Block of the Rapid Component of the Delayed Rectifier Potassium Current by the Prokinetic Agent Cisapride Underlies Drug-Related Lengthening of the QT Interval

Abstract

Block of I(Kr) gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of I(Kr) is also likely to underlie prolongation of the QT interval observed in patients receiving clinically recommended doses of cisapride as well as severe cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.

Cisapride inhibits meal‐stimulated gastric acid secretion and post‐prandial gastric acidity in subjects with gastro‐oesophageal reflux disease

“…We considered the possibility that cisapride might be able to inhibit gastric acid secretion in humans because of the previous findings that gastric parietal cells possess KCNQ1 potassium channels that are involved in gastric acid secretion, 17 and that cisapride can inhibit potassium conductance via similar potassium channels from other tissues. [18][19][20][21][22][23] Although we have not directly examined the effect of cisapride on KCNQ1 channels in human gastric parietal cells, our results do raise the possibility that gastric KCNQ1 potassium channels may play an important role in meal-stimulated gastric acid secretion in GERD, and perhaps in healthy subjects as well. It is also possible that the action of cisapride on serotonin 5-HT 4 and 5-HT 3 receptors might in some way produce the inhibition of gastric acid secretion; however, we are unaware of a role of these receptors in gastric acid secretion.…”

“…Agents that can inhibit gastric but not cardiac KCNQ1 potassium channels 19 could possibly represent novel drugs for the treatment of GERD and other acid-peptic disorders.…”

“…17 Cisapride can inhibit potassium conductance via the human cardiac potassium channel and, by so doing, can induce cardiac conduction abnormalities. [18][19][20] (This effect led to the drug being withdrawn for general human use. 21 ) Cisapride can also inhibit potassium current in human-ether-a-go-go (HERG) channels expressed in cells transfected with the HERG gene, 22,23 and can inhibit HERG-like potassium conductance in oesophageal smooth muscle cells.…”

Turbulent electrical activity at sharp-edged inexcitable obstacles in a model for human cardiac tissue

“…Amiodarone is also found to decrease the conduction velocity and the wavelength of signals in healthy cardiac tissue, whereas in ischemic tissue the same drug leads to an increase of the wavelength. Cardiac arrhythmias can also occur as a result of adverse side effects of noncardiological drugs, e.g., cisapride (13,19,76,80), which works mainly by inhibiting I Kr . In a cardiomyocyte, cisapride The size of the obstacle is 0.8 cm ϫ 3.6 cm, and the pacing site is a region enclosed within a square of side 0.8 cm.…”

The Dog's Role in the Preclinical Assessment of QT Interval Prolongation

“…A cursory examination of the compounds associated with these properties reveal a highly diverse chemical structure set and seemingly nonrelated pharmacological targets. These therapeutics include several antibiotics (24,35) (some macrolides; erythromycin and other protein synthesis inhibitors, fluoroquinolones, DNA synthesis inhibitors; grepafloxacin), antifungals (3, 57) (fluconazole, ketoconazole), an agent for gastrointestinal prokinesis (17,37,50,66) (cisapride), histamine H1 receptor antagonists (5,9,14,25,36,38,39,72,75) (terfenadine, diphenhydramine, astemizole, phenothiazine derivatives), as well as antipsychotic agents (44) (phenothiazine derivatives, haloperidol, sertindole, risperidone). These compounds, although certainly not meant to be an exhaustive list, have been shown to cause serious and potentially fatal cardiac arrhythmias.…”