The influence of cervical and periarterial sympathectomy on endothelium-dependent and endothelium-independent relaxations of the mature rabbit carotid artery was studied in vitro. The responses to adenosine, vasoactive intestinal polypeptide and substance P in sympathectomized and control rabbit carotid artery rings were recorded and analyzed. The effects of endothelium removal were also investigated. The maximal relaxation achieved by substance P, which produces endothelium-dependent relaxation, was significantly inhibited in 3 weeks in postsympathectomy arterial preparations as compared to controls. Adenosine and vasoactive intestinal polypeptide, which produce endothelium-independent relaxation, elicited similar relaxation in all tissues. These results demonstrated that the response to substance P was impaired by cervical and periarterial sympathectomy. The decreased maximum response to substance P may be the result of a decreased NK-1 receptor subtype density or excitation/response coupling, or it may be due to an impaired production and/or liberation of endothelium-derived relaxing factor (EDRF).