Circulation, Vol 85, 1491-1500, Copyright © 1992 by American Heart Association
L Carlsson, C Abrahamsson, L Drews and G Duker
BACKGROUND. Earlier observations have indicated that repolarization-
delaying agents may, under certain circumstances, have the propensity to
induce polymorphous ventricular tachyarrhythmias (PVTs) (i.e., torsade de
pointes). We have studied whether the potassium channel opener pinacidil
and two of its pyridylcyanoguanidine analogues (P1075 and P1188) have any
antiarrhythmic effects on clofilium-induced PVTs and triggered responses in
rabbits in vivo and in vitro. METHODS AND RESULTS. Anesthetized rabbits
were pretreated with propranolol (2 mumol/kg i.v.) and subsequently given a
concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally
15 minutes) and the alpha 1-agonist methoxamine (70 nmol/kg/min). In
vehicle-pretreated rabbits (n = 19), clofilium invariably induced PVTs,
which closely resembled torsade de pointes and were preceded by a marked
prolongation of the QTU interval (27 +/- 2.4%, p less than 0.001). In a
separate group of seven rabbits in which monophasic action potentials were
recorded from the left ventricular endocardium, the tachyarrhythmia was
preceded by deflections consistent with early afterdepolarizations (EADs)
of the plateau repolarization phase of the monophasic action potentials.
Intravenous administration of the pyridylcyanoguanidines in doses reducing
mean arterial blood pressure by 25 or 50 mm Hg, respectively, was
associated with a dose-dependent attenuation in the occurrence of
clofilium-induced PVTs. In the pinacidil-pretreated rabbits (0.41 mumol/kg
or 1.86 mumol/kg i.v.), the occurrence of PVTs was reduced from seven of
seven rabbits to five of six and to three of seven rabbits (p = 0.035
versus vehicle-pretreated controls), respectively. In rabbits pretreated
with the low dose of P1075 (0.01 mumol/kg i.v.), PVT occurrence was reduced
from six of six rabbits to two of six rabbits (p = 0.030), whereas in six
rabbits given the high dose of P1075 (0.13 mumol/kg), no PVTs appeared (p =
0.001). When the sulfonylurea glibenclamide (10 mumol/kg i.v.) was
administered to rabbits before P1075 (0.13 mumol/kg) was infused, clofilium
induced PVTs in five of six rabbits (not significantly different from the
incidence in the vehicle-pretreated rabbits). Pretreatment with P1188 (4.36
mumol/kg or 11.88 mumol/kg i.v.) caused a reduction in the occurrence of
PVT from six of six rabbits to five of six and to none of six rabbits (p =
0.001), respectively. In the six animals pretreated with the high dose of
P1188 in which no clofilium-induced arrhythmias were elicited,
glibenclamide (20 mumol/kg i.v.) was injected after the entire dose of
clofilium had been administered. In these rabbits, premature ventricular
systoles and PVTs appeared within a few minutes in five and four of the
animals, respectively. In contrast to the pyridylcyanoguanidines, diltiazem
pretreatment (0.9 mumol/kg i.v., decreasing arterial pressure by 50 mm Hg)
did not attenuate PVT occurrence (five of six rabbits). Acute
administration of P1075 (0.13 mumol/kg) during recurrent attacks of PVTs
abruptly regularized the rhythm in 12 of 13 animals and diminished EADs
observed in monophasic action potentials recorded from the left ventricular
endocardium. In in vitro experiments, action potentials were simultaneously
recorded from rabbit Purkinje fibers and ventricular muscle cells.
Clofilium markedly prolonged action potential duration in Purkinje fibers
but not in ventricular muscle cells, and eventually, bradycardia-dependent
EADs and triggered activity were elicited. P1075 completely abolished EADs
and triggered activity in all (six of six) experiments. Glibenclamide
antagonized the suppressive effect of P1075; hence, EADs and triggered
responses reappeared and resembled those present before P1075. CONCLUSIONS.
These results suggest that ATP-sensitive potassium channel
activatBACKGROUND. Earlier observations have indicated that
repolarization-delaying agents may, under certain circumstances, have the
propensity to induce polymorp
ARTICLES
Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization
Department of Cardiovascular Pharmacology, Astra Hassle AB, Molndal, Sweden.
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