Endothelin, angiotensin II and adenosine in acute cyclosporine A nephrotoxicity

We previously developed a model of acute cyclosporine A (CsA)-induced vasom otor nephrotoxicity in rabbits. In the present study, we evaluated the role of endothelin (ET), angiotensin II (AII) and adenosine in this experimenta l 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 insuffici ency in all animals. Then, rabbits were administered bosentan (10 mg/kg; an tagonist of ETA/B receptors), perindopril (20 mu g/kg; angiotensin-converti ng enzyme inhibitor), or theophylline (1 mg/kg; adenosine receptor blocker at micromolar concentrations). After a 40-min equilibration period, renal f unction was assessed again for 30 min. Bosentan, perindopril and theophylli ne 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 wa s unchanged with bosentan, decreased with perindopril (-10+/-9%) and increa sed with theophylline (+24+/-5%). The overall results suggest that ET, AII and adenosine are involved in the acute renal failure induced by CsA. We co nclude that CsA administration for 5 days induced a vasomotor nephropathy w ith ET- and adenosine-mediated afferent arteriolar constriction as well as ET- and AII-mediated efferent arteriolar constriction.