Voltage-dependent inhibition of the ATP-sensitive K+ current by the class Ia agent disopyramide in cat ventricular myocytes.

The inhibition of the adenosine triphosphate-sensitive K+ (KATP) current by disopyramide, a class Ia antiarrhythmic drug, was studied using whole cell voltage clamp in cat ventricular myocytes at 37 degrees C and was compared to that seen with quinidine, a prototypical class Ia drug. The inhibition of the levcromakalim-induced KATP current was concentration dependent, with Ki, at -20 mV, of 4.9 +/- 0.6 and 1.5 +/- 0.1 microM for disopyramide and quinidine, respectively. Disopyramide also inhibited the KATP current elicited during the metabolic inhibition induced by the uncoupler CCCP. Disopyramide (9 microM) produced a 75% inhibition in comparison to the 82% inhibition of the levcromakalim-elicited current. The degree of inhibition increased with depolarization. This effect was quantified using the fractional electrical distance (delta) as an index of the voltage dependence, yielding equivalent voltage dependency values of 0.48 +/- 0.02 and 0.51 +/- 0.08 for disopyramide and quinidine, respectively. Depolarizing and repolarizing voltage steps in presence of tetrodotoxin (5-30 microM), nitrendipine (1 microM), and 4-aminopyridine (1.5 microM) failed to reveal clear kinetics of block and unblock, suggesting either a very fast block (< 3 ms) or a tonic (i.e., time-independent) inhibition. The preferential inhibition of KATP channels at depolarized potentials during metabolic inhibition may contribute to preserve the ability of class Ia agents to prolong action potential duration without compromising resting potential.

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action.

Celikalim (WAY-120491) increases K+ outward flux in dog and human airway smooth muscle.

The ability of the potassium channel opener celikalim (WAY-120491) to increase potassium conductance in airway smooth muscle cells was investigated. The rate of 86Rb+ efflux was measured from dog trachealis muscle strips and human trachealis smooth muscle cells in culture. Whole-cell currents were recorded from dog trachealis smooth muscle cells freshly dissociated using the nystatin-perforated patch technique. Celikalim (1-10 microM) enhanced the rate of 86Rb+ efflux from dog airway smooth muscle in a concentration-dependent manner. At 1 microM, the rate of 86Rb+ efflux was enhanced by 25% in human airway smooth muscle cells. In current recordings, celikalim (1 microM) elicited a glyburide-sensitive outward current, increasing the steady-state current from 367 +/- 20 pA to 688 +/- 172 pA at +20 mV (n = 5). At -60 mV, a voltage closer to the resting potential, the holding current was increased by only +26 +/- 15 pA (n = 5). This smaller increase was sufficient to hyperpolarize the membrane by 8 mV. These results indicate that celikalim is a potent potassium channel opener in dog and human airway smooth muscles. The present data support the hypothesis that an increase in resting K+ conductance by potassium channel openers may account for their relaxing effect in airway smooth muscles.