Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties

Figures

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  Figure 1. Action potential configurations (A), steady-state rate-dependent action potential durations at 90% of repolarization (APD90, (B)), and APD90 restitution relations (C) measured in multicellular human, canine, guinea pig, rabbit, and rat ventricular preparations using sharp 3 M KCl-filled microelectrodes. The restitution curves were obtained by gradually increasing the diastolic interval following a train of action potential stimulated at a stable cycle length. Symbols and bars are mean ± SEM values; (n) denotes the number of preparations studied [57].

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  Figure 2. L-type Ca2+ currents in human (A) and canine (B) ventricular myocytes of epicardial (EPI) and endocardial (ENDO) origin. Command action potentials above and ICa recordings below. ICa was excised by 1 µM nifedipine. Note the double-peaked ICa records in EPI and the single-peaked ones in ENDO preparations in both species. (C) Comparison of peak current densities between pooled human and canine ICa obtained under conventional voltage clamp conditions. At test potentials of +5 mV or more negative, significant differences were observed (human ICa was greater), while no significant differences were found at +10 mV or more positive voltages. Columns and bars are mean ± SEM values, (n) denotes the number of myocytes studied, the asterisk (*) indicates significant differences between human and canine ICa data. (Data from references [21,22,24]).

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  Figure 3. Transient outward K+ currents in human and canine left ventricular myocytes. (A) Differences in action potential morphology in canine ventricular cells derived from the subepicardial (EPI), midmyocardial (MID), and subendocardial (ENDO) layers. (B) Command action potentials (top) and transient outward K+ current (Ito1) records (bottom) taken from midmyocardial human and canine myocytes under action potential voltage clamp conditions. The cycle length of stimulation was 700 ms in the canine and 1000 ms in the human cells. (C) Average Ito1 densities. Ito1 was defined as a 100 µM chromanol 293B-sensitive current. Columns and bars are mean ± SEM values, (n) denotes the number of myocytes studied. Unpublished data from Varró et al.

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  Figure 4. (A–C) Late Na+ current (INa-late) in human and canine ventricular myocytes. INa-late was recorded under conventional voltage clamp (A) and action potential voltage clamp conditions (B). The current in this latter case was excised by 10 µM TTX. Pulse protocols are shown above. (C) Peak densities of INa-late measured with action potential voltage clamp in human and canine myocytes. (D) Representative INCX, defined as a 10 mM Ni2+-sensitive current, recorded using a voltage ramp (−40 mV -> + 60mV -> −100 mV -> −40 mV). (E) Peak inward (measured at −80 mV) and outward (measured at +50 mV) NCX current densities. Columns and bars are mean ± SEM values, (n) denotes the number of myocytes studied. (Data from references [17,21]).

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  Figure 5. Comparison of peak IKr, IKs, and IK1 current densities in human and canine ventricular myocytes under action potential voltage clamp conditions (A,B). IKr, IKs, and IK1 were excised by 5 µM E-4031, 0.1 µM L-735,821, and 500 µM BaCl2, respectively. (C) Expression of the main channel proteins in human and canine ventricular myocardium. Columns and bars are mean ± SEM values, (n) denotes the number of myocytes in (B), and myocardial samples in (C), the asterisks (*) indicate significant differences between human and canine data. (Data from reference [21]).

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  Figure 6. Phase-plane analysis of IKr (excised by 1 µM E-4031, (A)) and IK1 (excised by 10 µM BaCl2, (B)) obtained under action potential voltage clamp conditions in human and canine ventricular myocytes. Representative current–voltage relationships were compared at two different pacing cycle lengths (0.4 and 5 s). The currents showed no rate-dependent properties and displayed similar current–voltage relationships in the two species. Note that the peak amplitude of IKr was identical in the canine and human myocytes, while the peak amplitude of IK1 was three-fold greater in dogs than in humans. (Data from reference [23]).

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  Figure 7. Regional inhomogeneity of the channel protein expression pattern in human and canine ventricular myocardium. (A,B) Epicardial versus midmyocardial distribution. (C,D) Apical versus basal distribution. Columns and bars are mean ± SEM values, (n) denotes the number of myocardial samples studied, the asterisks (*) indicate significant differences from the ratio of 1. (Data from references [19,20]).