ABSTRACT
The ability of thromboxane synthetase inhibition to reverse acute cyclosporin A (CsA)-induced nephrotoxicity in the rat was investigated. CsA administration (50 mg/kg/day p.o. for 14 days) to male Sprague-Dawley rats caused a significant 50% decline in creatinine clearance rates, an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage by day 14. These changes were associated with a 5-6-fold increase in urinary thromboxane B2 excretion (from pretreatment values of 28.1 +/- 7.9 to 122.6 +/- 38.9 and 165.8 +/- 39.0 eta g/24 hr body weight on days 7 and 14, respectively). Excretion rates of 6-keto-prostaglandin F1 alpha and prostaglandin E2 were, however, unaffected by CsA administration. Co-treatment with a thromboxane synthetase inhibitor (CGS 12970; 8-[3-methyl-2-(3-pyridyl)-1-indolyl]-octanoic acid) from day 7 (10 mg/kg/day) normalized thromboxane B2 excretion, resulted in creatine clearance rates which were similar to pretreatment values on days 10 and 14, reduced NAG enzymuria on day 10 and prevented acute proximal tubular vacuolation. However, the severity of chronic CsA nephrotoxicity, namely chronic tubular damage and microcalcification at the corticomedullary junction, was not diminished by the thromboxane synthetase inhibition. These results demonstrate that (i) elevated thromboxane synthesis plays an important role in the development of acute CsA nephrotoxicity and (ii) that different and/or additional mechanisms are involved in the pathogenesis of chronic nephrotoxicity.
Subject(s)
Cyclosporine/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Kidney Diseases/chemically induced , Thromboxane-A Synthase/antagonists & inhibitors , Animals , Body Weight/drug effects , Cyclosporine/administration & dosage , Cyclosporine/toxicity , Kidney Diseases/pathology , Kidney Diseases/urine , Male , Prostaglandins/urine , Pyridines/administration & dosage , Rats , Rats, Sprague-Dawley , Thromboxane B2/urineABSTRACT
One component of cyclosporin A (CsA) nephrotoxicity is thromboxane (Tx) A2 induced renal vasoconstriction. This study was designed to investigate whether coadministration of angiotensin converting enzyme inhibitors (ACEI) and thromboxane synthetase inhibition (TSI) could act synergistically to improve the glomerular filtration rate in CsA treated animals. CsA administration (50 mg/kg/day p.o.) to Sprague-Dawley rats for 14 days caused a significant decline in creatinine clearance (CCR), an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage. These changes were associated with a ten-fold increase in urinary TxB2 excretion (from pretreatment values of 17.2 +/- 6.0 ng/day to 174.9 +/- 65.4 ng/day on day 14). Treatment with TSI normalized TxB2 excretion; this was associated with partial protection against CsA induced changes in CCR and NAG enzymuria and the complete prevention of acute proximal tubular vacuolation. However, the coadministration of both TSI and ACEI removed the protective effects exerted by TSI alone and resulted in elevated urinary TxB2 levels similar to those observed in other CsA treated groups. Treatment with ACEI alone did not affect CsA nephrotoxicity. We suggest that elevated TxB2 synthesis is in part responsible for some aspects of renal functional and morphological damage, but that CsA nephrotoxicity is multifactorial and may result from direct cellular toxicity in addition to vascular changes.
