Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 25, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp213
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Reverse rate dependency is an intrinsic property of canine cardiac preparations
1 Department of Physiology, University of Debrecen, Debrecen, Hungary
2 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
3 Dipartimento di Biotecnologie e Bioscienze, Universita di Milano-Bicocca, Milano, Italy
4 Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
Correspondence: Péter P Nánási, Department of Physiology, University of Debrecen, H-4012 Debrecen, Nagyerdei krt 98, Hungary. Phone/Fax: +36-52-416634 / +36-52-432289, E-mail: nanasi{at}phys.dote.hu
Aims: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate-dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects.
Methods: Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CL) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (Im) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between Im and APD was tested by numerical modeling.
Results: Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl2) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. Im measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between Im and APD.
Conclusions: RRD of APD modulation is shared, although with differences in magnitude, by interventions of very different nature. RRD can be interpreted as a consequence of the relationship between Im and APD and, as such, is expected in all species having positive APD-CL relationship. This implies that development of agents prolonging APD with direct rate-dependency, or even completely devoid of RRD, may be difficult to achieve.
KEYWORDS Action potential duration; Reverse rate dependence; Ventricular repolarization; Membrane current; Dog myocytes
Time for primary review: 22 Days