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EO-122, a newly developed structural analog of lidocaine, has recently been shown to suppress ventricular arrhythmias in a few clinical studies in patients and in experimental animals. In the present study, we investigated the effects of EO-122 on the electrophysiological properties of guinea pig papillary muscle and ventricular myocytes by means of standard microelectrode and whole-cell recording techniques, respectively, At the concentration range of 10(-7)-10(-4) M (cycle length, 2000 ms), resting potential and action potential duration (APD90) were not altered by the drug. Action potential amplitude and APD50 were reduced (p less than 0.01) by 10(-4) M, and Vmax was reduced (p less than 0.01) by EO-122 greater than or equal to 10(-5) M. The effect of EO-122 on Vmax was use-dependent. At 10(-6) and 10(-5) M (cycle length, 2000 ms), the time constant for onset of block (tau on) was 37.0 +/- 13.2 and 26.0 +/- 3.4 s, respectively. The recovery kinetics from use-dependent block was not monoexponential, and the estimated "time constant" for recovery was 76.5 s. We examined the effects of EO-122, 10(-5) M, on the membrane currents in ventricular myocytes and found that the drug attenuated the slow inward current (Isi). EO-122 reduced peak Isi by 68.6 +/- 5.2% (p less than 0.005), whereas the outward current was unchanged. The present study demonstrates that EO-122 blocks both the fast inward (Na+) and the slow inward (Ca2+) channels, and these effects are probably responsible for the antiarrhythmic effects of the drug.

Whereas action potential (AP) duration, area, and repolarization vary considerably, ventricular AP characteristics such as resting membrane potential, AP amplitude, and maximal upstroke velocity of phase 0 depolarization appear similar in a variety of mammalian species. As it has been shown that modifications of the thyroid state are associated with alterations in ventricular electrophysiological properties, we hypothesized that some variations in transmembrane potentials among mammalian species result in part from differences in the individual thyroid states. To test this hypothesis, we used standard microelectrode techniques to study ventricular APs in the dog, mole-rat, guinea pig, rat, mouse, and shrew, which encompass a wide range of thyroid states. In these species O2 consumption ranges from 0.38 (in the shrew) to 4.05 ml O2 X g-1 X h-1 (in the dog). We found that resting membrane potential and AP amplitude, duration, and area were inversely correlated with O2 consumption. The correlation coefficients between these parameters with O2 consumption were -0.92, -0.78, -0.91, and -0.92, respectively. We further tested the hypothesis in guinea pigs in which we modified the thyroid state in opposite directions by thyroxine administration and by propylthiouracil treatment. In the hypothyroid myocardium, AP duration (cycle length = 2,000 ms) markedly increased (P less than 0.001), whereas in the hyperthyroid myocardium, resting membrane potential and AP amplitude (P less than 0.01) and duration (P less than 0.001) decreased. We conclude that interspecies variations in ventricular electrophysiological properties can be correlated with the thyroid state, which may be an important determinant of these properties.

Barbiturates, which are widely used in clinical anesthesia, exert a negative inotropic effect on the myocardium. To investigate the mechanism for the negative inotropism, we studied the effect of sodium pentobarbital (SP) on the action potential and the slow inward current recorded from guinea pig ventricular myocytes. We found that SP at 0.6, 1.0, and 1.6 microM decreased action potential duration at 50% repolarization by 17 +/- 6, 25 +/- 11, and 29 +/- 8%, respectively (p less than 0.05, n = 4). At the concentration range of 0.6-1.6 microM, resting potential and action potential amplitude were unaffected. Voltage-clamp studies in ventricular myocytes demonstrated that SP at 0.6, 1.0, and 1.6 microM reduced the peak slow inward current by 30 +/- 4, 36 +/- 14, and 67 +/- 5%, respectively (p less than 0.005, n = 4). In conclusion, SP, a frequently used anesthetic, decreases the slow inward current in guinea pig ventricular myocytes at clinically relevant concentrations.