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Susanne Radicke - One of the best experts on this subject based on the ideXlab platform.
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the transmembrane β subunits kcne1 kcne2 and dpp6 modify pharmacological effects of the antiarrhythmic agent Tedisamil on the transient outward current ito
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Daniele Sblattero, Claudio Santoro, Susanne Radicke, Diego Cotella, Ursula Ravens, Erich WettwerAbstract:Accessory β-subunits modulate the pharmacology of ion channel blockers. The aim was to investigate differences in effects of the antiarrhythmic agent and open-channel blocker Tedisamil on transient outward current I to (Kv4.3) when coexpressed with β-subunits potassium voltage-gated channel, Isk-related family, member 1 (KCNE1), potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), or dipeptidyl-aminopeptidase-like protein 6 (DPP6) which modulate I to kinetics. Tedisamil inhibited I to with IC50 values of 16 μM for Kv4.3+KChIP2, 11 μM in the presence of KCNE1, and 14 μM for KCNE2. Values were higher in the presence of DPP6 or DPP6+KCNE2 (35 and 26 μM). K d values of Tedisamil binding and rate constants were not affected by KCNE or DPP6. I to kinetics were accelerated by KCNE and DPP6, inactivation to a larger extent with DPP6. Tedisamil did not affect activation time course but apparently accelerated inactivation in all channel subunit combinations tested. Deletion of the intracellular domain of KCNE2 or DPP6 resulted in slowing of kinetics and increased Tedisamil sensitivity (IC50 4 and 7 μM). It is concluded that apparent effects of DPP6 and deletion mutants (KCNE2 and DPP6) are due to the acceleration or slowing effects of the β-subunits on I to kinetics.
Erich Wettwer - One of the best experts on this subject based on the ideXlab platform.
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the transmembrane β subunits kcne1 kcne2 and dpp6 modify pharmacological effects of the antiarrhythmic agent Tedisamil on the transient outward current ito
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Daniele Sblattero, Claudio Santoro, Susanne Radicke, Diego Cotella, Ursula Ravens, Erich WettwerAbstract:Accessory β-subunits modulate the pharmacology of ion channel blockers. The aim was to investigate differences in effects of the antiarrhythmic agent and open-channel blocker Tedisamil on transient outward current I to (Kv4.3) when coexpressed with β-subunits potassium voltage-gated channel, Isk-related family, member 1 (KCNE1), potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), or dipeptidyl-aminopeptidase-like protein 6 (DPP6) which modulate I to kinetics. Tedisamil inhibited I to with IC50 values of 16 μM for Kv4.3+KChIP2, 11 μM in the presence of KCNE1, and 14 μM for KCNE2. Values were higher in the presence of DPP6 or DPP6+KCNE2 (35 and 26 μM). K d values of Tedisamil binding and rate constants were not affected by KCNE or DPP6. I to kinetics were accelerated by KCNE and DPP6, inactivation to a larger extent with DPP6. Tedisamil did not affect activation time course but apparently accelerated inactivation in all channel subunit combinations tested. Deletion of the intracellular domain of KCNE2 or DPP6 resulted in slowing of kinetics and increased Tedisamil sensitivity (IC50 4 and 7 μM). It is concluded that apparent effects of DPP6 and deletion mutants (KCNE2 and DPP6) are due to the acceleration or slowing effects of the β-subunits on I to kinetics.
Veselin Mitrovic - One of the best experts on this subject based on the ideXlab platform.
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Hemodynamic, Antiischemic, and Neurohumoral Effects of Tedisamil and Atenolol in Patients with Coronary Artery Disease
Cardiovascular Drugs and Therapy, 2000Co-Authors: Veselin Mitrovic, Heinz F Pitschner, Aleksandra Miskovic, Matthias Straub, Jochen Thormann, Christian HammAbstract:Clinical drawbacks of beta-blocker treatment in stable angina have motivated researchers to provide alternative heart-rate-lowering agents, such as Tedisamil, which additionally exerts antiischemic and antiarrhythmic effects by blockade of cellular repolarizing K^+ currents. Forty-eight patients with stable angina pectoris were investigated (doubleblind, randomized, parallel grouped) comparing the hemodynamic, antiischemic, metabolic and neurohumoral effects of Tedisamil 100 mg b.i.d. and atenolol 50 mg b.i.d. after a single dose and over 6 days of treatment. Tedisamil and atenolol produced a decrease in heart rate both at rest [day 1:-13.6 versus −15.4 bpm; day 6: −14.8 versus −22.2 bpm, resp.; p > 0.05] and exercise [day 1; −9.1 versus −18.3 bpm; p = 0.001; day 6; −12.0 versus −24.8 bpm, resp.; p = 0.001], while anginal threshold increased. Cardiac output decreased with Tedisamil and atenolol at rest [day 1: −1.01 versus −1.19 l/min; p > 0.05; day 6: −0.86 versus −1.10 l/min, resp.; p > 0.05] and exercise [day 1: −0.82 versus −1.28 l/min; p > 0.05; day 6: −0.65 versus −2.68 l/min, resp.; p = 0.03], while stroke volume remained unchanged. Right atrial pressure changed during exercise only: it decreased with Tedisamil (−1.7 mmHg) and increased with atenolol (+3.7 mmHg) (p < .001). Mean pulmonary capillary wedge pressures decreased both at rest (−0.5 mmHg) and exercise (−6.9 mmHg) in the Tedisamil group but tended to increase with atenolol on day 6 of treatment [rest: +1.7; exercise: +3.7 mmHg) (p = 0.03). Arterial pressure decreased under atenolol treatment only. Exercise-induced plasma norepinephrine levels were reduced by Tedisamil (−93 pg/ml) but elevated by atenolol (+172 pg/ml) (p = 0.001). As compared to atenolol, Tedisamil produced a prolongation of QT_c interval [+31 versus 8 ms] at initial values of 0.408 ± 0.018 s with PQ and QRS remaining unaltered. In patients with stable angina, Tedisamil (100 mg b.i.d.) as compared to atenolol (50 mg b.i.d.) generated similar hemodynamic, neurohumoral and antiischemic effects. The antiischemic efficacy of Tedisamil, as measured by ST segment depression and angina threshold, was comparable to that of atenolol.
