Cyclosporin reduces renal blood flow through vasoconstriction of arcuate arteries in the hydronephrotic rat model.
Besides its beneficial effects in organ transplantation cyclosporin (CyA) exhibits nephrotoxic (and other) side effects. CyA nephrotoxicity is associated with a decrease in glomerular filtration rate. Two mechanisms of action have emerged. First, tubular destruction with secondary reduction in renal blood flow and glomerular filtration rate; second, decrease in renal blood flow with secondary interstitial fibrosis. We studied the effect of an acute infusion of CyA in the hydronephrotic rat kidney model, which lacks tubular structures completely. Hence, only the direct vascular effects of CyA were determined. Five groups (G) of rats were studied by television microscopy. G I (n = 7) received CyA (30 mg/kg, i.v.) dissolved in cremophore/plasma; G II (n = 5), time control 1, received cremophore/plasma instead of CyA; G III (n = 8), received CyA 30 mg/kg followed by 20 mg/kg CyA i.v. dissolved in an ethanol/tween solution; G IV (n = 3), time control 2 received ethanol/tween alone in the experimental period; in G V, CyA was applied locally onto the surface of the kidney with concentrations increasing from 10(-7) to 10(-5) M. CyA caused profound reduction in the diameter of arcuate arteries in groups I and III, in contrast to the time control groups II and IV. The vasoconstriction could be partially reversed by the calcium-channel blocker nitrendipine, and completely reversed with acetyl-choline. Glomerular blood flow decreased due to CyA and could not be completely normalized by either drug. Increasing the dosage from 30 to 50 mg/kg was not associated with further reduction in blood flow. Local application of CyA (G V) did not demonstrate vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
Zimmerhackl
L B
LB
Kinderklinik der Universität Freiburg.
Fretschner
M
M
Steinhausen
M
M
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003524:Cyclosporins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006869:Hydronephrosis / Q000473:pathology*; D007262:Infusions, Intravenous; D007678:Kidney Glomerulus / Q000098:blood supply; D008833:Microcirculation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011920:Rats, Inbred WF; D012079:Renal Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D003524:Cyclosporins