Functional characterization of contractions to tegaserod in human isolated proximal and distal coronary arteries.

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.

Investigation of serotonin type 4 receptor expression in human and non-human primate gastrointestinal samples.

BACKGROUND: The serotonin type 4 (5-HT4) receptor has been associated with functions of the gastrointestinal tract such as modulation of the peristaltic reflex, smooth muscle tone, intestinal secretion and visceral sensitivity. The activation of peripheral 5-HT4 receptors with agonists such as tegaserod has been shown to accelerate gastric emptying and improve symptoms of constipation in animals and humans. However, detailed data on the expression profile and on the localization of this receptor subtype are lacking so far. OBJECTIVE: To study the pattern and expression levels of 5-HT4 receptor messenger RNA expression in the gut. METHOD: Normal tissue samples were collected from the whole gastrointestinal tract of patients undergoing abdominal surgery and, in addition, of monkeys. We performed a comprehensive analysis of 5-HT4 receptor expression by quantitative reverse transcription-polymerase chain reaction, using human and non-human primate tissues from the oesophagus to the rectum. In addition, the brain and heart of non-human primates were analysed. RESULTS: Significantly higher levels of 5-HT4 receptor mRNA were measured in the human stomach, duodenum, jejunum, ileum and caecum and also in the corresponding non-human primate gut segments, ranging from 2- to 12-fold compared with the liver. No differences were found between females and males of both human and non-human primates. CONCLUSIONS: These results show 5-HT4 receptor mRNA expression throughout the gastrointestinal tract in humans and primates, and also support the preclinical and clinical findings of 5-HT4 receptors ligands exhibiting multiple effects throughout the gastrointestinal tract.

Effects of tegaserod on bile composition and hepatic secretion in Richardson ground squirrels on an enriched cholesterol diet.

BACKGROUND: Tegaserod is effective in treating IBS patients with constipation, and does not alter gallbladder motility in healthy individuals or in patients with IBS. However, it is not known if tegaserod affects the biliary tract in gallstone disease, so to this end the effects of tegaserod on bile composition and hepatic secretion of Richardson ground squirrels maintained on an enriched cholesterol diet were examined. RESULTS: Animals were fed either a control (0.03%) or enriched (1%) cholesterol diet for 28 days, and treated s.c. with tegaserod (0.1 mg/kg BID) or vehicle. Bile flow, bile acid, phospholipids and cholesterol secretion were measured with standard methods. Tegaserod treatment or enriched cholesterol diet, alone or combination, did not alter body or liver weights. The enriched cholesterol diet increased cholesterol saturation index (CSI), cholesterol concentrations in gallbladder and hepatic duct bile by approximately 50% and decreased bile acids in gallbladder bile by 17%. Tegaserod treatment reversed these cholesterol-induced changes. None of the treatments, drug or diet, altered fasting gallbladder volume, bile flow and bile salts or phospholipid secretion in normal diet and cholesterol-fed animals. However, tegaserod treatment prevented the decreases in bile acid pool size and cycling frequency caused by the enriched cholesterol diet, consequent to re-establishing normal bile acid to concentrations in the gall bladder. Tegaserod had no effect on these parameters with normal diet animals. CONCLUSION: Tegaserod treatment results in increased enterohepatic cycling and lowers cholesterol saturation in the bile of cholesterol-fed animals. These effects would decrease conditions favorable to cholesterol gallstone formation.

Noninvasive assessment of gastric emptying by near-infrared fluorescence reflectance imaging in mice: pharmacological validation with tegaserod, cisapride, and clonidine.

Noninvasive near-infrared fluorescence reflectance imaging (FRI) is an in vivo technique to assess physiological and molecular processes in the intact organism. Here we describe a method to assess gastric emptying in mice. TentaGel beads with covalently bound cyanine dye (Cy5.5) conjugates as fluorescent probe were administered by oral gavage. The amount of intragastric beads/label was derived from the fluorescence signal intensity measured in a region of interest corresponding to the mouse stomach. The FRI signal intensity decreased as a function of time reflecting gastric emptying. In control mice, the gastric half-emptying time was in agreement with literature data. Pharmacological modulation of gastric motility allowed the evaluation of the sensitivity of the FRI-based method. Gastric emptying was either stimulated or inhibited by treatment with the 5-HT(4) receptor agonists tegaserod (Zelnorm) and cisapride or the alpha(2)-receptor agonist clonidine, respectively. Tegaserod and cisapride dose-dependently accelerated gastric emptying. In contrast, clonidine dose-dependently delayed gastric emptying. In conclusion, FRI using fluorescently labeled beads allows the reliable determination of gastric emptying as well as the assessment of pharmacological interventions. The technique thus offers the potential to characterize molecular targets and pathways involved in physiological regulation and pharmacological modulation of gastric emptying.