The mechanism of action of calcium antagonists on arrhythmias in early myocardial ischaemia: studies with nifedipine and DHM9

Abstract

1 Nifedipine and DHM9 (carboxymethyl methyl 1,4-dihydro-2,6-dimethyl-443-nitrophenyl)-3,5-pyridinedicarboxylate) were studied for their effects on arrhythmias resulting from regional myocardial ischaemia in conscious rats, and for their effects on left ventricular developed pressure in vitro.2 Nifedipine possessed antiarrhythmic activity at a high dose of 10mgkg-' i.v., but not at 0.5 or 2mgrkg-. Ventricular fibrillation (VF), tachycardia (VT), and ventricular premature beats (VPB) were all attenuated to a similar degree; nifedipine did not have a selectivity of action for high frequency arrhythmias. 3 Before coronary occlusion, the three doses of nifedipine reduced arterial blood pressure by a similar magnitude, indicating a similar (maximal) degree of systemic vasodilatation. The reductions in blood pressure were accompanied by reflex tachycardia. Heart rate and blood pressure did not correlate with the incidence or severity of arrhythmias. 4 DHM9 had no influence on arrhythmias, haemodynamic variables or the ECG, even at 20mgkg-1i.v.5 Nifedipine concentration-dependently reduced contractility in perfused paced (5 Hz) rat ventricles in vitro. Raising the concentration of K+ in the perfusion fluid from 3 to l0mequiv.l-P increased the potency (-log1o EC50) of nifedipine up to four fold, and caused a significant depression in excitability. 6 DHM9 at up to 3 x 10 5M had no significant influence on ventricular contractility in vitro. 7 The results provided indirect evidence in support of the hypothesis that calcium antagonists inhibit ischaemia-induced arrhythmias by virtue of inhibition of the slow inward current (Ij) in the ischaemic ventricular myocardium.

Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade

“…The present data do indicate, however, that blockade of L-type Ca 2 þ channels by 17b-estradiol could account for the observed antiarrhythmic actions. Ca 2 þ channels blockers have been shown to be antiarrhythmic in models of myocardial ischaemia (Coker and Parratt, 1983;Curtis and Walker, 1988) including the anaesthetized rat (Curtis et al, 1984).…”

“…Ca 2 þ channel blockers have antiarrhythmic activity during acute myocardial ischaemia (Coker and Parratt, 1983;Curtis and Walker, 1988). Ischaemic damage can partially depolarize ventricular cells, thus inactivating the fast Na þ current, which results in the cells becoming dependent on L-type calcium current (I CaL ) for the upstroke of their action potential.…”

Phase 2 ventricular arrhythmias in acute myocardial infarction: a neglected target for therapeutic antiarrhythmic drug development and for safety pharmacology evaluation

“…(1984), (8) Beatch et al . (1991), (9) Curtis & Walker (1988), (10) Curtis et al . (1984), (11) Curtis et al .…”

“…From a practical viewpoint, study is possible. For example, with rats there are the advantages of their ability to survive phase 1 VF if resuscitation is attempted by the simple technique of ‘thump‐version’ (flicking the chest with a forefinger) with a success rate of up to 100% (Curtis & Walker, 1986; 1988) allowing study of phase 2 VF to proceed. Importantly, phase 2 VF occurs spontaneously following coronary ligation in rats (Curtis et al ., 1987), permitting detection of drug actions without the need for programmed electrical stimulation.…”

“…Our premise is that the temporal changes in the biochemical and associated electrophysiological milieu that occur during the transition from acute ischaemia to infarction and were described above (Wit, 1989; Janse, 1991; Curtis et al ., 1993a, 1993b) have pharmacological importance. It is interesting, therefore, that many of the drugs that are known to prevent phase 1 VF in rats at low dosage are ineffective (or are effective, but only at unacceptably high doses) against phase 2 VF in the same species / model (Curtis et al ., 1984; Curtis & Walker, 1988; Beatch et al ., 1991; Igwemezie et al ., 1992). In other words, drugs appear to act differently on phase 2 versus phase 1 VF.…”