Date of Graduation

1997

Document Type

Dissertation/Thesis

Abstract

The objective of this research was to determine if endothelin is a mediator of hexachloro-1,3-butadiene (HCBD)-induced acute renal failure. The nephrotoxicity associated with HCBD is acute tubular necrosis (ATN). HCBD-induced ATN is characterized by a decrease in renal blood flow (RBF), mediating a decline in the glomerular filtration rate (GFR), polyuria, glucosuria, proteinuria and natriuresis. These effects on the kidney are mimicked by the endogenous peptide endothelin. Endothelin is produced by many different cell types and is the most potent endogenous vasoconstrictor peptide identified to date. The renal vasculature is particularly sensitive to the vasoconstrictive action of endothelin. Endothelin causes a decrease in RBF and GFR and a natriuresis. To study the involvement of endothelin in HCBD-induced ATN, phosphoramidon, an endothelin-converting enzyme inhibitor, or bosentan, an endothelin receptor antagonist, was used to block the effects of endothelin. Initial studies were done by administering either phosphoramidon or bosentan before and after HCBD to establish a role for endothelin. Both phosphoramidon and bosentan were able to block the HCBD-induced decrease in GFR. This same study indicated that endothelin may be involved in the loss of the urinary concentrating mechanism associated with HCBD. Both drugs were able to decrease the polyuria and lessen the decline in urine osmolality. Further studies focused on the phase of ATN endothelin was involved in. To study the initiation phase, bosentan was administered before HCBD only. The results from this study demonstrated that endothelin was not involved in the initiation phase. Bosentan was not able to prevent the decrease in the GFR or the loss of the urinary concentrating mechanism. To study the maintenance phase, bosentan was administered 24 hours after HCBD. The results from this study demonstrated that endothelin is involved in maintaining ATN. Bosentan was able to reverse the decline in GFR and to reverse the natriuresis and decline in fluid reabsorption associated with HCBD. It was concluded from these experiments that endothelin is involved in the maintenance phase of HCBD-induced ATN. Endothelin most likely acts to decrease RBF mediating the decline in GFR. Endothelin is also involved in the loss of the urinary concentrating mechanism.

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