Effect of tacrolimus and cyclosporine on renal microcirculation and nitric oxide production.
OBJECTIVE
Cyclosporine (CSA) and tacrolimus (TAC) frequently induce nephrotoxicity and similar pathologic changes. Acute CSA-induced nephrotoxicity has been reported to be mediated by activation of vasoconstrictors such as endothelin. The purpose of the present study was to investigate the acute effects of TAC and CSA on the renal microcirculation and upon a vasodilator such as nitric oxide (NO) production.


METHODS
Renal blood flow (RBF) in the microcirculation was measured by a Laser Doppler flow meter in uninephrectomised rats. RBF, mean arterial pressure (MAP), and renal vascular resistance (RVR) were measured in the following groups: (a) TAC (0.1 to 2.0 mg/kg/h, n = 3 approximately 6); CSA (20 and 50 mg/kg/h, n = 5); (b) L-NAME (10 mg/kg), an NO synthase inhibitor, 8 minutes prior to TAC (0.5 and 1.5 mg/kg/h, n = 5), or CSA (20 and 50 mg/kg/h, n = 5). Stable NO end-products, serum NO(2) and NO(3), were measured by the Griess method (n = 5).


RESULTS
None of the parameters were changed by TAC alone, whereas TAC with L-NAME significantly reduced RBF (-28 +/- 7%) and increased RVR (46 +/- 17%) in a dose-dependent manner. CSA alone significantly reduced RBF (-37 +/- 6%) and increased RVR (69 +/- 22%) without any changes in MAP. The effects of CSA were enhanced by L-NAME. Serum concentration of NO(2) + NO(3) was significantly reduced by both L-NAME alone and CSA (50 mg/kg) (P < .05), while there were no changes with TAC (1.5 mg/kg).


CONCLUSIONS
Blockade of NO production enhance the vasoconstrictive effect of CSA, and unmasked such an effect of TAC. These results suggest that the nephrotoxicity of CSA and TAC may involve the NO system.
Watarai
Y
Y
Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. watarai@med.hokudai.ac.jp
Morita
K
K
Shimoda
N
N
Miura
M
M
Yoshioka
M
M
Togashi
H
H
Nonomura
K
K
Koyanagi
T
T
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D023421:Models, Animal; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D016559:Tacrolimus / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D016572:Cyclosporine; D016559:Tacrolimus