John K. Campbell

Effects of amiodarone on cardiac electrophysiology and inducibility of arrhythmias in chronically infarcted dogs: late arrhythmias, haemodynamics, and sympatholytic actions.

Summary: The electrophysiological and antiarrhythmic effects of acute (2 and 10 mg/kg i.v.) and chronic (400 mg/day p.o. for 28 days) amiodarone (AM) treatment were compared in anaesthetised dogs with 5–6-day-old myocardial infarcts. Intravenous AM prolonged the RR interval, sinus node recovery time, the PR interval, and atrial to His conduction time by 36, 33, 25, and 36%, respectively. Corresponding increases after oral amiodarone were 50, 57, 12, and 26%. Atrial and His–Purkinje conduction times were unchanged. Atrial and ventricular refractory periods were increased especially after oral treatment. Oral AM additionally prolonged QRS, QT, and paced QT (by 4, 34, and 19%, respectively). Effects of oral AM on ventricular repolarisation and on the fast inward sodium current were confirmed in vitro. Both modes of AM administration protected against inducible arrhythmias, an effect that was more marked during normal sinus rhythm than during pacing in orally treated dogs. Oral amiodarone failed to protect against spontaneous late arrhythmias 24 h after infarction whilst both modes of administration noncompetitively inhibited isoprenaline-induced tachycardia. Oral AM reduced blood pressure (13%) and LV dP/dt/P (24%) whereas cardiac output was maintained by an increase in stroke volume. It was concluded that oral AM is haemodynamically well tolerated and that prolonged ventricular repolarisation enhanced by bradycardia together with sympatholytic actions may be important mechanisms for antiarrhythmic efficacy, whereas the mechanisms involved in i.v. efficacy are less clear but may depend, at least partly, on sympatholytic actions and perhaps (tentatively) on sodium channel block in Purkinje tissue.

Comparative effects of bepridil and verapamil on isolated coronary and systemic vascular and cardiac muscle

The relaxant effects of the antianginal agent bepridil, a drug with calcium antagonistic actions, and verapamil on isolated pig coronary (C) and rabbit aortic (A) smooth muscle were compared. Both drugs competitively antagonised calcium in Tris buffered but not in bicarbonate buffered medium. Both agents relaxed K+-depolarised C and inhibited contractile responses to noradrenaline plus anoxia. Bepridil was approximately 10 fold less potent than verapamil. The two drugs exerted similar calcium antagonistic effects in guinea pig papillary muscle but showed dissimilar profiles in atrial muscle in that responses in the presence of bepridil appeared to be frequency dependent. It is concluded that bepridil inhibits responses to anoxia and competitively antagonises calcium in vascular smooth muscle. On atrial tissue, bepridil, unlike verapamil, appears to exert additional actions possibly involving other ion channels.

Comparative electrophysiological effects of disopyramide and bepridil on rabbit atrial, papillary, and Purkinje tissue: modification by reduced extracellular potassium

The electrophysiological actions of bepridil were compared with those of disopyramide in rabbit atrial, Purkinje, and papillary muscles in both normokalaemic (5.6 mM K +) and low K+ medium. In normokalaemic medium, the major electrophysiological effects of bepridil (10–40 μ M) were a reduction in the maximum rate of rise of phase 0 of the action potential (MRD) of atrial and Purkinje fibres and prolongation of the atrial action potential duration (APD). Higher concentrations (40–100 μ M) reduced MRD of papillary muscle without markedly affecting APD. Disopyramide (40–100 μM) reduced MRD and prolonged APD in similar concentrations in all three tissues. Reducing extracellular (EC) K + to 2.8 mM decreased the effects of bepridil on MRD in all tissues but only significantly reduced the response to disopyramide in papillary muscle. Enhancement of APD prolongation by disopyramide in all tissues resulted when EC K + was reduced, whereas only papillary muscle APD showed a marked prolongation in response to bepridil. These results demonstrate that the class I effect of bepridil is highly K+ dependent. It may be expected that QTc prolongation produced by both these drugs will be more marked in patients with low serum potassium levels.

