Long-term serotonin effects in the rat are prevented by terguride.
Long-term hyperserotoninemia induces heart valve disease in rats, and cases of cardiac valvulopathies have been reported in patients using ergolines, possibly through activation of the 5-hydroxytryptamine(2B) (5HT(2B)) receptor. The ergoline terguride (transdihydrolisuride) is a 5HT(2B/2C) receptor antagonist. Using a rat model, we have investigated whether terguride could prevent serotonin-induced changes in general and heart disease specifically. During 4 months, twelve Sprague-Dawley rats were given daily subcutaneous serotonin injections; twelve rats received a combination of serotonin injections and terguride by gavage, whereas ten rats were untreated controls. Using echocardiography, rats with aortic insufficiency were found in all 3 groups, while pulmonary insufficiency was only found in two rats injected with serotonin alone. Animals given serotonin alone had significantly higher heart weights compared to the controls (p=0.029) and rats given terguride (p=0.034). Rats injected with serotonin alone developed macroscopic skin changes at the injection sites, histologically identified as orthokeratosis and acanthosis. Terguride completely prevented these changes (p=0.0001, p=0.0003). Liver weights were higher in the animals given serotonin alone compared to controls (p=0.014) and terguride treated animals (p=0.009). Stomach weights were higher in animals given serotonin alone compared to rats given terguride (p=0.012). In the mesenchymal cell-line MC3T3-E1, terguride almost completely inhibited serotonin-induced proliferation (p<0.01). Serotonin increases heart, liver and stomach weights, possibly through enhanced proliferation. Terguride inhibits these effects. We propose that terguride may have beneficial effects in the treatment of diseases such as carcinoid syndrome, where serotonin plays an important pathogenic role.
Hauso
Øyvind
Ø
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
Gustafsson
Björn I
BI
Loennechen
Jan P
JP
Stunes
Astrid K
AK
Nordrum
Ivar
I
Waldum
Helge L
HL
D016475:3T3 Cells; D000818:Animals; D002275:Carcinoid Heart Disease / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D004452:Echocardiography; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008090:Lisuride / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000008:administration & dosage / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013270:Stomach / Q000187:drug effects / Q000473:pathology
C006208:dironyl; D012701:Serotonin; D008090:Lisuride