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

被引:29
作者
Gardner, MP
Houghton, DC
Andoh, TF
Lindsley, J
Bennett, WM
机构
[1] OREGON HLTH SCI UNIV, DEPT MED, DIV NEPHROL HYPERTENS & CLIN PHARMACOL, PORTLAND, OR 97201 USA
[2] OREGON HLTH SCI UNIV, DEPT PATHOL, PORTLAND, OR 97201 USA
关键词
D O I
10.1097/00007890-199605270-00017
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 meek 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.
引用
收藏
页码:1506 / 1512
页数:7
相关论文
共 54 条
[1]   SUPPRESSION OF PLASMA-RENIN ACTIVITY BY CYCLOSPORINE [J].
BANTLE, JP ;
BOUDREAU, RJ ;
FERRIS, TF .
AMERICAN JOURNAL OF MEDICINE, 1987, 83 (01) :59-64
[2]  
BAXTER CR, 1982, RES COMMUN CHEM PATH, V37, P305
[3]   CHRONIC BLOCKADE OF NITRIC-OXIDE SYNTHESIS IN THE RAT PRODUCES SYSTEMIC HYPERTENSION AND GLOMERULAR DAMAGE [J].
BAYLIS, C ;
MITRUKA, B ;
DENG, A .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (01) :278-281
[4]   APPARENT HYDROXYL RADICAL PRODUCTION BY PEROXYNITRITE - IMPLICATIONS FOR ENDOTHELIAL INJURY FROM NITRIC-OXIDE AND SUPEROXIDE [J].
BECKMAN, JS ;
BECKMAN, TW ;
CHEN, J ;
MARSHALL, PA ;
FREEMAN, BA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (04) :1620-1624
[5]   ISCHEMIC-INJURY MEDIATOR [J].
BECKMAN, JS .
NATURE, 1990, 345 (6270) :27-28
[6]   SYSTEMIC HYPERTENSION AFTER CARDIAC TRANSPLANTATION - EFFECT OF CYCLOSPORINE ON THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM [J].
BELLET, M ;
CABROL, C ;
SASSANO, P ;
LEGER, P ;
CORVOL, P ;
MENARD, J .
AMERICAN JOURNAL OF CARDIOLOGY, 1985, 56 (15) :927-931
[7]  
BENNETT WM, 1986, ANNU REV MED, V37, P215
[8]   ROLE OF NITRIC-OXIDE IN RENAL HEMODYNAMIC ABNORMALITIES OF CYCLOSPORINE NEPHROTOXICITY [J].
BOBADILLA, NA ;
TAPIA, E ;
FRANCO, M ;
LOPEZ, P ;
MENDOZA, S ;
GARCIATORRES, R ;
ALVARADO, JA ;
HERRERAACOSTA, J .
KIDNEY INTERNATIONAL, 1994, 46 (03) :773-779
[9]  
BURDMANN EA, IN PRESS AM J PHYSL
[10]  
CHAN BBK, 1992, CIRCULATION, V86, P295