Co-participation of thromboxane A2 and leukotriene C4 and D4 in mediating cyclosporine-induced acute renal failure.
The relative role of thromboxane (TxA2) and sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) in the acute renal failure induced by cyclosporine was studied in the rats. Bolus i.v. administration of 20 mg/kg of CsA but not vehicle to adult male Sprague-Dawley rats resulted in a significant fall in glomerular filtration rate from 0.85 +/- 0.10 and renal plasma flow (RPF) 2.45 +/- 0.14 ml/min/100 g body wt to values at 20 min of 0.47 +/- 0.03 and 1.01 +/- 0.12 ml/min/100 g body wt (P less than 0.01), respectively, without a fall in mean arterial pressure. This hemodynamic effect was maintained for the following 40-min period. Pretreatment of rats with the TxA2 receptor antagonist GR32191 (3 mg/kg i.v.) allowed a partial but significant preservation of GFR (0.60 +/- 0.05 ml/min/100 g body wt) and RPF (1.55 +/- 0.12 ml/min/100 g body wt). In addition, the antagonism of endogenously produced LTC4 and LTD4 with the putative receptor antagonist L-649,923 (1 mg/kg i.v.) partially prevented the fall in GFR (0.65 +/- 0.07 ml/min/100 g body wt) and RPF (1.80 +/- 0.18 ml/min/100 g body wt) at 20 min after CsA injection. The combined administration of GR32191 and L-649,923 completely abolished the CsA-induced decline in GFR (0.80 +/- 0.09 ml/min/100 g body wt) and RPF (2.40 +/- 0.12 ml/min/100 g body wt). These findings suggest that TxA2 and LTC4/LTD4 participate in mediating renal function deterioration induced by acute CsA administration in the rat.
Perico
N
N
Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo, Italy.
Pasini
M
M
Gaspari
F
F
Abbate
M
M
Remuzzi
G
G
D058186:Acute Kidney Injury / Q000139:chemically induced*; D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics; D004336:Drug Antagonism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010654:Phenylbutyrates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000502:physiology*; D013928:Thromboxane A2 / Q000502:physiology*
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D010654:Phenylbutyrates; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013189:SRS-A; D013928:Thromboxane A2; D016572:Cyclosporine; C050033:L 649923; C060013:vapiprost