A pathophysiological role for endothelin (ET), one of the most potent vasoconstrictor peptides, has been suggested in ATN and during kidney allograft rejection. As ET is known to have predominantly local effects, we investigated intrarenal ET content in 82 kidney transplant biopsies and 10 normal control kidneys. ET-immunostaining, using a polyclonal anti-ET-1 antibody was investigated in 4 intrarenal vascular beds (glomeruli, capillaries, arterioles, arteries) and in tubular epithelium. Normal kidneys showed a strong staining of endothelial cells in all vessels and of tubular epithelium. In biopsies with signs for acute vascular rejection a marked decrease in ET staining intensity was seen. In contrast, normal staining similar to control kidneys was detected in interstitial rejection and in ATN. The presence of chronic CyA toxicity, however, lead to a significant reduction of endothelial ET staining. Neither mean doses nor trough levels of CyA correlated closely with the immunostaining findings. Plasma big-ET levels were elevated during vascular rejection, but not in interstitial rejection and ATN. This study demonstrates a significant reduction of ET immunostaining in intrarenal vascular endothelium of kidney transplant biopsies showing signs of endothelial damage. In vascular allograft rejection these changes are often associated with a concomitant rise in plasma ET levels. Our findings support a postulated role of ET in vascular rejection and during CyA toxicity and show that endothelial damage, independent of its genesis, can lead to a reduction of intrarenal ET content.