Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity.
We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. As exogenous adenosine infusion mimics the haemodynamic changes that characterize acute renal failure (ARF), we wanted to know whether adenosine was a mediator in this model and whether an adenosine receptor blocker could prevent the CsA-induced ARF. Group 1 were untreated controls. Group 2 received CsA (25 mg/kg per day) for 5 days. Renal function parameters were measured, showing ARF in all animals compared to controls. Theophylline (1 mg/kg i.v. bolus) was then administered and renal function was reassessed. Theophylline significantly reduced renal vascular resistance (-8%) and increased renal blood flow (RBF) (+20%), glomerular filtration rate (GFR) (+50%), filtration fraction (+24%) and diuresis (+73%), suggesting that adenosine was involved in the CsA-induced ARF. In group 3, theophylline (30 mg/kg per day) was given concomitantly with CsA for 5 days. GFR was normalized, but theophylline did not hinder the drop in RBF seen with CsA alone in group 2. Microscopy observation of the kidneys showed that chronic theophylline administration aggravated the morphological changes induced by CsA alone. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with an adenosine-mediated afferent arteriolar constriction which cannot be prevented by concomitant theophylline administration.
Prévot
A
A
Laboratoire de Néphrologie-Hémaphérèse-Transplantation (UPRES EA 563) and Service de Pédiatrie 2, Centre Hospitalier Universitaire, 10 Bd Maréchal de Lattre de Tassigny, 21034 Dijon Cedex, France. prevotanne@hotmail.com
Liet
Jean-Michel
JM
Semama
Denis S
DS
Justrabo
E
E
Guignard
Jean-Pierre
JP
Gouyon
Jean-Bernard
JB
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D016572:Cyclosporine / Q000097:blood / Q000506:poisoning*; D004334:Drug Administration Schedule; D005919:Glomerular Filtration Rate; D007166:Immunosuppressive Agents / Q000097:blood / Q000506:poisoning*; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D011817:Rabbits; D013806:Theophylline / Q000008:administration & dosage* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D058915:Purinergic P1 Receptor Antagonists; D016572:Cyclosporine; D013806:Theophylline