Effect of thromboxane synthetase inhibition and angiotensin converting enzyme inhibition on acute cyclosporin A nephrotoxicity.
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.
Grieve
E M
EM
Department of Medicine & Therapeutics, University of Aberdeen, U.K.
Hawksworth
G M
GM
Simpson
J G
JG
Whiting
P H
PH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003524:Cyclosporins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014563:Urodynamics / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D003524:Cyclosporins; D011725:Pyridines; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D013930:Thromboxane-A Synthase; C052134:libenzapril