Mechanism of FK506-induced renal hypoperfusion and its reversion in rats

A,IM: To investigate the mechanism of renal hypoperfusion induced by tacrol imus ( FK506) and to test the related agents acting against the process. ME THODS: Experiments were performed in 6 groups of isolated perfused rat kidn eys (IPRK). The parameters of renal function and the concentration of endot helin in the perfusate and urine were assessed at an interval of 15 min. Fo ur groups of IPRK were perfused with normal saline and varied concentration s of FK506 (10 nmol/L-10 mu mol/L) to set up a control and a hypoperfusion model. The other 2 groups were used as hypoperfusion models to test the act ions of endothelin receptor antagonist FR139317 and calcium channel blocker diltiazem. RESULTS: Hypoperfusion model was established in IPRK by adding FK506 10 mu mol/L in the perfusate, with the significant decreases of perfu sate flow rate (PFR) and glomerular filtration rate (GFR), the significant increase of perfusion resistance (PR) and the concomitant increase of endot helin 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 increa sed PR was not ( P > 0.05). However, the addition of diltiazem reversed bot h the increase of PR and the decrease of GFR completely ( P < 0.01). CONCLU SION: 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.