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Tegaserod, but not TD-5108, has effects in porcine and canine isolated coronary arteries The 5-HT 4 receptor agonist and gastrointestinal prokinetic agent, tegaserod, has significant 5-HT 1D, 5-HT 2A, 5-HT 2B and 5-HT 2C receptor affinity (Beattie et al., 2004; Theravance, unpublished observations). The use of tegaserod in the treatment of chronic constipation and constipation-predominant irritable bowel syndrome in the United States is now restricted due to a perceived risk of serious ischemic cardiovascular events (i.e. myocardial infarction, unstable angina and stroke) in patients with pre -existing cardiovascular disease or risk factors (Pasricha, 2007) . The main goal of this study was to investigate whether tegaserod has any 5-HT receptor-mediated activity in isolated coronary arteries that could be relevant to its cardiac adverse effects. The activity of TD-5108 (1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonylmethyl-amino)propyl]-8-azabicyclo [3.2.1]oct-3-yl)amide) , a selective 5-HT 4 receptor agonist recently shown to have efficacy in chronic constipation patients (Goldberg et al., 2007), was also evaluated. Pentobarbital-anaesthetized a dult, male and female Yorkshire and Yucatan pigs, and beagle dogs were euthanized with intravenous potassium chloride. Rings (2-3 mm in width) of the endothelium-denuded left anterior descending coronary artery were mounted (under 1.5 g tension) in tissue baths filled with Krebs-Henseleit buffer (95% O 2/5% CO 2, 37°C). Changes in coronary arterial isometric force were recorded. Tissues were challenged repeatedly with 5-HT (3 µM) until the amplitude of responses was consistent. Data were expressed relative to the primed 5-HT response. A cumulative concentration-response curve to 5-HT, tegaserod or TD-5108 was constructed. 5-HT concentration-response curves were also constructed in the presence of tegaserod, TD-5108 or the selective 5-HT 2A or 5-HT 4 antagonists, ketanserin or piboserod, respectively. 5-HT contracted the porcine and canine coronary arteries in a concentration-dependent manner with mean (± s.e.m.) pEC 50 values of 6.5 ± 0.04 (n=5) and 7.3 ± 0.2 (n=5), respectively. In the porcine coronary artery (n=5), ketanserin (0.1 µM; pK b = 8.7), but not piboserod (0.1 µM), produced a parallel rightward shift in the 5-HT concentration-response curve. Neither tegaserod nor TD-5108 (1 nM - 30 µM; n=5) had an effect on the resting tension of the porcine coronary artery. Tegaserod (3 and 30 µM), but not TD-5108, was associated with a concentration-dependent rightward shift in the 5-HT concentration-response curve and marked suppression of the 5-HT maximum (55.2 ± 10.2% and 11.9 ± 12.9% at 3 and 30 µM tegaserod vs. 111.6 ± 8.7% for the control, respectively; n=5 or 6). In the canine coronary artery, tegaserod, but not TD-5108 (1 - 10 µM; n=4), produced a variable contraction (intrinsic activity ranging from 0 - 34% of the 5-HT maximum). The data are consistent with an interaction of tegaserod at non-5-HT 4 (possibly at 5-HT 1 and 5-HT 2) receptors. Identification of the receptor type(s) responsible, and any relevance to tegaserod’s effects in humans, requires further study. The lack of effects of TD-5108 in the coronary vasculature is consistent with its high degree of 5-HT 4 receptor selectivity. |
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