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.

Long-term serotonin administration induces heart valve disease in rats.

BACKGROUND: The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. METHODS AND RESULTS: Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B and the serotonin transporter 5-HTT. CONCLUSIONS: For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.