Cardiopulmonary responses to histamine and methacholine bronchochallenge were examined and compared in unanesthetized spontaneously breathing guinea pigs. All animals had surgically implanted intrapleural catheters and some had arterial or right heart catheters as well. Animals were placed in plethysmographs, and exposed to ascending doses of aerosolized agonists. The provocative dose, i.e. the dose that caused a clear bronchospastic response, was defined as the concentration that increased intrapleural pressure to at least 20 cm H2O. Results showed that bronchospasm was further characterized by decreases in dynamic lung compliance and arterial PO2 and an increase in airway resistance. The accumulation of trapped gas in the lung after challenge, measured in the excised collapsed lung, correlated with the increase in intrapleural pressure and with the fall in lung compliance. Male guinea pigs between 3 and 15 weeks of age did not vary in sensitivity to histamine. Methacholine and histamine were equipotent and produced similar responses. Tachyphylaxis was not demonstrated for either compound. In addition, the provocative dose for the drugs remained stable on a day to day basis. These results offer insight into the nature of the bronchospastic response in guinea pigs and provide new data on response methacholine. (Copyright (c) 1990 by The American Society for Pharmacology and Experimental Therapeutics.)