments showed that THA reduced the inwardly rectifying and the timedependent outward K+ currents as well as the slow inward Ca2" current.4 The degree of block of the inwardly rectifying K+ current depended on the membrane potential, being more pronounced at more positive potentials.

“…Tested on cardiac myocytes from the chick embryo, bretylium (applied either extracellularly or intracellularly) was observed to inhibit the outward K + -current induced by a depolarizing voltage step (Bkaily et al, 1988) and the antidysrhythmic activity of this agent has been attributed to K+-channel blockade (Bacaner et al, 1986). The present observation that adrenergic neurone blocking agents, including bretylium, antagonize KCOs in suppressing the spontaneous tone of the trachea is entirely consistent with the idea that the former group of compounds have K+-channel inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

Tracheal relaxation induced by potassium channel opening drugs: its antagonism by adrenergic neurone blocking agents

Berry

Small

Foster

1992

1 We have studied the ability of some adrenergic neurone blocking agents to inhibit the tracheal relaxant actions of isoprenaline, theophylline and the potassium channel openers (KCOs) BRL 38227, pinacidil and RP 52891. 2 BRL 38227, isoprenaline, pinacidil, RP 52891 and theophylline each caused concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachealis. The maximal relaxant effects of isoprenaline and pinacidil were equal to that of theophylline. In contrast, the maximal effects of BRL 38227 and RP 52891 were approximately 85-95% of that of theophylline.3 Guanethidine (5-5001iM) did not itself modify the spontaneous tone of the trachealis muscle but antagonized BRL 38227 in a concentration-dependent manner. Guanethidine (50 LM) also antagonized pinacidil and RP 52891. However, guanethidine did not antagonize either isoprenaline or theophylline. 4 Bretylium (50 LM) did not itself modify the spontaneous tone of the trachealis muscle but antagonized BRL 38227, pinacidil and RP 52891. Bretylium did not antagonize either isoprenaline or theophylline. 5Guanidine (50 and 500 j1M) did not itself modify the spontaneous tone of the trachea and failed to modify the tracheal relaxant activity both of BRL 38227 and theophylline.6 BRL 38227 (1 and 10 fiM) stimulated, in a concentration-dependent manner, the efflux of 86Rb+ from strips of bovine trachealis muscle that had been pre-loaded with the radiotracer. Guanethidine (50 iM), bretylium (50 JiM) and debrisoquine (50 jiM) did not themselves modify the efflux of 86Rb+ from bovine trachealis but each of these agents markedly inhibited the stimulant effect of BRL 38227 (10 jiM) on 86Rb+ efflux. 7 It is concluded that the adrenergic neurone blocking agents guanethidine and bretylium can inhibit the tracheal relaxant actions of KCOs such as BRL 38227, pinacidil and RP 52891 without antagonizing isoprenaline or theophylline. The ability of the adrenergic neurone blocking agents to antagonize BRL 38227 in promoting 86Rb+ efflux from trachealis muscle may suggest that the adrenergic neurone blocking agents act to prevent the opening of the plasmalemmal K+-channel that is involved in the tracheal relaxant actions of the KCOs.