Experiments were designed to determine whether or not acute rejection of allotransplanted lungs altered endothelin-content and receptors in recipient heart and kidneys. Five groups of dogs were studied: 1) unoperated, non-immunosuppressed; 2) unoperated, immunosuppressed; 3) single lung autotransplanted, non-immunosuppressed; 4) nonrejecting single lung allotransplanted (allotransplant, immunosuppressed), and 5) rejecting single lung allotransplanted (allotransplant, rejecting). Operated animals were sacrificed eight days after the surgical intervention. Immunosuppression began the day of surgery and continued for five days. At this time, immunosuppression was either maintained in some animals (allotransplanted, immunosuppressed) or discontinued so that rejection would occur (allotransplanted, rejecting). Unoperated, immunosuppressed animals were maintained on the same drug schedule as the allotransplanted, rejecting animals. Serum levels of endothelin-1 were comparable among groups. However, tissue-content of endothelin was elevated only in kidneys of dogs with rejecting allografts. Competitive-inhibition curves for radiolabeled endothelin-1 by unlabeled endothelin-1, -3 and sarafotoxin S6C were obtained using membranes prepared from renal cortex, outer and inner medulla. Inhibition was significant for a one-site binding model with endothelin-1 and two-site binding model for endothelin-3 and sarafotoxin S6c in membranes from all regions of the kidney. The ratio of high to low affmity sites increased with acute rejection in the outer and inner medulla. The results suggest that renal endothelin-content and receptors are altered during acute rejection of lung allografts in the absence of cyclosporin. Such changes may affect renal vascular resistance and function in animals with rejecting lung allografts independent of nephrotoxic affects of immunosuppressants.
Bibliographical noteFunding Information:
The authors gratefully acknowledge and thank Drs. Allison McLarty, Amita Rastogi, Henrik Schersten and Fabio Ricagna for the surgical preparation of the animals. This work was supported by a grant from the Mayo Clinic and Foundation.
- lung transplantation