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Basic Res Cardiol (2010) 105:315323 DOI 10.1007/s00395-009-0082-7
ORIGINAL CONTRIBUTION
Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations
Lszl Brndi Lszl Virg Norbert Jost Zoltn Horvth Istvn Koncz
Rita Papp Gbor Harmati Balzs Horvth Norbert Szentandrssy Tams Bnysz
Jnos Magyar Antonio Zaza Andrs Varr Pter P. Nnsi
Received: 30 November 2009 / Revised: 10 December 2009 / Accepted: 21 December 2009 / Published online: 3 February 2010 Springer-Verlag 2010
Abstract 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 claried. The aim of the present work was to further elucidate the mechanisms responsible for RRD in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit and guinea pig ventricular myocardium in a rate-dependent manner varying the cycle length (CL) between 0.3 and 5 s. Rate-dependent drug effects were studied using agents known to lengthen or shorten action potentials, and these drug-induced changes in APD were correlated with baseline APD values. Both drug-induced lengthening (by dofetilide, sotalol, E-4031, BaCl2, veratrine,
BAY K 8644) and shortening (by mexiletine, tetrodotoxin, lemakalim) of action potentials displayed RRD,i.e., changes in APD were greater at longer than at
shorter CLs. In rabbit, where APD is a biphasic function of CL, the drug-induced APD changes were proportional to baseline APD values but not to CL. Similar results were obtained when repolarization was modied by injection of inward or outward current pulses in isolated canine cardiomyocytes. In each case the change in APD was proportional to baseline APD (i.e., that measured before the superfusion of drug or injection of current). Also, the net membrane current (Inet), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD and consequently with to CL. The results indicate that RRD is a common characteristic of all the drugs tested regardless of the modied ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between Inet and APD.
Keywords Ventricular repolarization Action potential
duration Reverse rate dependence Membrane current
Human myocardium...