Block of the delayed rectifier current (I sub(K)) by the 5-HT sub(3) antagonists ondansetron and granisetron in feline ventricular myocytes

• Published in: British journal of pharmacology Vol. 113; no. 2; pp. 527 - 535
• Main Authors: De Lorenzi, FG, Bridal, T R, Spinelli, W
• Format: Journal Article
• Language: English
• Published: 01.01.1994
• ISSN: 0007-1188

We investigated the effects of two 5-HT sub(3) antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (I sub(K)) of feline ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degree C with the patch clamp technique. Ondansetron and granisetron blocked I sub(K) with a K sub(D) of 1.7 plus or minus 1.0 and 4.3 plus or minus 1.7 mu M, respectively. At a higher concentration (30 mu M), both drugs blocked the inward rectifier (I sub(K)1). The block of I sub(K) was dependent on channel activation. Both drugs slowed the decay of I sub(K) 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. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block ( delta ) was 0.10 plus or minus 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. Ondansetron (1 mu M) and granisetron (3 mu M) 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.