title: Functional characterization of contractions to tegaserod in human isolated proximal and distal coronary arteries.
abstract: Tegaserod, a 5-HT(4) receptor agonist, has been used to treat idiopathic constipation and constipation-predominant irritable bowel disease. It has recently been suggested that tegaserod has an affinity for 5-HT(1B) receptors, which mediate vasoconstriction. As some patients have experienced cardiac ischemia during treatment with tegaserod, we assessed contractions to tegaserod in healthy and diseased human isolated coronary arteries and compared the results with those obtained using sumatriptan, an established 5-HT(1B) receptor agonist. Proximal and distal human coronary arteries were divided into sets of healthy and diseased tissues based on functional endothelial responses. Concentration-response curves to tegaserod and sumatriptan were constructed to assess their contractile potential. Tegaserod's antagonist properties at 5-HT(1B) receptors were studied by constructing concentration-response curves to sumatriptan in the absence or presence of tegaserod (1 microM). Sumatriptan induced concentration-dependent contractions, which were greater in distal than in proximal coronary artery segments. In the proximal segments, tegaserod induced contractions only at concentrations of 10 microM or higher, while in distal segments contractions were generally absent. Tegaserod did not antagonize sumatriptan-induced contractions. There was no difference between the results obtained in healthy and diseased coronary arteries. In conclusion, tegaserod induced contractions in human proximal coronary arteries at concentrations 1000 times higher than C(max) (6 mg bid). Hence, tegaserod does not exhibit a relevant vasoconstrictor potential in the human coronary artery. Further, tegaserod did not behave as an antagonist at 5-HT(1B) receptors. Additional studies may be warranted to investigate the use of 5-HT(4) agonists in patients with cardiovascular risk factors.
authors.affiliation: Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Kayi Y
authors.initials: KY
authors.lastname: Chan
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: Frank P J
authors.initials: FP
authors.lastname: Leijten
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Pfannkuche
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van den Bogaerdt
authors.forename: Alexander H J
authors.initials: AH
authors.lastname: Danser
authors.forename: Antoinette
authors.initials: A
authors.lastname: MaassenVanDenBrink
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001549:Benzamides / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001549:Benzamides; D007211:Indoles; D011725:Pyridines; D012333:RNA, Messenger; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D044422:Receptors, Serotonin, 5-HT4; C103477:3-(3-(dimethylamino)propyl)-4-hydroxy-N-(4-(4-pyridinyl)phenyl)benzamide; C105050:tegaserod; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D018170:Sumatriptan