当前位置： SCI文献检索 > TRANSPLANTATION期刊下所有文献 > Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.

Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.

Abstract：

:Cyclosporine (CsA) administration and nitric oxide (NO) blockade promote similar chronic renal hemodynamic alterations in rats. We evaluated various clinical CsA doses under conditions of NO blockade using L-NAME (N-nitro L-arginine methyl ester). Groups of Sprague-Dawley rats kept on a normal salt (+NaCl) or low-salt (-NaCl) diet were given CsA 7.5 mg/kg, 2.5 mg/kg, or vehicle (VH) for 21 days. CsA or VH treatment was preceded by one week of L-NAME and continued for three weeks. Inulin clearance, CsA blood level, and weekly blood pressure change were assessed at 28 days. Marked CsA dose dependent reductions in GFR in -NaCl animals (P < 0.01 versus VH + L-NAME) and +NaCl animals (P < 0.05 versus VH + L-NAME, +NaCl) as well as blood pressure elevations (P < 0.01 versus VH + L-NAME at 28 days) occurred in groups concurrently treated with CsA and L-NAME. In addition, Impaired renal function and morphologic lesions in rats (CsA 2.5 mg/kg) receiving L-NAME or CsA alone demonstrated CsA blood levels within the therapeutic range of human renal transplant patients. VH groups treated with L-NAME alone produced blood pressure elevations but were spared of renal functional or morphological alterations. Primary renal morphologic lesions in CsA treated animals included proximal tubule collapse and vacuolization and, less frequently, interstitial edema and vacuolization of interstitial cells. Unique to rats treated simultaneously with CsA and L-NAME were vascular abnormalities consisting of endothelial and arteriolar medial hyperplasia and occasional acute medial necrosis. In conclusion, acute CsA nephrotoxicity can be enhanced by simultaneous NO blockade, suggesting NO has a protective effect in CsA-induced nephropathy. These results can be achieved with a drug exposure profile that correlates with clinical therapy.

journal_name

Transplantation

journal_title

Transplantation

authors

Gardner MP,Houghton DC,Andoh TF,Lindsley J,Bennett WM

doi

10.1097/00007890-199605270-00017

subject

Has Abstract

pub_date

1996-05-27 00:00:00

pages

1506-12

issue

eissn

0041-1337

issn

1534-6080

journal_volume

pub_type

杂志文章

在线工具

Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.