Little is known regarding changes in reactivity of the vasculature of transplanted solid organs. Experiments were designed to differentiate the effects of denervation and rejection on the function of the endothelium and smooth muscle of pulmonary arteries in transplanted lungs of the dog. Single lungs were transplanted as autografts to study the effects of denervation or as allografts to study the additional effects of rejection. Immunosuppression was stopped in animals receiving allografts 5 days after operation, and rejection was allowed to proceed for an average of 3 days. Animals receiving autografts were studied after the same time period. There were no differences in concentrations of circulating leukocytes, platelets, or lymphocytes between the two groups. Circulating concentrations of angiotensin-converting enzyme were significantly reduced during rejection; concentrations of endothelin were unchanged. Rings of pulmonary arteries with and without endothelium were suspended for the measurement of isometric force in organ chambers. Contractions to angiotensin I and endothelin were less in rejecting than in autotransplanted arteries, whereas those to 5- hydroxytryptamine were enhanced. Contractions to norepinephrine were comparable in both autograft and rejecting allograft arteries. Relaxations to isoproterenol were greater in the autograft than in the rejecting autografted arteries; the opposite was observed for relaxations to histamine. Endothelium-dependent relaxations to adenosine diphosphate and bradykinin but not to calcium ionophore A23187 were reduced with rejection; relaxations to nitric oxide were unchanged. These results suggest that transplantation per se affects vascular reactivity. However, there are selective dysfunctions of receptor-operated mechanisms in arteries that are associated with rejection and that are distinct from denervation. Further, serum concentrations of angiotensin converting enzyme may be an indicator of rejection of transplanted lungs.