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Defibrillation strength shocks delivered within an action potential (AP) delay repolarization. Shock-induced AP duration extension (APDE) may prolong refractoriness and terminate or prevent reinitiation of reentry, favoring defibrillation. This study examined LY-190147 (LY) effects on defibrillation threshold (DFT) in 11 dogs. Ventricular effective refractory period (VERP) and epicardial monophasic AP duration at 75% repolarization (APD75) were recorded at 300-, 400-, 500-, and 600-ms pacing cycle length (CL). APDE was measured as the time to 50% repolarization after a DFT strength shock delivered at 50, 25, and 0 ms before or 25 ms after VERP during pacing at 300 ms CL in 4 of the dogs. We made all recordings before drug administration and after infusions of 0.03, 0.3, and 3.0 mg/kg LY, using 1.5-h dosing intervals. LY lowered DFT in a saturating dose-response manner whether expressed as shock peak voltage (V) or energy. LY decreased DFT-V from 357 +/- 77 V before drug to 331 +/- 60 V (-6 +/- 12%), 290 +/- 43 V (-17 +/- 13%, p < 0.001), and 312 +/- 45 V (-11 +/- 12%, p < 0.05) at 0.03, 0.3, and 3.0 mg/kg, respectively. Similarly, LY treatment decreased defibrillation energy requirements from 6.9 +/- 2.7 J before drug by 7 +/- 25%, 26 +/- 24%, and 12 +/- 25% at the same doses. At 300-600 ms CL, LY prolonged APD75 by an average of 10 +/- 8% at 0.03 mg/kg, 17 +/- 6% at 0.3 mg/kg, and 24 +/- 9% at 3 mg/kg. At these CL, LY prolonged VERP by an average of 4 +/- 6% at 0.03 mg/kg, 15 +/- 10% at 0.3 mg/kg, and 11 +/- 9% at 3 mg/kg. APDE was increased from 62 +/- 9 ms before to 68 +/- 14, 80 +/- 16 (p < 0.001) and 72 +/- 13 ms (p < 0.05) at 0.03, 0.3, and 3.0 mg/kg LY, respectively. Therefore, LY prolonged VERP and APDE and affected DFT in the same saturating dose-response manner. LY may facilitate defibrillation by increasing the duration of postshock refractoriness.

Tedisamil is a new bradycardic agent, previously shown to block transient outward and delayed rectifier potassium currents in cardiac tissue [1,2]. In the present study tedisamil caused bradycardia and Q-Tc widening in rats and primates. Q-Tc widening is indicative of class III antiarrhythmic actions. In keeping with this, tedisamil had antiarrhythmic activity against electrical and ischemia-induced arrhythmias in rats. In rats, 0.5–4 mg/kg IV tedisamil caused parallel and dose-related increases in action-potential duration, “Q-Tc” interval, and refractory period; and decreases in maximum ventricular following frequency. In primates after 0.5–2.0 mg/kg IV, findings were similar for indices of Q-T widening and decreases in maximum ventricular following frequency. Tedisamil did not change QRS width, nor did it increase threshold currents for capture of ventricles, nor for fibrillo-flutter at doses below 4 mg/kg in rats. These findings were consistent with the lack of significant sodium-channel blockade. However, upon increasing the dose to 4 mg/kg, ventricular fibrillo-flutter could not be induced in rats by electrical stimulation; instead, only ventricular tachycardias with slow rates occurred. Ischemia-induced ventricular fibrillation was reduced in a dose-related manner by tedisamil in rats. The overall incidence of ischemia-induced ventricular tachycardia was not markedly reduced, but rates during tachycardic episodes were lower. When pacing was used to overcome tedisamil-induced bradycardia, antiarrhythmic actions during ischemia were more pronounced. These findings are consistent with the hypothesis that tedisamil increased refractoriness, which resulted in extended path lengths for reentry circuits and slower rates during episodes of ventricular tachycardia. High doses of tedisamil increased path lengths so much that the multiple reentry circuits of fibrillation could no longer occur. The limited study in primates suggests similar mechanisms could occur in humans.

1. The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea-pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed-rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening. 2. Action potentials were recorded from isolated guinea-pig ventricular myocytes using the perforated-patch patch-clamp technique, and monophasic action potentials were recorded from Langendorff-perfused guinea-pig ventricles using a contact epicardial probe. 3. Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28+/-4 s and the amount of slow shortening was 21.9+/-0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff-perfused ventricles. 4. Terikalant dose-dependently increased APD and the increase was enhanced by rapid pacing ('positive' rate-dependence). The drug dose-dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows 'reverse' rate-dependent APD widening, had no significant effect on the time constant or amount of slow shortening. 5. These observations suggest that IK1 plays a role in rate-dependent shortening of APD. The results appear to support the hypothesis that 'reverse' rate-dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate-dependent slow shortening of APD.

This study reports the use of a novel agent, RSD1000 [(+/-)-trans-[2-(4-morpholinyl)cyclohexyl]naphthalene-1-acetate mono hydrochloride], to test the hypothesis that a drug with pKa close to the pH found in ischemic tissue may have selective antiarrhythmic actions against ischemia-induced arrhythmias. The antiarrhythmic ED50 for RSD1000 against ischemic arrhythmias was 2.5 +/- 0.1 micromol/kg/min in rats. This value was significantly lower than doses that suppressed electrically induced arrhythmias. In isolated rat hearts, RSD1000 was approximately 40 times more potent in producing ECG changes (i.e., P-R and QRS prolongation) in acid (pHo = 6.4) and high [K+]o (10.8 mM) buffer than in normal buffer (pHo = 7.4; [K+]o = 3.4 mM). In patch-clamped, whole-cell rat cardiac myocytes, inhibition of sodium (INa) currents by RSD1000 was pH- and use-dependent. The IC50 for INa blockade was lower (P.05) in acid (0.8 +/- 0.1 microM) than in pH 7.3 (2.9 +/- 0.3 microM), respectively, whereas the IC50 for blockade of transient outward potassium current (ITO) at pH = 6.4 and 7.3 was 3.3 +/- 0.4 and 2.8 +/- 0.1 microM, respectively. Mixed ion channel block in ischemic myocardium with minimal effects on normal cardiac tissue, as governed by the low pKa of RSD1000, may account for its antiarrhythmic activity against ischemia-induced arrhythmias.

