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Tegaserod Stimulates 5-HT4 Serotonin Receptors in the Isolated Human Atrium
Christin Hesse1, Joachim Neumann1, Valerie Compan2
1Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany.
International Journal of Molecular Sciences
|October 26, 2024
Summary
Tegaserod, a 5-HT4 receptor agonist used for bowel diseases, stimulates human cardiac atrial 5-HT4 receptors. This action involves cyclic adenosine monophosphate (cAMP)-dependent pathways, influencing heart contractility.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Tegaserod is a 5-HT4 serotonin receptor agonist used for treating bowel diseases.
- The 5-HT4 receptor's role in cardiac function is not fully understood.
- Investigating tegaserod's cardiac effects is crucial for understanding its broader physiological impact.
Purpose of the Study:
- To determine if tegaserod stimulates human cardiac atrial 5-HT4 receptors.
- To elucidate the signaling pathways involved in tegaserod's cardiac effects.
- To characterize tegaserod's inotropic and chronotropic actions in cardiac tissues.
Main Methods:
- Utilized genetically modified mice overexpressing human 5-HT4 receptors (5-HT4-TG) and wild-type (WT) littermates.
- Performed Western blot analysis to confirm receptor expression levels.
- Studied isolated human atrial preparations (HAPs) to assess tegaserod's effects on contractility and response to other agents.
Main Results:
- Tegaserod demonstrated concentration- and time-dependent positive inotropic and chronotropic effects in 5-HT4-TG mouse hearts, but not in WT hearts.
- Western blot confirmed significantly higher 5-HT4 receptor expression in 5-HT4-TG mice.
- In human atrial preparations, tegaserod increased contraction force, reduced relaxation time, and increased tension development rate, acting as a partial agonist.
- These effects were enhanced by cilostamide and attenuated by the 5-HT4 antagonist GR 125487, suggesting a cAMP-dependent mechanism.
Conclusions:
- Tegaserod stimulates human cardiac atrial 5-HT4 receptors.
- The mechanism involves cyclic adenosine monophosphate (cAMP)-dependent pathways.
- Tegaserod exhibits partial agonist activity at cardiac 5-HT4 receptors, impacting contractility.
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