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

Michael P. Gardner, Donald Houghton, Takeshi F. Andoh, Jessie Lindsley, William M. Bennett

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1506-1512
Number of pages7
JournalTransplantation
Volume61
Issue number10
DOIs
StatePublished - May 27 1996

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NG-Nitroarginine Methyl Ester
Cyclosporine
Nitric Oxide
Kidney
Blood Pressure
Sodium-Restricted Diet
Inulin
Hyperplasia
Blood Vessels
Sprague Dawley Rats
Edema
Necrosis
Therapeutics
Salts
Hemodynamics
Transplants

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition. / Gardner, Michael P.; Houghton, Donald; Andoh, Takeshi F.; Lindsley, Jessie; Bennett, William M.

In: Transplantation, Vol. 61, No. 10, 27.05.1996, p. 1506-1512.

Research output: Contribution to journalArticle

Gardner, Michael P. ; Houghton, Donald ; Andoh, Takeshi F. ; Lindsley, Jessie ; Bennett, William M. / Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition. In: Transplantation. 1996 ; Vol. 61, No. 10. pp. 1506-1512.
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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.",
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