Endothelin-receptor blockade mitigates the adverse effect of preretrieval warm ischemia on posttransplantation renal function in rats.
BACKGROUND
Ischemia-reperfusion injury has been established as a nonimmunologic risk factor for the development of chronic graft nephropathy after renal transplantation. This objective of this study was to determine if oral administration of an endothelin-1 receptor (ET-R) antagonist over a 2-month period after renal transplantation would mitigate long-term dysfunction associated with 30 min of preretrieval warm ischemia (pre-WI).


METHODS
The left kidney was retrieved from 250-g Lewis rats. Recipients underwent left nephrectomy and isografting using standard techniques. Animals were divided into three groups: nonischemic controls (no pre-WI, n=8); ischemic controls (pre-WI only, n=6); and pre-WI kidneys in which recipients received the ET(A/B) receptor antagonist, A182086, daily (30 mg/kg/day) (pre-WI/ET-R antagonist, n=6). Isograft glomerular filtration rate (GFR) was measured at 2 months.


RESULTS
Measurement of GFR (mL/min) were as follows: no pre-WI, 2.1+/-0.26; pre-WI only, 1.24+/-0.14 (P<0.05 vs. no pre-WI); and pre-WI/ET-R antagonist, 2.3+/-0.45 (P<0.05 vs. pre-WI only and P=NS vs. no pre-WI).


CONCLUSIONS
Chronic administration of a nonselective ET-R antagonist given after the ischemic insult, mitigated the decline in GFR at 2 months. These observations provide an experimental rationale for further investigation of the potential long-term protective effect of nonselective ET-R blockade versus ischemia-reperfusion injury in the clinical setting.
Inman
Sharon R
SR
Biomedical Sciences, Ohio University, Athens, OH 45701, USA.
Plott
Wanda K
WK
Pomilee
Ray A
RA
Antonelli
Jodi A
JA
Lewis
Richard M
RM
D000818:Animals; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000517:prevention & control*; D016030:Kidney Transplantation; D009392:Nephrectomy; D011184:Postoperative Period; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012079:Renal Circulation; D013449:Sulfonamides / Q000494:pharmacology*
C467893:A 182086; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D013449:Sulfonamides