Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans.
OBJECTIVE
To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity.


RESULTS
Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins.


CONCLUSIONS
The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.
Sturrock
N D
ND
Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, UK.
Lang
C C
CC
Struthers
A D
AD
D000328:Adult; D001834:Body Water / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004338:Drug Combinations; D004573:Electrolytes / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction
D004338:Drug Combinations; D004573:Electrolytes; D016572:Cyclosporine; D007213:Indomethacin