Monocrotaline (MCT) is a natural product that causes pulmonary hypertension in rats after metabolic activation to a pyrrole form (MCTP). To examine the vascular reactivity of the pulmonary bed, blood-perfused isolated lungs from MCTP- or vehicle-treated rats were challenged with angiotensin II (AII) and 5-hydroxytryptamine (5HT), and the resultant increases in perfusion pressure were measured. Fourteen days after a single exposure, the pressor responses to AII (0 25 or 0.50 microgram) and 5 HT (12.5 to 50 microgram) were approximately 3 times as great in isolated lungs of MCTP-treated rats as in those of control rats. When examined 7 days after exposure, the response to 25 micrograms 5HT but not to 0.25 microgram AII was enhanced by MCTP; MCT is known to decrease 5HT uptake by pulmonary capillary endothelial cells. Imipramine, a 5HT uptake inhibitor, did not alter the vascular responses to 25 micrograms 5HT in lungs from either control or MCTP-treated rats. The increased responsiveness of the pulmonary vasculature to AII and 5HT after MCTP exposure could play a role in the development and/or maintenance of pulmonary hypertension in this rat model.