The aim of the present study was to examine whether endogenous neuropeptides released from sensory nerves can potentiate airway responsiveness to histamine. Total pulmonary resistance (RL) was measured to assess the bronchial responsiveness to increasing doses of histamine (1.25, 2.5, 5, and 10 micrograms/kg) administered intravenously in 29 anesthetized and artificially ventilated guinea pigs. Pretreatment with aerosolized capsaicin (3 micrograms/ml for 15 to 60 s) 30 min before obtaining the dose-response to histamine significantly potentiated percent increase in RL caused by each dose of intravenously administered histamine. Pretreatment with substance P (0.5 ml/kg of 10(-5) M) administered intravenously also potentiated the airway responsiveness to histamine. As assessed by the amount of extravasation of Monastral blue pigments, both capsaicin aerosol and substance P injected intravenously induced increased vascular permeability in the tracheal mucosa. These findings suggest that endogenous neuropeptides, especially tachykinin such as substance P, can induce airway hyperresponsiveness to nonspecific stimuli and play a possible role in producing airway hyperresponsiveness in bronchial asthma.