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comparison of the potassium channel blocker Tedisamil with the beta adrenoceptor blocker esmolol and the calcium antagonist gallopamil in patients with coronary artery disease
Clinical Cardiology, 1998Co-Authors: Veselin Mitrovic, E Oehm, J Thormann, Heinz F Pitschner, Werner HaberboschAbstract:BACKGROUND: Tedisamil is a new bradycardic agent proven to exert anti-ischemic and antiarrhythmic effects by blockade of the different cardiac and vascular K+ currents. HYPOTHESIS: It was the aim of the present study to compare the favorable anti-ischemic effects of Tedisamil, with two long established representatives in the treatment of coronary artery disease (CAD), namely, the beta1 blocker esmolol and the Ca2 antagonist gallopamil. METHODS: The hemodynamic and neurohumoral effects of the new potassium channel blocker Tedisamil, an agent with negative chronotropic and class III antiarrhythmic properties, were compared with the ultra-short-acting beta1-selective adrenoceptor blocker esmolol and the calcium antagonist gallopamil. A total of 22 patients with angiographically proven CAD and reproducible ST-segment depression in the exercise electrocardiogram was included in two studies with an almost identical design and inclusion criteria. The investigation was carried out using right heart catheterization and bicycle ergometry. A subgroup of 8 patients receiving 0.3 mg/kg body weight Tedisamil intravenously (i.v.) in an open dose-finding study was compared with a 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 intraindividual comparison. RESULTS: Tedisamil and esmolol reduced heart rate at rest by 13% (p < 0.001), and 6% (p < 0.05), and at maximum working levels by 8% (p < 0.01) and 9% (p < 0.05), respectively. Gallopamil increased heart rate at rest by 7% (p < 0.05), with only slight changes occurring during exercise. Corresponding findings for each drug were observed for cardiac output both at rest and during exercise [Tedisamil: at rest -10% (NS), max. exercise -8%; esmolol: at rest -14% (NS), max. exercise -18% (NS); gallopamil: no significant changes]. Compared with Tedisamil, stroke volume was reduced by esmolol [at rest and max. workload: -9% (NS)] and gallopamil [rest: -6% (NS), max. exercise: -2% (NS)]. Of the indirect parameters of ventricular function, that is, mean capillary wedge pressure (PCWPm) and right ventricular ejection fraction, only PCWPm demonstrated significant differences between Tedisamil and gallopamil (+18% and -6% at rest, +17% and -21% during exercise, respectively; p < 0.001). Compared with gallopamil, both Tedisamil and esmolol were superior in their effects on rate-pressure product, myocardial oxygen consumption, and ST-segment depression, whereas plasma lactate concentration was more reduced by Tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular. CONCLUSION: Tedisamil and esmolol showed almost equipotent anti-ischemic effects at the doses administered. Tedisamil acts mainly by reductions in heart rate, and esmolol, though to a lesser degree, also by reductions in systolic blood pressure. The mechanism of gallopamil is to reduce afterload and to improve coronary perfusion. At the doses applied, however, it has lower antianginal potency compared with Tedisamil and esmolol.
