Potential beneficial effects of potassium channel blockade by tedisamil in isolated perfused working rat heart with coronary artery ligation

Abstract

Tedisamil, a potassium channel blocker, is known to produce bradycardia. The hypothesis tested was that tcdisamil-induced bradycardia should improve the mechanical and metabolic properties of the ischemic myocardium.['sing isolated perfused rat heart with coronary-artery ligalion, tedisamil was compared with alinidine, verapamil, and propranolol. The end points were myocardial mechanical function and oxygen uptake. In coronary-ligated hearts, tedisamil (1.83 x 10 -~ M) decreased heart rate, increased left ventricular dl'/dt,,,,, and increased pressure power production. Efficiency of work rose with tedisamil. Alinidine (7 x l0 -~ ?,l) also decreased heart rate without altering left ventricular dP/dtm, ,, power production, or myocardial efficiency. Verapamil (1.5 x 10 -~ 31) did not alter heart rate but decreased left ventricular dl'/dtm, ~, while power production and myocardial efficiency also fell. I'roprano[ol (1 x 10 -3 )I) caused changes similar to verapamil, except that the heart rate also fell. Dobutamine (1.18 x 10-: M) increased cardiac output and oxygen uptake without altering mechanical efficieno'. Of the drugs tested and in the concentrations used in the coronary ligated rat heart, it was only tedisamil that had the capacity to cause less decrease in mechanical work and in myocardial efficiency than in controls.Tedisamil is an agent known to prolong the actionpotential duration of the rat heart and to induce bradycardia [1]. The mode of action is thought to be a combination of blockade of two time-dependent potassium channels, T O and the delayed rectifier. These properties should make tedisamil a useful drug in the management of acute myocardial isehemia, when both a reduction of myocardial oxygen uptake following a reduction of heart rate and inhibition of acute ischemic arrhythmias [2] are desired. These potentially antiischemic properties of tedisamil were assessed in the isolated working rat-heart preparation with coronary-artery ligation. This drug was compared with alinidine, another agent that causes a bradycardia independent of adrenergic or calcium blockade, and with established antiischemic agents, such as verapamil and propranolol. Because tedisamil appeared to have a positive inotropic effect in this preparation, comparisons were also made with the beta I agonist, dobutamine. Materials and MethodsHearts fl'om male Spraglm-Dawley rats (250-350 g) given 200 IU of hepavin were excised, arrested in icecold perfusate, and mounted by the aorta for a preperfusion period of 10 minutes. The left atrium was cannulated to allow atrial perfusion [3] with a filling pressure of 11 cm H,O and an aortic column height of 96 cm H.zO. The perfusate consisted of a KrebsHenseleit bicarbonate medium (pH 7.4 at 37°C) containing (mM) NaC1 118.5, KC1 4.75, CaCI., 2.5, KH.;P04 1.19, MgS04 1.19, and NaHCQ 25.0. Glucose 11 ram was the substrate. Experimental designHearts (n = 18 for tedisamil and control hearts with ligation; n = 6 for hearts perfused with alinidine, verapamil, propranolol, dobutamine, and control hea...

Effects of tedisamil (KC‐8857) on cardiac electrophysiology and ventricular fibrillation in the rabbit isolated heart

“…Both positive and negative inotropic actions of tedisamil have been reported in in vivo and in vitro investigations as well as an improvement in cardiac function during myocardial ischaemia. These effects of tedisamil on cardiac function, however, were attributed primarily to its bradycardic action and subsequent favourable influence on the oxygen supply/ demand balance in the ischaemic hearts (Grohs et al, 1989;Duchosal & Opie, 1992;Raberger et al, 1992). The bradycardic effect of tedisamil (under normoxia) was not observed in our investigation since the heart was paced throughout the experimental protocol (Table 2).…”

Tedisamil

“…Therefore, tedisamil might be expected to exhibit an antiischemic effect, and this has been investigated in both in vitro and in vivo experiments. In rat isolated working hearts, tedisamil induced a dose-dependent reduction in heart rate with a simultaneous increase in left ventricular pressure, (+)dP/dr,,,,,, stroke volume, and cardiac work without any change in coronary and aortic output (28). This hemodynamic activity appears rather unique since it combines a bradycardic effect similar to that of propranolol or alinidine with a positive inotropic effect as observed with dobutamine.…”

“…It is interesting to note that within the same animal family, sensitivity to tedisamil might differ as illustrated in this figure which shows that tedisamilinduced decrease in heart rate is more pronounced in baboons (Pupio sp). than in monkeys A positive inotropic effect of tedisamil was demonstrated in rat isolated normoxic working hearts (28). However, evidence for a positive inotropic effect of tedisamil in vivo is less clear.…”

“…The bradycardic activity of tedisamil has been described in rats (20,27,28,50,65), guinea pigs (20,50,60,61), cats (21), rabbits (60,61,76), dogs (39,40,81), and primates (2,21). However, the sensitivity of the heart rate response to tedisamil differs according to the species.…”

Tedisamil in Coronary Disease: Additional Benefits in the Therapy of Atrial Fibrillation?

“…Our own studies have been done in the isolated coronary-ligated rat heart (8). Tedisamil, when given to the nonligated heart, reduced the heart rate and increased the stroke volume.…”