title: Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations.
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 clarified. 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, BaCl(2), 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 modified 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 (I (net)), 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 modified ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between I (net) and APD.
authors.affiliation: Department of Physiology, University of Debrecen, 4012 Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Bárándi
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Horváth
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Rita
authors.initials: R
authors.lastname: Papp
authors.forename: Gábor
authors.initials: G
authors.lastname: Harmati
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.forename: Norbert
authors.initials: N
authors.lastname: Szentandrássy
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester