Mechanism of FK506-induced renal hypoperfusion and its reversion in rats.
OBJECTIVE
To investigate the mechanism of renal hypoperfusion induced by tacrolimus (FK506) and to test the related agents acting against the process.


METHODS
Experiments were performed in 6 groups of isolated perfused rat kidneys (IPRK). The parameters of renal function and the concentration of endothelin in the perfusate and urine were assessed at an interval of 15 min. Four groups of IPRK were perfused with normal saline and varied concentrations of FK506 (10 nmol/L-10 micromol/L) to set up a control and a hypoperfusion model. The other 2 groups were used as hypoperfusion models to test the actions of endothelin receptor antagonist FR139317 and calcium channel blocker diltiazem.


RESULTS
Hypoperfusion model was established in IPRK by adding FK506 10 micromol/L in the perfusate, with the significant decreases of perfusate flow rate (PFR) and glomerular filtration rate (GFR), the significant increase of perfusion resistance (PR) and the concomitant increase of endothelin in perfusate and urine (P < 0.01). When FR139317 was added into the perfusate, only the depressed GFR was improved (P < 0.05) while the increased PR was not (P > 0.05). However, the addition of diltiazem reversed both the increase of PR and the decrease of GFR completely (P < 0.01).


CONCLUSIONS
Endothelin is likely to play an important role in the pathogenesis of FK506-induced acute renal hypoperfusion. Diltiazem can completely prevent the renal hypoperfusion induced by FK506 in IPRK.
Chen
J C
JC
Laboratory of Urology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China. Cjiacun@yahoo.com
Ma
P
P
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D016232:Endothelins / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D010477:Perfusion / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology; D014554:Urination
D002121:Calcium Channel Blockers; D016232:Endothelins; D007166:Immunosuppressive Agents; D004110:Diltiazem; D016559:Tacrolimus