Pharmacological and physiological assessment of serotonin formation and degradation in isolated preparations from mouse and human hearts.

Abstract

Using transgenic (TG) mice that overexpress the human serotonin (5-HT)4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT4a receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias.NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT.

• Authors: Ulrich Gergs, Franziska Jung, Igor B Buchwalow, Britt Hofmann, Andreas Simm, Hendrik Treede, Joachim Neumann
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 313 Issue 6 Pg. H1087-H1097 (Dec 01 2017) ISSN: 1522-1539 [Electronic] United States
• PMID: 28916638 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 the American Physiological Society.

Chemical References

• Aromatic Amino Acid Decarboxylase Inhibitors
• Cardiotonic Agents
• Equilibrative Nucleoside Transport Proteins
• Monoamine Oxidase Inhibitors
• Organic Cation Transport Proteins
• Serotonin Agents
• Serotonin Plasma Membrane Transport Proteins
• Receptors, Serotonin, 5-HT4
• Serotonin
• 5-Hydroxytryptophan
• Monoamine Oxidase
• monoamine oxidase A, human
• Aromatic-L-Amino-Acid Decarboxylases

Topics

• 5-Hydroxytryptophan (metabolism, pharmacology)
• Animals
• Aromatic Amino Acid Decarboxylase Inhibitors (pharmacology)
• Aromatic-L-Amino-Acid Decarboxylases (metabolism)
• Cardiotonic Agents (pharmacology)
• Dose-Response Relationship, Drug
• Equilibrative Nucleoside Transport Proteins (metabolism)
• Female
• Heart Atria (drug effects, enzymology, metabolism)
• Heart Rate
• Humans
• Isolated Heart Preparation
• Male
• Mice, Transgenic
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (pharmacology)
• Myocardial Contraction
• Myocytes, Cardiac (drug effects, enzymology, metabolism)
• Organic Cation Transport Proteins (metabolism)
• Receptors, Serotonin, 5-HT4 (genetics, metabolism)
• Serotonin (metabolism)
• Serotonin Agents (pharmacology)
• Serotonin Plasma Membrane Transport Proteins (metabolism)
• Signal Transduction