piperidines and monocrotaline-pyrrole

Monocrotaline pyrrole (MCTP) causes endothelial cell damage, pulmonary hypertension and right ventricular hypertrophy in rats by an undetermined mechanism. A role for 5-hydroxytryptamine (5-HT) in the cardiopulmonary response to MCTP has been suggested. To investigate the role of 5-HT, the effects of two 5-HT receptor antagonists were examined in MCTP-treated rats. Cotreatment with metergoline, an antagonist which binds to both 5-HT1 and 5-HT2 receptors, did not alter MCTP-induced elevation of lung weight or right ventricular hypertrophy. 5-HT-induced vascular smooth muscle contractions are mediated by 5-HT2 receptors; therefore, MCTP-treated rats were cotreated with ketanserin (KET), a specific 5-HT2 receptor antagonist. At a dosing regimen of KET that inhibited the 5-HT-induced platelet shape change in platelet-rich plasma and the 5-HT-induced increase in perfusion pressure in isolated lungs, KET did not affect the elevation in lung weight or the increased accumulation of 125I-albumin in the lung tissue of MCTP-treated rats. Moreover, MCTP-induced right ventricular hypertrophy was not attenuated by KET. These results indicate that cotreatment with either of these two 5-HT receptor antagonists does not alter the lung injury or right ventricular hypertrophic response to MCTP and suggest that 5-HT is not necessary for MCTP-induced toxicity.

Topics: Angiotensin II; Animals; Blood Platelets; Blood Pressure; Cardiomegaly; Ergolines; Ketanserin; Lung; Male; Metergoline; Monocrotaline; Organ Size; Piperidines; Pyrrolizidine Alkaloids; Rats; Receptors, Serotonin; Serotonin