Plenary
Lecture
Reverse rate-dependent nature of drug-induced changes in
action potential duration is an intrinsic property of
mammalian and human myocardium
![](Nanasi.jpg)
Professor Peter P. Nanasi
Department of Physiology
University of Debrecen
Hungary
E-mail:
nanasi.peter@med.unideb.hu
Abstract: All currently used class 3 antiarrhythmics
carry serious proarrhythmic risk, which is associated
with lengthening of action potential duration (APD) in a
reverse rate-dependent manner, i.e. lengthening of APD
is greater at longer than at shorter cycle lengths.
Although several theories have been developed so far to
explain this reverse rate-dependency, its mechanism has
not been fully clarified. Here we propose a simple
mechanism to explain the reverse rate-dependency of drug
effects in the mammalian heart. Rate-dependent
drug-effects of various origin were studied using agents
known to lengthen or shorten action potentials allowing
thus to determine the drug-induced changes in APD as a
function of the cycle length. Both drug-induced
lengthening and shortening of APD displayed reverse
rate-dependency in human, canine, and guinea pig
preparations, but not in rabbit and rat myocardium.
Similar results were obtained when repolarization was
modified by injection of inward or outward current
pulses in isolated canine cardiomyocytes. In contrast to
reverse rate-dependence, drug-induced changes in APD
well correlated with baseline (pre-drug) APD values in
all preparations studied. Since the net membrane
current, determined from the action potential waveform
was inversely proportional to APD, and consequently to
cycle length, it is concluded that that reverse
rate-dependency may simply reflect the inverse
relationship linking net membrane current to APD. In
summary, reverse rate-dependency is an intrinsic
property of drug action in the hearts of species showing
positive APD - cycle length relationship, including
humans. This implies that development of a pure K+
channel blocking agent without reverse rate-dependent
effects has little chance to succeed. A more promising
approach might be to combine prolongation of action
potential duration with interventions suitable to
minimize arrhythmogenesis at slow heart rates. This can
likely be achieved by combining K+ channel blocking
drugs with blockers of plateau inward currents, such as
L-type Ca2+ current and window Na+ current. This view is
supported by the results obtained by either combining
two distinct molecules, or by applying single drugs
having intrinsically combined modes of action.
Brief biography of the speaker:
Peter P. Nanasi was born in 1956, at Debrecen, Hungary.
He graduated from the University Medical School of
Debrecen with an M.D. degree in 1980. He obtained his
Ph.D. degree in 1992, and he received the D.Sc. degree
from the Medical Branch of the Hungarian Academy of
Sciences in 1999. From 1980, he has been working at the
Department of Physiology, University of Debrecen - as a
full professor since 2002. At the same time, he is the
chairman of the "Department of Oral Physiology and
Pharmacology" at the Faculty of Dentistry since 2001.
During his career, he has spent 2 years in the United
States, at the Children's Hospital Medical Center and at
the Department of Pharmacology and Cell Biophysics,
University of Cincinnati, Ohio with professors David A.
Lathrop and Shirley H. Bryant. His research interest
covers the physiology and pharmacology of cardiac ion
channels, including the frequency-dependent
interactions, regulation of action potential duration,
and cellular mechanisms of antiarrhythmic and
proarrhythmic actions. He is member of the Physiological
Society, British Pharmacological Society, European
Working Group on Cardiac Cellular Electrophysiology,
MyoNaK, and the International Academy of Cardiovascular
Sciences. He has published 119 full length papers
(IF=310) and 6 book chapters in English language. He was
also involved in more than 160 lectures and posters in
the field of cellular cardiac electrophysiology.
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