BIPHASIC RESPONSE OF ACTION-POTENTIAL DURATION TO METABOLIC INHIBITION IN RABBIT AND HUMAN VENTRICULAR MYOCYTES - ROLE OF TRANSIENT OUTWARDCURRENT AND ATP-REGULATED POTASSIUM CURRENT

Inhibition of cell metabolism is associated with significant changes i n action potential duration. The aim of this study was to investigate the time course of the changes in action potential duration during met abolic inhibition and to determine what changes in membrane currents a re responsible. The amphotericin perforated patch clamp technique was used to study membrane currents and voltage in single rabbit and human Ventricular myocytes. In all myocytes inhibition of cell metabolism, induced by hypoxia (Po-2<5 mmHg) or by addition of 100 mu M 2,4-dinitr ophenol (DNP), resulted in action potential shortening, which was acco mpanied by an increase in outward current, likely to be carried by ATP -regulated potassium channels. In about 65% of the rabbit and 50% of t he human ventricular myocytes, however, action potential shortening wa s preceded by an initial prolongation. During this action potential pr olongation, the L-type calcium current and the steady-state outward cu rrent remained unchanged, The transient outward current (I-to), howeve r, was almost completely inhibited, suggesting that the action potenti al prolongation is caused by a decreased I-to. This interpretation was further supported by the observations that: (I) Action potential prol ongation was found in all subepicardial myocytes, as was I-to, but onl y in a minority of the subendocardial myocytes. (2) Addition of DNP fa iled to cause action potential prolongation in subepicardial myocytes in the presence of 4-aminopyridine, a blocker of I-to. In conclusion, these data suggest that the phenomenon of action potential prolongatio n preceding action potential shortening during metabolic inhibition is mainly restricted to myocytes from subepicardial origin, and is due t o a decrease in I-to. (C) 1996 Academic Press Limited