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.

Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction.

OBJECTIVE: Although it is generally accepted that endurance training improves cardiac function after myocardial infarction the sub-cellular mechanisms are uncertain. The present study reports the effects of aerobic endurance training on myocardial mass, myocyte dimensions, contractile function, Ca2+ handling, and myofilament responsiveness to Ca2+ in cardiomyocytes from healthy and failing rat hearts. METHODS: Adult female Sprague-Dawley rats ran on a treadmill 1.5 h/day, 5 days a week for 8 weeks. Exercise intervals alternated between 8 min at 85-90% of V(O(2max)) and 2 min at 50-60%. Training started 4 weeks after ligation of the left coronary artery (TR-INF, n=11) or sham operation (TR-SHAM, n=6). Sedentary animals (SED-SHAM, n=6; SED-INF, n=13) were controls. RESULTS: After 6 weeks V(O(2max)) in TR-INF and TR-SHAM leveled off 65% above sedentary controls. In TR-SHAM, left and right ventricle weights were approximately 25% higher than in SED-SHAM, myocytes were approximately 13% longer; width remained unchanged. At physiological stimulation frequencies, relative myocyte shortening was markedly higher whereas peak systolic [Ca2+] and t(1/2) of Ca2+ transient decay were 10-20% lower, indicating higher Ca2+ sensitivity in cardiomyocytes from trained rats, compared to respective controls. In TR-INF the left and right ventricular weights, and myocyte length and width were 15, 23, 12, and 20% less than in SED-INF. Endurance training significantly increased the myocardial SR Ca2+ pump (SERCA-2) and sarcolemmal Na+-Ca2+-exchanger (NCX) protein levels to the extent that TR-INF did not differ from SED-SHAM. CONCLUSION: This is the first study to show that aerobic endurance training attenuates the ventricular and cellular hypertrophy in failing hearts. Furthermore, training consistently restores contractile function, intracellular Ca2+ handling, and Ca2+-sensitivity in cardiomyocytes from rats with myocardial infarction.

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.