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hemodynamic and antiischemic effects of Tedisamil in humans
Cardiovascular Drugs and Therapy, 1992Co-Authors: Veselin Mitrovic, E Oehm, J Thormann, A Liebrich, M. SchlepperAbstract:Twenty-four patients with angiographically documented coronary artery disease, chronic stable angina, and reproducible ST-segment depression took part in this openlabel, baseline-controlled study on the hemodynamic, antiischemic, metabolic, and neurohumoral effects of Tedisamil following IV doses of 0.1, 0.2, and 0.3 mg/kg (eight patients in each dose group). Tedisamil produced a dose-dependent decrease in both heart rate [rest: 2.4, 7.5 (p .01), resp.]. While cardiac output was found decreased due to the heart-rate reduction both at rest [−8.5%, −5.7%, and −10.2% (p<.05), respectively] and during exercise (2–8%), being significant only at rest in the highest dose group, stroke volume remained unaltered. Pulmonary artery pressure, pulmonary capillary wedge pressure, right-ventricular ejection fraction, and pulmonary vascular resistance were without significant changes. Blood pressure and systemic vascular resistance tended to increase, associated with a decrease in plasma catecholamines (20–40%). Tedisamil produced a dose-dependent prolongation of QTc duration [+2%, +6%, +12% (p<.05), respectively] with PQ and QRS unaltered. The elimination half-life of Tedisamil IV ranges between 6.8 and 7.8 hours. In conclusion, Tedisamil, at a dose of 0.3 mg/kg IV, was well tolerated and was found to have favorable hemodynamic and antiischemic effects in patients with ischemic heart disease.
Michael J A Walker - One of the best experts on this subject based on the ideXlab platform.
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Tedisamil and lidocaine enhance each other s antiarrhythmic activity against ischaemia induced arrhythmias in rats
British Journal of Pharmacology, 2003Co-Authors: Guilda Sarraf, Terrance D. Barrett, Michael J A WalkerAbstract:1. Combinations of the action potential-widening drug Tedisamil (Class III antiarrhythmic activity), and the inactivated state sodium channel blocker lidocaine (Class Ib antiarrhythmic activity) were assessed for antiarrhythmic actions in a rat model of ischaemia-induced arrhythmias and for electrophysiological actions in normal rat myocardial tissue. 2. Both Tedisamil and lidocaine dose-dependently suppressed ischaemia-induced arrhythmias. The ED(50) values were 3.0+/-1.3 and 4.9+/-0.6 micro mol kg(-1) min(-1), respectively. 3. Combinations of the two drugs acted synergistically such that the ED(50) for Tedisamil was reduced to 0.8+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) lidocaine. Similarly, the ED(50) for lidocaine was reduced to 0.7+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) Tedisamil (both P<0.05). 4. In a separate series of experiments in which normal ventricular tissue was electrically stimulated, 2 micro mol kg(-1) min(-1) lidocaine produced a leftward shift in the dose-response curve for Tedisamil's effect on effective refractory period (P<0.05). This dose of lidocaine had no effect on its own. These data indicate that the synergistic actions of combinations of Tedisamil and lidocaine were mediated, at least in part, by extension of effective refractory period in normal myocardial tissue. 5. In contrast to the strategy of developing drugs that are selective for a single electrophysiological mechanism, the results of the present study suggest that effective antiarrhythmic drugs might be developed by optimising the combination of two complimentary electrophysiological mechanisms (i.e., action potential-prolonging activity and inactivated state sodium channel blockade).
Claudio Santoro - One of the best experts on this subject based on the ideXlab platform.
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the transmembrane β subunits kcne1 kcne2 and dpp6 modify pharmacological effects of the antiarrhythmic agent Tedisamil on the transient outward current ito
Naunyn-schmiedebergs Archives of Pharmacology, 2009Co-Authors: Daniele Sblattero, Claudio Santoro, Susanne Radicke, Diego Cotella, Ursula Ravens, Erich WettwerAbstract:Accessory β-subunits modulate the pharmacology of ion channel blockers. The aim was to investigate differences in effects of the antiarrhythmic agent and open-channel blocker Tedisamil on transient outward current I to (Kv4.3) when coexpressed with β-subunits potassium voltage-gated channel, Isk-related family, member 1 (KCNE1), potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), or dipeptidyl-aminopeptidase-like protein 6 (DPP6) which modulate I to kinetics. Tedisamil inhibited I to with IC50 values of 16 μM for Kv4.3+KChIP2, 11 μM in the presence of KCNE1, and 14 μM for KCNE2. Values were higher in the presence of DPP6 or DPP6+KCNE2 (35 and 26 μM). K d values of Tedisamil binding and rate constants were not affected by KCNE or DPP6. I to kinetics were accelerated by KCNE and DPP6, inactivation to a larger extent with DPP6. Tedisamil did not affect activation time course but apparently accelerated inactivation in all channel subunit combinations tested. Deletion of the intracellular domain of KCNE2 or DPP6 resulted in slowing of kinetics and increased Tedisamil sensitivity (IC50 4 and 7 μM). It is concluded that apparent effects of DPP6 and deletion mutants (KCNE2 and DPP6) are due to the acceleration or slowing effects of the β-subunits on I to kinetics.
