In various mammalian species, shapes of action potentials vary within the cardiac wall because of differences in transient outward current (Ito). A prominent I,. exists in human ventricular myocytes, but cells have not been separated according to their original localization. Human ventricular myocytes were isolated from separated subepicardial and subendocardial tissue, and regional variations in 'to were studied. Ito was larger in subepicardial than subendocardial cells. Current density at +60 mV was 7.9±0.7 pA/pF (n=28) in subepicardial cells and 2.3+±0.3 pA/pF (n=16) in subendocardial cells. When cells from explanted failing and nonfailing donor hearts were compared, 'to was not different in subepicardial cells; however, it was larger in subendocardial cells from nonfailing hearts. The potential of half-maximal activation (V0.5) was more positive in subendocardial cells (+25.6+3.5 mV, n=15) than in subepicardial cells (+9.2±1.8 mV, n=28). There was no difference in Vo.s between cells from failing and nonfailing hearts. 'to inactivation was similar in all cell types and independent of membrane depolarization (time constant [r]= =60 milliseconds at 22°C). The potential of half-maximal steady-state inactivation was similar in all cell types. Recovery from inactivation of Io was fast in subepicardial cells at -100 mV (r=24+4 milliseconds, n=6), exceeding control values transiently (overshoot), and slow at -40 mV without overshoot (r=638+91 milliseconds, n=6). In subendocardial cells, I, recovered at -100 mV with a fast phase (r=25 milliseconds) and a slow phase (r=328 milliseconds), and recovery was not complete after 6 seconds at -100 mV. In conclusion, regional differences in Ito between subepicardial and subendocardial cells may have clinical implications with respect to rhythmic disturbance during heart failure. (Circ Res. 1994;75:473-482 thought to contribute to the physiological regulation of excitation and conduction, and their disturbance during heart disease may lead to cardiac arrhythmia.3 Therefore, regional properties of I,o were studied not only in cells from terminally failing hearts but also in cells from healthy donor hearts. These results have been published in part in abstract form.10 Materials and Methods Characterization of PatientsMyocytes were obtained from 10 explanted hearts from patients with heart failure and from four nonfailing donor hearts that could not be transplanted for technical reasons. Details of patient data are listed in Table 1. Cell IsolationTissue samples derived from human left ventricle were transported in cold cardioplegic solution maintained at 4°C and supplemented with 2,3-butanedione monoxime (30 mmol/L) for protection of the tissue against damage from Ca 2+ overload."1 In the laboratory, the sample was placed in Ca2-free oxygen-saturated solution. Epicardial fat and connective tissue were removed from the muscle specimen. To separate subepicardial and subendocardial tissue layers, -3-mm segments from either side of the ventricular wall were used, and the m...
1. Outward currents were studied in myocytes isolated from human atrial and subepicardial ventricular myocardium using the whole-cell voltage clamp technique at 220C. The Nae current was inactivated with prepulses to -40 mV and the Ca2P current was eliminated by both reducing extracellular [Ca2+] to 0 5 mm and addition of 100 /M CdCl2 to the bath solution. 2. In human myocytes, three different outward currents were observed. A slowly inactivating sustained outward current, I,,, was found in atrial but not ventricular myocytes. A rapidly inactivating outward current, It., of similar current density was observed in cells from the two tissues. An additional uncharacterized non-inactivating background current of similar size was observed in atrial and in ventricular myocytes.3. It. and I4o could be differentiated in atrial myocytes by their different kinetics and potential dependence of inactivation, and their different sensitivities to block by 4-aminopyridine, suggesting that two individual channel types were involved.4. In atrial cells, inactivation of I. was more rapid and steady-state inactivation occurred at more negative membrane potentials than in ventricular cells. Furthermore, the recovery of It. from inactivation was slower and without overshoot in atrial myocytes. In addition, 4-aminopyridine-induced block of It. was more efficient in atrial than in ventricular cells. These observations suggest that the channels responsible for atrial and ventricular It. were not identical. 5. We conclude that the differences in outward currents substantially contribute to the particular shapes of human atrial and ventricular action potentials. The existence of I.. in atrial cells only provides a clinically interesting target for anti-arrhythmic drug action, since blockers of Iko would selectively prolong the atrial refractory period, leaving ventricular refractoriness unaltered.The action potential shape shows characteristic differences between atrium and ventricle in several animal models, e.g. the guinea-pig (Hume & Uehara, 1985). Inhomogeneities in repolarizing currents between atria and ventricles generated these action potential shape differences. The action potential of human atrium is markedly shorter than that of ventricle, and possesses no clear plateau phase (Trautwein, Kassebaum, Nelson & Hecht, 1962). A careful comparison between the outward currents of human atrial and ventricular myocytes has, however, not been undertaken.The transient outward current (It.) is a major repolarizing current in both human atrium (Escande, Coulombe, Faivre,
Summary— The contribution of Na+, Ca2+, and various K+ currents to the shape of the cardiac action potential is outlined based on the relation between electrophysiological properties and structure of channel molecules. These currents have also been found in human ventricular myocytes, where the most prominent K+ current is a transient outward current that is not influenced by methylsulfonanilide antiarrhythmic drugs. Combined knowledge of electrophysiological and molecular properties of ion channels is likely to form the basis for rational design of future drugs.
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