To explore the hypothesis that class III antiarrhythmics reduce defibrillation threshold (DFT) by prolonging postshock refractoriness.The effect of a new selective potassium channel blocker, dofetilide (DOFlow 2.5 micrograms/kg bolus plus 0.9 microgram/kg/h; DOFmed 10 micrograms/kg bolus plus 3.6 micrograms/kg/h; and DOFhigh 25 micrograms/kg bolus plus 9 micrograms/kg/h), on DFT was compared with that of placebo in anesthetized open chest dogs (n = 6 per group). The effects of dofetilide on refractory period extension (RPE) were assessed by using DFT strength shocks delivered at various stages of repolarization.DFT was significantly decreased in the DOFhigh group, whether expressed as shock peak voltage or energy (P0.05 compared with changes in placebo). At baseline, a shock timing of ventricular effective refractory period of 25 ms resulted in RPE of 100 +/- 24 ms, 80 +/- 11 ms, 91 +/- 14 ms and 90 +/- 20 ms in the placebo, DOFlow, DOFmed, and DOFhigh groups, respectively. After infusion, these RPE values were unchanged in the placebo group but tended to increase in the dofetilide treatment groups. DOFhigh significantly increased RPE by 20 +/- 18 ms (P0.05 compared with baseline values and changes in placebo). Dofetilide-induced changes in RPE and DFT were significantly correlated when expressed as voltage (r2 = 0.78, P0.01), current (r2 = 0.80, P0.01) and energy (r2 = 0.53, P0.01).These results show that dofetilide prolonged RPE at a plasma level that reduced DFT, thus providing support for the hypothesis that selective prolongation of refractoriness may synergize with shock-induced RPE to decrease the energy requirements for defibrillation.

A fully automated program has been developed for analysing digitised cardiac monophasic action potentials (MAPs) of several animal species. Under diverse conditions, the program’s performance is evaluated by comparison with high-resolution manual analysis of action potential duration, MAP detection, baseline and plateau determination. For each variable, the differences between both forms of analysis are categorised according to species (rabbit, dog or baboon), intervention (control, sematilide or LY-190147), rhythm source (sinus or paced), and rates. They are then examined using ANOVA (null hypothesis: no difference between methods for any category). Intra-group differences are significant for baseline selection (p

The sensitivity of the delayed rectifier K+ current (I(K)) to intracellular Mg2+ was investigated in guinea pig ventricular myocytes using the whole cell patch-clamp technique. An increase in free intracellular Mg2+ concentration ([Mg2+]i) led to a dose-dependent decrease in I(K) with a half-maximal effect of approximately 20 nM. Activation of I(K) was shifted toward more positive voltages on increasing [Mg2+]i, but little effect was observed on activation and deactivation kinetics. Isoproterenol increased I(K) and was partially reversible in both control and 100 nM [Mg2+]i. The antiarrhythmic drug dofetilide was used to separate I(K) into its two components, rapidly activating (I(Kr)) and slowly activating (I(Ks)). The magnitude of both components decreased to a similar extent with an increase in [Mg2+]i. As [Mg2+]i was reduced, however, the number of experiments in which the dofetilide-sensitive current I(Kr) displayed inward rectification was reduced. In contrast to results previously reported for frog myocytes, it is unlikely that Mg2+ effects on guinea pig I(K) are mediated by a protein phosphatase.

The following investigation was designed to assess whether or not streptozotocin diabetes has an influence on the number and severity of ventricular arrhythmias following coronary artery occlusion in the conscious rat. In addition, electrocardiogram and haemodynamic data were compared between streptozotocin diabetic groups and control. Diabetes was induced in male Sprague–Dawley rats with streptozotocin (55 mg/kg iv) and left anterior descending coronary artery ligation was performed either 6 or 9 weeks later. Rats were allowed to recover from preparative surgery for 1 week prior to ligation. Streptozotocin diabetes (untreated or insulin controlled) appeared to have little influence on the variables tested. When exposed to equivalent degrees of ischaemia (the rat is a microangiopathy-resistant species), the streptozotocin diabetic rat heart was not appreciably more prone to arrhythmias of any type compared with control.

Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of class I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by assessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbital-anesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 micrograms/kg of bolus + infusion of 10 micrograms/kg/hr) which blocked only neuronal activity, and a high dose (TTXh, 50 micrograms/kg of bolus + infusion of 50 micrograms/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in blood pressure and heart rate caused by TTX, hexamethonium, nitroprusside and propranolol were also used. Only TTXh possessed antiarrhythmic activity in rats subjected to myocardial ischemia (produced by ligation of the left anterior descending coronary artery). Arrhythmia scores (mean, n = 9) were: saline, 3.8; hexamethonium, 3.8; nitroprusside, 3.2; nitroprusside + propranolol, 4.3; low TTX, 3.9; and TTXh, 0.9. Only TTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KCl filled microelectrodes) as well as action potential height, and concomitantly prolonged the P-R and QRS intervals of normal hearts. In conclusion, our study demonstrated that drugs which produced hypotension, bradycardia and loss of autonomic function were not antiarrhythmic. On the other hand, the marked antiarrhythmic activity of TTXh appeared to depend upon ventricular gNa blockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa blockade.