Ventricular Muscle Action Potential Duration Research Articles

Reversal of Hypothermia-Induced Action Potential Lengthening by the K ATP Channel Agonist Bimakalim in Isolated Guinea Pig Ventricular Muscle

1. ATP-sensitive potassium (K ATP) channel openers shorten cardiac ventricular muscle action potential duration (APD), reduce resting and developed contractile force, and have been shown to provide cardioprotection when given before, during, and after either short-term ischemia or long-term hypothermia. The authors’ aim was to determine the concentration-dependent effect of the potent K ATP channel opener bimakalim on transmembrane action potential changes induced by mild (27°C) and moderate (20°C) hypothermia in isolated guinea pig ventricular muscle. 2. Conventional microelectrode techniques were used to record action potentials (APs) in single myocytes during normothermia (37°C) and hypothermia in the presence and absence of 0.1 to 30 μmol·l −1 bimakalim. 3. Hypothermia alone increased APD and depolarized the diastolic membrane potential (DMP): APD 90=141.7±7.0 msec and DMP −86.2±1.4 mV n=6 at 37°C versus 235.7±7.8 msec and −75.6±1.0 mV at 20°C n=7 . At 37°C, bimakalim (0.1–10 μmol·l −1) shortened APD in a concentration-dependent fashion. 4. APD 90 was markedly reduced from 141.7±7.0 msec without bimakalim to 9.5±2.6 msec with 10 μmol·l −1 bimakalim n=6 ; this effect was blocked by glibenclamide. DMP was hyperpolarized by bimakalim. More bimakalim was required to shorten APs during mild and moderate hypothermia. The 50% effective concentration (EC 50) of bimakalim required to maximally shorten APD 90 was 0.96±0.10 μmol·l −1 at 37°C; this increased to 3.96±0.24 μmol·l − at 27°C, and to 12.34±0.72 μmol·l −1 at 20°C. Relative to hypothermia-induced depolarization, bimakalim hyperpolarized DMP toward drug-free values obtained at 37°C. 5. These results indicate that hypothermia shifts the bimakalim concentration APD 90 response curve to the right such that 13 times more bimakalim is required at 20°C shorten APD by the same amount as at 37°C. Bimakalim also reverses hypothermia-induced AP lengthening and tends to reverse the hypothermia-induced decrease in DMP. 6. These findings aid in our understanding of the cardioprotective effects of K ATP channel openers during hypothermia.

Differential Electrophysiologic Effects of Chronically Administered Amiodarone on Canine Purkinje Fibers versus Ventricular Muscle.

BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 µM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 µM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 µM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 µM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 µM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 µM dofetilide + 20 µM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 µM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Comparison of the Electromechanical Effects of Vesnarinone and Amrinone in Isolated Dog Purkinje Strands and Ventricular Trabeculae.

BACKGROUND: Conventional microelectrode techniques were used to compare the concentration-dependent effects of vesnarinone (0.1-100 µM) and amrinone (1 µM-1 mM) on action potential duration (APD) and developed force in both isolated dog ventricular trabeculae and Purkinje strands. METHODS AND RESULTS: Both drugs increased contractility of trabecular muscle preparations, while, in Purkinje strands, vesnarinone failed to increase developed force during continuous pacing at 2 Hz. Vesnarinone lengthened APD in both preparations; although this effect was more marked in Purkinje strands. Ventricular muscle APD was not affected by amrinone (1 µM to 1 mM), while, in Purkinje strands, amrinone produced a biphasic effect on APD. Low concentrations (1-100 µM) of amrinone shortened Purkinje fiber APD, while only the highest concentration (1 mM) used lengthened APD. In addition, in Purkinje strand preparations the effects of vesnarinone (10 µM) on APD and developed force were proportional to pacing cycle length at frequencies slower than 2 Hz; however, at frequencies faster than 2 Hz vesnarinone decreased developed force while APD was lengthened. In ventricular trabecular muscle preparations, the effects of vesnarinone were not affected by frequency. CONCLUSIONS: These results indicate clear differences between the effects of vesnarinone and amrinone in isolated cardiac preparations. These differences in experimental effects in isolated cardiac preparations may help provide an explanation for the disappointing clinical response of patients in heart failure to amrinone, while vesnarinone has appeared to be beneficial.

Acute effects of amiodarone on the electrophysiologic properties of isolated neonatal and adult cardiac fibers

The acute cellular electrophysiologic actions of amiodarone on isolated neonatal and adult canine ventricular muscle and Purkinje fibers were evaluated using standard microelectrode techniques. Amiodarone, 10(-6) to 5 X 10(-5) M (0.68 to 34 micrograms/ml), significantly (p less than 0.05) prolonged adult ventricular muscle action potential duration and voltage-dependent refractoriness at all concentrations, thereby demonstrating typical class III antiarrhythmic effects. Similar concentrations had no significant effects on neonatal ventricular muscle. Amiodarone significantly shortened action potential duration and refractoriness of both neonatal and adult Purkinje fibers, with neonatal fibers having a greater sensitivity to the drug. At the standard stimulation rate of 1 Hz, amiodarone had no effects on action potential amplitude or maximal rate of rise of phase 0 of the action potential (Vmax) of any tissues. At faster stimulation frequencies (2 to 4 Hz), amiodarone produced frequency-dependent decreases in action potential amplitude and Vmax of all neonatal and adult preparations. The data indicate that amiodarone exhibits a complex aggregate of electrophysiologic actions that include significant frequency-related class I effects. Compared with adult myocardium, neonatal tissues demonstrated altered responsiveness to amiodarone, a feature common to many antiarrhythmic compounds.

Comparative study of the effects of salinomycin and monensin on electrophysiologic and contractile properties of canine myocardium

The effects of the monocarboxylic ionophore, salinomycin (K+-selective), on isometric twitcches, high K+-induced contracture and transmembrane action potentials were compared with those of the monocarboxylic ionophore, monensin (Na+-selective), in isolated canine right ventricular muscle. In a concentration (5 × 10−6) which did not produce changes in resting force, salinomycin increased peak active force ( P0, + 170 ± 36%, mean % change from control ±S.D., P< 0.01). and relaxation and maximal rates of force development (dP/dtmax, + 123 ± 33%, P < 0.01) and relaxation (−dP/dtmax, + 180 ± 40%, P < 0.01) of the isometric twitch. A similar response pattern was found for 5 × 10−6 M monensin (P0, + 90 ± 24%, P < 0.01; dP/dtmax, + 137 ± 19%, P < 0.01; −dP/dtmax, + 145 ± 20%, P < 0.01). In contrast to their effects on isometric twitches, salinomycin reduced peak K+ contracture force (Pc, −35 ± 14%, P < 0.01) whereas monensin increased it (Pc, +30 ± 12%, P < 0.02). Ventricular muscle action potential duration was shortened similarly by the ionophores. β-Adrenergic receptor blockade with nadolol diminished salinomycin's effects on the isometric twitch and K+ contracture, but not its effect to shorten the action potential. Monensin's actions were unaffected by nadolol. These results suggest that salinomycin's effects arise from both a direct modulation of K+ movement and the release of endogenous catecholamine. In contrast, monensin may act to alter intracellular Na+ which in turn leads to Na+Ca2+ exchange and Ca2+ -mediated modulation of K+ movement.