In view of bronchoconstrictor and proliferative effects of tachykinins (TKs; mainly substance P and neurokinin A), as well as increased TK release during tissue injury, we hypothesized that monocrotaline (MCT)-induced ventilatory dysfunction and pulmonary hypertension may be mediated via TKs. In phase 1 of the study (n = 19 rats), we tested and found that elevated lung substance P level and suppressed neutral endopeptidase activity occurred 1-2 wk post-MCT (60 mg/kg sc). Both phase 2 (n = 32) and phase 3 (n = 32) young Sprague-Dawley rats were divided into five groups: control, sham, capsaicin, MCT, and capsaicin + MCT. Rats in the control group received no treatment. Each sham rat received the vehicles. Chronic capsaicin treatment was used to deplete neuropeptides. Each MCT rat received a single injection of MCT 1 wk (phase 2) or 3 wk (phase 3) before the functional study. Each capsaicin + MCT rat received the MCT administration 3 days after the completion of capsaicin pretreatment. In the MCT group, there were significant decreases in dynamic compliance, quasi-static compliance, and the maximal expiratory flow rate at 50% total lung capacity in phase 2, which was accompanied by significant increases in pulmonary arterial pressure, the weight ratio of right ventricle/(left ventricle + septum), and the arterial medial wall thickness in phase 3. In the capsaicin + MCT group, however, all the above MCT-induced changes were significantly attenuated or abolished. All values from the sham and capsaicin groups were not significantly different from those of the control group. These data demonstrate that MCT induces pneumotoxicity, accompanied by elevated levels of substance P in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)