Electrophysiological characterization of isolated human atrial myocytes exposed to tegaserod.
Tegaserod (Teg), a 5-hydroxytryptamine type-4 (5-HT(4)) receptor partial agonist, represents a novel treatment for irritable bowel syndrome with constipation and chronic constipation. Cardiovascular safety data from pooled clinical studies showed a signal suggestive of increased occurrence of ischaemic cardiovascular events in patients exposed to Teg versus placebo. Thereafter, marketing of Teg was suspended in the USA and other countries. The clinical data did not demonstrate a causative effect but raised questions of whether a non-recognized effect on the heart was present. Our aim was to evaluate for arrhythmogenic potential of Teg on human cardiomyocytes. Cells isolated from human atrial specimens during cardiac surgery were used to assess the effects of Teg (1, 10, 30 and 100 nM) on action potential and I(f) (funny current) by patch-clamp technique. Results showed that Teg (at all concentrations tested) did not significantly affect action potential characteristics of atrial myocytes when driven at different rates (0.2, 0.5 and 1 Hz). In contrast, 5HT significantly prolonged action potential duration (1 and 10 nM) and caused cell un-excitability (100 nM). Teg, at the highest concentration tested (100 nM, corresponding to 10 times C(max), produced by the recommended dose of 6 mg b.i.d.) increased the I(f) amplitude and caused a shift of its activation curve. This effect of a high concentration of Teg is not considered clinically relevant. When evaluated on single human atrial cells, Teg does not appear to exhibit arrhythmogenic properties, as it did not affect the action potential profile.
Suffredini
Silvia
S
Center of Molecular Medicine (C.I.M.M.B.A.), University of Florence, Italy. silvia.suffredini@unifi.it
Cerbai
Elisabetta
E
Giunti
Gabriele
G
El Mouelhi
Mohamed
M
Pfannkuche
Hans-Jürgen
HJ
Mugelli
Alessadro
A
D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D055724:Electrophysiological Phenomena; D005260:Female; D005765:Gastrointestinal Agents / Q000633:toxicity*; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000633:toxicity*
D005765:Gastrointestinal Agents; D007211:Indoles; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C105050:tegaserod