Role of endothelin ET(A) receptor antagonism in the post-transplant renal response to angiotensin II in the rat.
The role of endothelins in the renal damage associated with ischaemic-reperfusion (I-R) injury during organ transplantation was determined by selective blockade of the ET(A) receptors with the receptor antagonist ABT-627. The integrity of kidney function was determined 2 and 8 weeks after transplantation by investigation of the renal response to angiotensin II. Under pentobarbitone anaesthesia (70 mg x kg(-1), I.P.), rats underwent a right nephrectomy. Transplantation of the left kidney was performed after 2 h cold ischaemia without or with ABT-627 treatment. Control animals underwent left renal denervation. The renal response to angiotensin II was measured 2 weeks later following blockade of endogenous production of angiotensin II with captopril. A further transplant group was allowed to recover for 8 weeks before the terminal study. In the control group, angiotensin II reduced renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (UV), and fractional sodium excretion (FE(Na)) by 29 +/- 5 %, 19 +/- 4 %, 25 +/- 4 % and 32 +/- 7 %, respectively. Conversely, in the transplant group, angiotensin II left RBF unchanged and increased GFR (59 +/- 12 %) and UV (93 +/- 8 %). FE(Na) decreased by 24 +/- 9 %. In both the transplant group treated with ABT-627 and the long-term recovery group, the renal response to angiotensin II was normalised. In conclusion, renal transplantation following 2 h cold I-R injury resulted in a temporary abnormal renal response to angiotensin II, which was reversed by ET(A) receptor antagonism at the time of transplantation.
Hammad
F T
FT
Department of Physiology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Wheatley
A M
AM
Davis
G
G
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002216:Captopril / Q000494:pharmacology; D003080:Cold Temperature; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007511:Ischemia / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000804:Angiotensin II; D002216:Captopril; D012964:Sodium; D000077868:Atrasentan