A Comparative Study of the Rapid (IKr) and Slow (IKs) Delayed Rectifier Potassium Currents in Undiseased Human, Dog, Rabbit, and Guinea Pig Cardiac Ventricular Preparations.

To understand the large inter-species variations in drug effects on repolarization, the properties of the rapid (IKr) and the slow (IKs) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch clamp and conventional microelectrode techniques at 37 °C. The amplitude of the E-4031-sensitive IKr tail current measured at -40 mV after a 1 s long test pulse of 20 mV, which was very similar in HM and DM but significant larger in RM and GM. The L-735,821-sensitive IKs tail current was considerably larger in GM than in RM. In HM, the IKs tail was even smaller than in DM. At 30 mV, the IKr component was activated extremely rapidly and monoexponentially in each studied species. The deactivation of the IKr component in HM, DM, and RM measured at -40 mV. After a 30 mV pulse, it was slow and biexponential, while in GM, the IKr tail current was best fitted triexponentially. At 30 mV, the IKs component activated slowly and had an apparent monoxponential time course in HM, DM, and RM. In contrast, in GM, the activation was clearly biexponential. In HM, DM, and RM, IKs component deactivation measured at -40 mV was fast and monoexponential, while in GM, in addition to the fast component, another slower component was also revealed. These results suggest that the IK in HM resembles that measured in DM and RM and considerably differs from that observed in GM. These findings suggest that the dog and rabbit are more appropriate species than the guinea pig for preclinical evaluation of new potential drugs expected to affect cardiac repolarization.

Species-dependent differences in the inhibition of various potassium currents and in their effects on repolarization in cardiac ventricular muscle.

Even though rodents are accessible model animals, their electrophysiological properties are deeply different from those of humans, making the translation of rat studies to humans rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of humans by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the IK1 current (10 µmol/L barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dogs, and did not affect it in humans. On the contrary, IKr inhibition (50 nmol/L dofetilide) significantly prolonged repolarization in humans, rabbits, and dogs, but not in rats. Inhibition of the IKur current (1 µmol/L XEN-D0101) only prolonged rat ventricular repolarization and had no effect in humans or dogs. Inhibition of the IKs (500 nmol/L HMR-1556) and Ito currents (100 µmol/L chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest translational value and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments.

Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle.

INTRODUCTION: Re-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species. METHODS: Action potentials were recorded in preparations obtained from rat, guinea pig, rabbit, and dog hearts; and from undiseased human donor hearts using the conventional microelectrode technique. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5,000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1,000 ms BCL. RESULTS: Marked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective IKr inhibitors E-4031 and sotalol increased overall APD and slowed the restitution kinetics, while IKs inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics. DISCUSSION: Frequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of Ito in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of INa, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as INa or Ito, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.

Relationships between the antihypertensive effects of bisoprolol and levels of plasma atrial natriuretic peptide in hypertensive patients.

Previous studies have demonstrated that beta-blockade increases the levels of plasma atrial natriuretic peptide (ANP), but relationships between this effect and the antihypertensive action of beta-blockade remain unknown. In this study we investigated the amplitude and determinants of bisoprolol-induced ANP increase and the relationships between this increase and the antihypertensive effect of bisoprolol. Nineteen patients with mild to moderate hypertension were included in the study. In the first phase of the study (cross-over, placebo controlled, randomized phase), the effects of 10 mg bisoprolol on plasma ANP at rest and during exercise were compared to placebo. The antihypertensive action of bisoprolol was then evaluated after a 2-week period of treatment (10 mg/day) using ambulatory blood pressure monitoring. Bisoprolol significantly increased plasma ANP level at rest (from 30.6 +/- 20.5 to 42.8 +/- 35.6; P < 0.05) and also during exercise (from 54.7 +/- 44.3 to 119.1 +/- 159.9; pg/mL +/- SD; P < 0.05). Plasma ANP at rest was not significantly correlated with left ventricular mass. After the 15 days of treatment, the bisoprolol-induced daytime diastolic blood pressure reduction was significantly correlated to the initial bisoprolol-induced plasma ANP increase (r = 0.49, P = 0.035). These results suggest that the antihypertensive effect of beta-blocking agents could be partly mediated by an increase of ANP release.