To investigate the role of endothelins in cigarette smoke-induced cell proliferation, we assessed the effect of two dual nonselective neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitors, phosphoramidon and CGS 26303, and of a specific NEP inhibitor, CGS 24592, on cell proliferation in the airways and arterial vasculature of the rat lung. Eight groups of rats were exposed to either room air (group 1, control), the smoke of 10 cigarettes (group 2, smoke only) or groups 1 and 2 in addition to a continuous iv infusion of CGS 24592, CGS 26303, or phosphoramidon (10 mg/kg/24 h). Cigarette smoke produced significant cell proliferation in the airways (epithelium and wall) and in the perialveolar ductular vessels (endothelium and wall). CGS 26303 reduced the smoke-induced proliferation in the endothelium and walls of the vessels adjacent to the alveolar ducts, and in the airway walls, but did not affect proliferation in the airway epithelium. CGS 24592 reduced cell proliferation in the airway wall. Phosphoramidon had no effect. These findings indicate that acute cigarette smoke-induced cell proliferation of the rat airways and pulmonary arterial vessels is mediated, at least in part, through release and actions of endothelins. The effectiveness of the more potent inhibitor, CGS 26303, appears to conform to its site of predominant expression.