Lead exposure induces dysfunction of the cyclic guanosine monophosphate-dependent vasodilator system through downregulation of soluble guanylate cyclase (sGC) expression. The endothelium not only releases vasodilators but also vasoconstrictors such as endothelin-1 (ET-1). Our aim was to explore the role of the vascular endothelium and ET-1 as possible mediators of lead-induced downregulation of sGC. Isolated aortic segments from Wistar Kyoto rats were incubated in the presence or absence of lead (1 parts per million) for 24 h. Endothelium was mechanically removed in some of the aorta segments. As reported previously, lead exposure induced downregulation of sGC protein expression in the intact aortic segments. However, lead exposure failed to significantly modify sGC-beta1 subunit expression in the endothelium-denuded aortic segments. Incubation with a selective ETA-type receptor inhibitor, BQ-123 (10(-6) mol/l), restored sGC protein expression in lead-exposed intact aortic segments. As it has also been previously observed, incubation in lead-containing medium resulted in the upregulation of cyclooxygenase-2 (COX-2) in the intact aortic segments. Denudation of endothelium partially abrogated this effect of lead. Incubation with BQ-123 prevented the lead-induced upregulation COX-2 in the intact aortic segments. However, neither ET-1 content nor ETA-type receptor expression were modified by lead exposure of the aortic segments. As conclusion, the endothelium through the activation of ETA-type receptors mediates the downregulation of sGC expression by lead in the vascular wall.