A third class of anti‐arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474

Abstract

Summary Both MJ 1999 and AH 3474 protected guinea‐pigs anaesthetized with urethane against ouabain‐induced ventricular fibrillation. MJ 1999 had 1/90, and AH 3474 1/30, of the activity of procaine in reducing the height of the action potential of frog sciatic nerve. MJ 1999 and AH 3474 reduced the rate of rise of intracellularly recorded action potentials at concentrations in excess of 160 × 10−6m (50 mg/l.). It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain‐induced fibrillation. MJ 1999, but not AH 3474, greatly prolonged the duration of the action potential in acute experiments on isolated atrial and ventricular muscle, and prolonged the Q‐Tc interval of the electrocardiogram in anaesthetized guinea‐pigs. It is suggested that this effect contributes to anti‐arrhythmic activity. At concentrations up to 80 × 10−6m AH 3474 had positive chronotropic and inotropic effects on isolated rabbit atrial muscle, but at higher concentrations these were superseded by negative effects. MJ 1999 was depressant at all concentrations studied, the threshold concentrations being 19 × 10−6m for chronotropic, and 162 × 10−6m for inotropic effects.

Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes.

“…In this preparation, indapamide blocked outward current in a time-, voltage-and concentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was without effect. The following features of the effect of indapamide strongly suggest selective block of IK,: (1) Indapamide block was significantly greater with 5000-millisec-S elective prolongation of cardiac repolarization was proposed as a mechanism of antiarrhythmic drug action over 20 years ago.' This "class III" action has become a major focus in antiarrhythmic drug development, because of the perceived liabilities of Na+ channel blockers2,3 and the theoretical advantages of class III therapy.4 1 Compounds that selectively prolong cardiac repolarization, unlike Na' channel blockers, improve survival in an animal model of ischemic ventricular fibrillation,4-6 facilitate ventricular defibrillation,7 and may augment cardiac contractility.8 However, in clinical trials, the action potential prolongation produced by antiarrhythmic drugs can also be associated with polymorphic ventricular tachycardia, the torsade de pointes syndrome.9-12 Available information indicates that this side effect is facilitated by slow heart rates and electrolyte disturbances, most commonly hypokalemia and/or hypomagnesemia.…”

Effects on cardiac muscle of the β‐adrenoceptor blocking drugs INPEA and LB46 in relation to their local anaesthetic action on nerve

“…(+)-Propranolol, which has only 0-01 times the 83-adrenoceptor blocking potency of the laevo isomer, is commonly regarded as being virtually devoid of activity, yet it was 2-5 times as potent as INPEA and it seems doubtful, therefore, whether the latter can seriously be classified as a '/3-adrenoceptor blocking drug' in vitro. On the other hand INPEA, like previously studied compounds with electrophilic substituents in the ring (practolol; Papp & Vaughan Williams, 1969;sotalol;Singh & Vaughan Williams, 1970c) appears to be relatively more active in vivo in comparison with lipophilic drugs than would be expected on the basis of its in vitro activity. The reason for this has not yet been fully elucidated, but may be related to the attachment of the lipophilic drugs to plasma protein.…”

“…The third class of antidysrhythmic action consists of a prolongation of the duration of the cardiac action potential such as is seen in hypothyroidism (Freedberg, Papp & Vaughan Williams, 1970), and in the presence of the antianginal drug amiodarone (Singh & Vaughan Williams, 1970b) and of the /3-adrenoceptor blocking drug MJ1999 (Singh & Vaughan Williams, 1970c). MJ1999, like INPEA, has the same side chain as isoprenaline and also has an electron-withdrawing group (methyl sulphonamide) in the para-position of the ring (Fig.…”

Ischemic, genetic and pharmacological origins of cardiac arrhythmias: The contribution of the Quebec Heart Institute

“…that arrhythmias mostly represent abnormal ion channel function (4)(5)(6). Of increasing concern both to clinicians and to the pharmaceutical industry is the proarrhythmic effect of drugs targeted for both antiarrhythmic therapy and for noncardiovascular indications.…”