Antiarrhythmic actions of tedisamil: Studies in rats and primates

Adaikan, Ganesh; Beatch, Gregory N.; Lee, T. L.; Ratnam, S. S.; Walker, Michael J.

doi:10.1007/bf00051020

Cited by 28 publications

(19 citation statements)

References 17 publications

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“…In fact, tedisamil exerted At rest In animal studies, tedisamil showed a dose-dependent bradycardic effect [4,23,24]. In humans, Bargheer et al, in minimal and no significant bradycardic effect at the submaximal workload during exercise, while atenolol and 10 resting patients with coronary artery disease, observed that tedisamil (0.3 mg kg −1 i.v.)…”

Section: Analysis Of Qt Interval Prolongation Treatment Comparisonsmentioning

confidence: 99%

“…However, the results of this study in healthy subjects An increase in action potential duration and a dosecannot be directly extrapolated to patients with ischaemic dependent QT interval prolongation have been shown heart disease. Further clinical studies in patients with during administration of tedisamil in animals studies [3, 4, myocardial ischaemia should be performed to confirm that 23,24]. In patients with coronary artery disease, Bargheer administration of tedisamil and a b-adrenoceptor blocker is et al observed a prolongation of the action potential not associated with an increase in unwanted cardiovascular duration and the ventricular effective refractory period [5].…”

Section: Tolerabilitymentioning

confidence: 99%

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Effects of tedisamil, atenolol and their combination on heart andrate‐dependent QT interval in healthy volunteers

Démolis

Martel

Funck‐Brentano

et al. 1997

Brit J Clinical Pharma

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AimsTedisamil is a new blocker of K + currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a b-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests. Methods The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers. Results This study showed that tedisamil exerted a significant ( P<0.05) bradycardic action at rest (−10 beats min −1 ; 95% CI: -6 to -15 beats min −1 ) similar to atenolol (−14 beats min −1 ; -11 to -17) and drug combination (−9 beats min −1 ; -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (−42 beats min; -37 to -47) and combination (−47 beats min −1 ; -41 to 52).Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000ms, but not at RR<700ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation.Conclusions These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.

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Section: Analysis Of Qt Interval Prolongation Treatment Comparisonsmentioning

confidence: 99%

Section: Tolerabilitymentioning

confidence: 99%

Effects of tedisamil, atenolol and their combination on heart andrate‐dependent QT interval in healthy volunteers

Démolis

Martel

Funck‐Brentano

et al. 1997

Brit J Clinical Pharma

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“…Prolongation of QT and QT c duration following tedisamil treatment, as an indicator of prolonged ventricular repolarization phase, may have an antiarrhythmic effect in patients with ischemia, as could be found in animal experiments [1,4,5]. Prolongation of QT, similar to Class I and III antiarrhythmic agents, contains the potential of a proarrhythmogenic effect with triggering of torsade de points and an increase in arrhythmogenic mortality.…”

Section: Mitrovic V Et Al Potassium Channel Openers and Blockers Inmentioning

confidence: 95%

Potassium Channel Openers and Blockers in Coronary Artery Disease Comparison to Betablockers and Calcium Antagonists

Mitrović¹,

Oehm²,

Thormann³

et al. 2000

Herz

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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 tedisa...

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“…It is known that tedisamil prolongs the actionpotential duration [17]. Two of the major effects on the heart, namely, bradycardia and prolongation of the action-potential duration, can both be explained by inhibition of outward potassium currents [18].…”

Section: Mechanism Of Increased Efticiency Of Workmentioning

confidence: 99%

“…The high heart rate and abnormally short action-potential duration of the rat heart, as well as the abnormally high external calcium used in this study, all constitute major reservations. Nonetheless, the combination of bradycardia and action-potential duration lengthening have been found not only in the rat but also in the baboon heart [17]. Bradycardia is likely to be protective from ischemia in all species, including humans, and the widened action-potential duration is likely to have antiarrhythmic qualities.…”

Section: Reservationsmentioning

confidence: 99%

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

Duchosal

Opie

1992

Cardiovasc Drug Ther

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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...

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Antiarrhythmic actions of tedisamil: Studies in rats and primates

Cited by 28 publications

References 17 publications

Effects of tedisamil, atenolol and their combination on heart andrate‐dependent QT interval in healthy volunteers

Effects of tedisamil, atenolol and their combination on heart andrate‐dependent QT interval in healthy volunteers

Potassium Channel Openers and Blockers in Coronary Artery Disease Comparison to Betablockers and Calcium Antagonists

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

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