Comparative Frequency-Dependent Effects of Three Class Ic Agents, Org 7797, F]ecanide, and Proprafenone, on ventricular Action Potential Duration

The frequency-dependent electrophysiological effects of three class lc agents, Org 7797 (0.5–5 μM), flecainide (1–20 μM), and propafenone (1–10 μM), were investigated using isolated guinea pig papillary muscle. Transmemhrane cellular action potentials were recorded using conventional microelectrode techniques at driving frequencies of 0.3, 1.0, and 2.0 Hz. In concentrations inducing similar frequency-dependent decreases in Vmax both flecainide and propafenone shortened action potential duration (AM at the two lower stimulation frequencies whereas increasing the driving frequency to 2 Hz attenuated drug-induced APD shortening: In contrast. Org 7797 did not shorten APD at any stimulation frequency, and indeed APD lengthening was observed at 2.0 Hz. Increases in the effective refractory period (ERP) were seen at 1.0 and 2.0 Hz in the presence of Org 7797 and at 2.0 Hz in the presence of flecainide, but ERP was either unchanged (2.0 Hz) or shortened by propafenone. The rate of onset of sodium channel block was faster in response to propafenone compared to Org 7797 and tlecainide. It was concluded that all three drugs may inhibit outward repolarising potassium currents, especially at higher stimulation frequencies: However, the concentrations of Org 7797 necessary to influence repolarisation may be closer to those required to induce sodium channel block compared to tlecainide and especially propafenone. These differences may influence drug-induced effects on wavelength resulting in differences in antilibrillatory efficacy.

Effects of Org 7797 on early, late and inducible arrythmias following coronary artery occlusion in rats and dogs

1 The class Ic steroidal antiarrhythmic agent, Org 7797, was compared with two other Ic agents, flecainide and propafenone for intravenous activity against ischaemia‐related cardiac arrhythmias and for electrophysiological actions in vivo. In addition the haemodynamic effects of Org 7797 were assessed in greyhounds. 2 Org 7797 (0.5 mg kg−1) significantly reduced the expected incidence of early ischaemia‐induced ventricular fibrillation (VF) in rats and greyhound dogs and at doses of 0.5–1.0 mg kg−1 antagonized reperfusion‐induced arrhythmias. Comparative studies in rats showed Org 7797 to be 2–4 times more potent than flecainide or propafenone. 3 Org 7797 (0.5 mg kg−1) slowed intracardiac conduction in anaesthetized beagles and again was at least 2–4 times more potent than flecainide or propafenone. 4 Org 7797 (0.5 and 2.0 mg kg−1), flecainide (1.0 and 2.0 mg kg−1) or propafenone (0.5 and 2.0 mg kg−1), did not significantly prevent induction of tachyarrhythmias (VT) in dogs with 5–6 day old myocardial infarcts although all 3 drugs appeared to prevent induced VF. All 3 drugs (notably fecainide) did however reduce the VT rate. 5 All 3 drugs (1–2 mg kg−1) suppressed spontaneous tachyarrhythmias in conscious beagle dogs with 1–2 day old infarcts. Propafenone was the least effective. 6 In an antifibrillatory dose (0.5 mg kg−1), the major haemodynamic effect of Org 7797 was a 10% increase in peripheral vascular resistance. Stroke volume, cardiac output and coronary blood flow were unchanged. In therapeutic doses, Org 7797 was also less negatively chronotropic than flecainide. 7 It was concluded that Org 7797 is a potent antifibrillatory agent which is haemodynamically well tolerated. Higher doses are required to suppress late ischaemia‐induced tachyarrhythmias which suggest that its antifibrillatory effects are the consequence of an action other than, or in addition to, sodium channel block.

Comparative effects of the isomers of bepridil on isolated coronary and aortic arteries

The vasodilator actions of racemic bepridil were compared with those of its laevo-(l) and dextro-(d) rotatory isomers in isolated rabbit aorta and pig coronary artery. The actions of bepridil (B), (l) B and (d) B were further compared with those of drugs known to act either by blockade of calcium entry or to inhibit calmodulin in pig coronary artery. (l) B and (d) B were equipotent in relaxing tonic contractions induced by phenylephrine in rabbit aorta but (d) B was approximately twice as potent as (l) B in relaxing tonic contractions induced by potassium (K+). Both (d) B and (l) B relaxed K+-induced contractions in coronary artery and, in higher concentrations, inhibited and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W7) were equipotent against both types of contraction whilst nifedipine and verapamil failed to reduce histamine-induced contractions. Both isomers of bepridil (like W7) shifted concentration-response curves to histamine in non-depolarized coronary artery in a noncompetitive manner. No potency differences were found between (l) B and (d) B in this tissues. It is concluded that intracellular actions, possibly calmodulin inhibition, play a substantial role in the vasodilator action of bepridil, a conclusion supported by the relative lack of stereospecificity shown by the bepridil isomers.

