Department of Physiology,
Queen's University,
Kingston, Ontario, Canada
To the Editor:
In the last 2 years or so, the use of nifedipine,
especially the short-acting form,1 2 has come
under increasing scrutiny. It has been in wide use for almost two
decades in the control of angina pectoris and hypertension but has been
associated in a dose-dependent3 manner with
unfavorable side effects like increased negative inotropy and
hypotension, proarrhythmia, and in some studies, increased
mortality,3 4 although this conclusion is not
without controversy.5 The adverse actions of
short-acting nifedipine in the acute situation in patients
with hypertension1 and/or preexisting
coronary heart disease are more
accepted,2 and one important finding is T-wave
inversion, which can be
asymptomatic.6
We would like to highlight a possible underlying mechanism based on the
sensitivity of myocardial potassium ion channels to calcium channel
antagonists. The first-generation drugs
(nifedipine, verapamil, and diltiazem) block
calcium channels in myocardium with a relatively high
affinity (Kd=200 to 300
nmol/L),7 but all three also block myocardial
potassium channels, both in mammalian ventricular myocytes,
with Kds of 0.5 to 1 µmol/L, and in
cloned channels.8 9 The plateau phase of the
cardiac action potential is normally terminated by repolarizing outward
potassium fluxes so that block can prolong the action potential,
causing a dispersion of refractoriness because these channels differ in
their regional distribution across the myocardial
wall10 and lead to instability of the resting
potential of the ventricular muscle. Interestingly, one
prominent effect is expected to be T-wave inversion related to
preferential block of epicardial potassium currents responsible for the
shorter epicardial action potential. Instability during the plateau or
at the resting potential, in combination with raised
catecholamine levels, may predispose to the generation of
early or late afterdepolarizations, which can give rise to important
ventricular arrhythmias.11
One particular potassium current, IKUR, a
rapidly activating delayed rectifier present
in12 and cloned from human heart as
hKv1.5,13 is particularly important in
determining the plateau duration of the human cardiac action potential.
Data exist showing that hKv1.5 is blocked by all three types of
Ca2+ antagonists. We described block
of hKv1.5 by verapamil in detail8 and
suggested a mechanism of open channel block from the inner pore.
Diltiazem and nifedipine block hKv1.5, and our recent data
suggest that nifedipine is also an open channel blocker
that acts predominantly at the external pore of hKv1.5
channels.9 Threshold effects of
nifedipine on hKv1.5 were at 100 nmol/L, whereas sublingual
and oral nifedipine, given as single doses, have been shown
to reach concentrations of 300 to 600
nmol/L,14 15 well within the range causing
significant potassium channel blockade in vitro. Furthermore, these
concentrations may well increase if significant renal impairment or
hypoperfusion occurs. Due to the high-resistance nature of the cardiac
action potential plateau, significant changes in duration could occur
with only minor block of the current. It seems reasonable then to
suggest that in situations where nifedipine is given
acutely at high dose, in the compromised myocardium, and
when catecholamine levels are high, such as during the
stress of acute infarction, potassium channel block by
nifedipine could exacerbate the likelihood of serious
arrhythmias.
References
1.
Grossman E, Messerli FH, Grodzicki T, Kowey P.
Should a moratorium be placed on sublingual nifedipine
capsules given for hypertensive emergencies and pseudoemergencies?
JAMA. 1996;276:1328–1331.
2.
Marwick C. FDA gives calcium channel blockers clean
bill of health but warns of short-acting nifedipine
hazards. JAMA. 1996;275:423–424.
3.
Furberg CD, Psaty BM, Meyer JV.
Nifedipine: dose-related increase in mortality in patients
with coronary heart disease. Circulation. 1995;92:1326–1331.
4.
Yusuf F. Calcium antagonists in
coronary artery disease and hypertension.
Circulation. 1995;92:1079–1082.
5.
Epstein M. Calcium antagonists: still
appropriate as first line antihypertensive agents. Am J
Hypertens. 1996;9:110–121.[Medline]
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6.
Phillips RA, Goldman ME, Ardeljan M, Eison HB,
Shimabukuro S, Krakoff LR. Isolated T-wave abnormalities and evaluation
of left ventricular wall motion after
nifedipine for severe hypertension. Am J
Hypertens. 1991;4:432–437.[Medline]
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7.
Charnet P, Ouadid H, Richard S, Nargeot J.
Electrophysiological analysis of the action
of nifedipine and nicardipine on myocardial
fibers. Fundam Clin Pharmacol. 1987;1:413–431.[Medline]
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8.
Rampe D, Wible B, Fedida D, Dage RC, Brown AM.
Verapamil blocks a rapidly activating delayed rectifier
K+ channel cloned from human heart. Mol
Pharmacol. 1993;44:642–648.[Abstract]
9.
Zhang X, Anderson JW, Fedida D. Characterization of
nifedipine block of the human heart delayed rectifier,
hKv1.5. J Pharmacol Exp Ther. 1997;281:1247–1256.
10.
Liu D-W, Gintant GA, Antzelevitch C. Ionic bases for
electrophysiological distinctions among
epicardial, midmyocardial, and endocardial myocytes from the free wall
of the canine left ventricle. Circ Res. 1993;72:671–687.
11.
January CT, Riddle JM. Early afterdepolarizations:
mechanisms of induction and block—a role for L-type
Ca2+ current. Circ Res. 1993;64:977–990.
12.
Wang Z, Fermini B, Nattel S. Sustained
depolarization-induced outward current in human atrial myocytes:
evidence for a novel delayed rectifier K+ current
similar to Kv1.5 cloned channel currents. Circ Res. 1993;73:1061–1076.
13.
Fedida D, Wible B, Wang Z, Fermini B, Faust F, Nattel
S, Brown AM. Identity of a novel delayed rectifier current from human
heart with a cloned K+ channel current.
Circ Res. 1993;73:210–216.[Abstract]
14.
McAllister RGJ. Kinetics and dynamics of
nifedipine after oral and sublingual doses. Am J
Med. 1986;81(suppl 6A):2–5.
15.
Taburet A, Singlas E, Colin J, Banzet O, Thibonnier M,
Corvol P. Pharmacokinetic studies of nifedipine tablet:
correlation with antihypertensive effects. Hypertension.
1983;5(suppl II):II-29–II-33.
© 1998 American Heart Association, Inc.
Correspondence
Potassium Channel–Blocking Actions of Nifedipine: A Cause for Morbidity at High Doses?
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