Endothelin, angiotensin II and adenosine in acute cyclosporine A nephrotoxicity.
We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. In the present study, we evaluated the role of endothelin (ET), angiotensin II (AII) and adenosine in this experimental model. All animals received CsA (25 mg/kg/day) for 5 days. Renal function parameters were first measured in a 30-min period, showing renal insufficiency in all animals. Then, rabbits were administered bosentan (10 mg/kg; antagonist of ET(AB) receptors), perindopril (20 microg/kg; angiotensin-converting enzyme inhibitor), or theophylline (1 mg/kg; adenosine receptor blocker at micromolar concentrations). After a 40-min equilibration period, renal function was assessed again for 30 min. Bosentan, perindopril and theophylline significantly reduced renal vascular resistance (-28+/-5%, -39+/-7% and -8+/-3%, respectively), and improved renal blood flow (+38+/-15%, +66+/-16% and +20+/-5%), glomerular filtration rate (+33+/-9%, +52+/-13% and +50+/-8%) and diuresis (+48+/-9%, +76+/-19% and +73+/-14%). Filtration fraction was unchanged with bosentan, decreased with perindopril (-10+/-9%) and increased with theophylline (+24+/-5%). The overall results suggest that ET, AII and adenosine are involved in the acute renal failure induced by CsA. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with ET- and adenosine-mediated afferent arteriolar constriction as well as ET- and AII-mediated efferent arteriolar constriction.
Prévot
A
A
Laboratoire de Néphrologie-Hémaphérèse-Transplantation (UPRES EA 563) and Service de Pédiatrie 2, Centre Hospitalier Universitaire, Dijion, France. anne.prevot@planetb.fr
Semama
D S
DS
Tendron
A
A
Justrabo
E
E
Guignard
J P
JP
Gouyon
J B
JB
D000208:Acute Disease; D000241:Adenosine / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000097:blood; D016232:Endothelins / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D020913:Perindopril / Q000494:pharmacology; D011817:Rabbits; D012079:Renal Circulation / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014867:Water / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D016232:Endothelins; D007166:Immunosuppressive Agents; D014867:Water; D000804:Angiotensin II; D016572:Cyclosporine; D013806:Theophylline; D000241:Adenosine; D020913:Perindopril