The effects of bepridil, compared with calcium-channel inhibitors and calmodulin antagonists on both spontaneous activity and contractions induced by potassium or phenylephrine in rat portal vein

Bepridil is known to block calcium channels in some vascular tissues. Recent work has shown that bepridil also antagonises calmodulin. The present study attempted to more fully characterize the vasodilator actions of bepridil by comparing it with the known calcium channel blocking drugs, nifedipine, diltiazem, verapamil and flunarizine, the calmodulin inhibitors, trifluoperazine and W7 and propylmethylenedioxyindene, which is thought to act intracellularly, on rat portal vein. The relative activities of the test drugs were compared on spontaneous activity and on all components of the contractile responses to potassium and phenylephrine. Bepridil inhibited all components of the potassium and phenylephrine responses equally, actions similar to those of the intracellular acting drugs. The exception to this was trifluoperazine which also exerted alpha-adrenoceptor blocking actions. In contrast the calcium channel blocking drugs, with the exception of verapamil, inhibited the tonic component of both spasmogen responses more than the phasic component. Bepridil like the intracellular acting drugs, but unlike the calcium channel blockers, markedly increased the frequency of spontaneous contractions whilst reducing amplitude. It is concluded that the profile of bepridil on rat portal vein more closely resembles that of intracellularly acting drugs than that of classical calcium channel inhibitors.

Comparison of the electrophysiological effects of Org 7797, disopyramide, mexiletine and propafenone in anaesthetized dogs with myocardial infarcts

1 The electrophysiological effects of intravenously administered Org 7797 were compared with those of disopyramide (class Ia), mexiletine (Ib) and propafenone (Ic) in anaesthetized dogs with 5–6 day‐old left ventricular myocardial infarcts. 2 Org 7797 (0.5 mg kg−1) slowed conduction at all levels of the myocardium as shown by increases in St‐A, AH, HV and QRS intervals, very modestly prolonged atrial and ventricular refractory periods and slightly shortened ventricular repolarization. Sinus node recovery time was increased whilst the RR interval was unchanged. A higher dose (2 mg kg−1) prolonged RR and rendered 5 out of 8 dogs unable to follow an atrial pacing stimulus of mean cycle length 322 ms. 3 Electrophysiological changes induced by propafenone (2 mg kg−1) were qualitatively similar to those of Org 7797 (0.5 mg kg−1). 4 Electrophysiological changes induced by mexiletine (2 mg kg−1) were small or insignificant. The most noticeable effect was a modest increase in the St‐A interval and a slight shortening of ventricular repolarization. A higher dose (8 mg kg−1) additionally slowed conduction in the His‐Purkinje system and in the ventricular myocardium. 5 Disopyramide (2 and 5 mg kg−1) prolonged all cardiac intervals including JTc, QTc and QT during pacing and prolonged cardiac refractory periods. 6 It was concluded that the electrophysiological profile of Org 7797 is more like that of the Ic agent propafenone than that of the class Ia and Ib drugs, disopyramide and mexiletine.

Effects of diet-induced hypokalaemia on the efficacy of antiarrhythmic drugs against ventricular arrhythmias evoked by coronary artery ligation in the anaesthetised rat.

Summary: The antiarrhythmic efficacies of intravenous quinidine (Q), disopyramide (D), prenylamine (P), bepridil (B), and practolol were compared in normokalaemic and dietary-induced hypokalaemic anaesthetised rats. Hypokalaemia markedly increased the severity of arrhythmias induced by coronary artery ligation and reduced the antiarrhythmic efficacy of all five drugs tested. After anaesthesia, hypokalaemia was associated with hypotension and bradycardia but not QTc prolongation. However, bradycardia was not seen in conscious hypokalaemic animals. Papillary muscles taken from hypokalaemic rats displayed a longer action potential duration but no increase in &OV0312;max compared with tissue taken from normokalaemic animals. It is concluded that hypokalaemia in the rat causes electrophysiological disturbances which may contribute both to the observed exacerbation of ischaemia-induced arrhythmias and to the reduced efficacy of Q, D, P, and B. The reduced efficacy of practolol might be explained by other consequences of hypokalaemia.