Renoprotective effects of the 21-aminosteroid U74389G in ischemia- reperfusion injury and cold storage preservation

Paul J. Garvin, Michael L. Niehoff, Sandra M. Robinson, Bhargav Mistry, Robert M Esterl, Tracy Heisler, Connie Combs, Andrew Berson, Harvey Solomon, Luis Salinas-Madrigal

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A- nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C- U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01±1.1 mg% vs. 3.32±0.96 mg%; ischemic control creatinine clearance = 0.069±0.03 ml/min vs. 0.206±0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5±10.0 vs. ischemic controls = 296.8±81.4; P=0.02). In Model 3 graft survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59±0.63 vs. Group C = 12.8±1.01; Group A BUN = 64.1±2.73 vs. Group C = 104.9±12.21)-however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15±0.3 vs. Group C = 2.10±0.06; Group A BUN = 27.0±6.0 vs. Group C = 31.1±6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.

Original languageEnglish (US)
Pages (from-to)194-201
Number of pages8
JournalTransplantation
Volume63
Issue number2
DOIs
StatePublished - Jan 27 1997
Externally publishedYes

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Reperfusion Injury
Creatinine
Warm Ischemia
Lipid Peroxidation
Reperfusion
Blood Urea Nitrogen
Autologous Transplantation
Nephrectomy
Ischemia
Graft Survival
Membrane Lipids
Free Radicals
Sprague Dawley Rats
Swine
Transplantation
Kidney
Weights and Measures
Serum
thiobarbituric acid

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Renoprotective effects of the 21-aminosteroid U74389G in ischemia- reperfusion injury and cold storage preservation. / Garvin, Paul J.; Niehoff, Michael L.; Robinson, Sandra M.; Mistry, Bhargav; Esterl, Robert M; Heisler, Tracy; Combs, Connie; Berson, Andrew; Solomon, Harvey; Salinas-Madrigal, Luis.

In: Transplantation, Vol. 63, No. 2, 27.01.1997, p. 194-201.

Research output: Contribution to journalArticle

Garvin, PJ, Niehoff, ML, Robinson, SM, Mistry, B, Esterl, RM, Heisler, T, Combs, C, Berson, A, Solomon, H & Salinas-Madrigal, L 1997, 'Renoprotective effects of the 21-aminosteroid U74389G in ischemia- reperfusion injury and cold storage preservation', Transplantation, vol. 63, no. 2, pp. 194-201. https://doi.org/10.1097/00007890-199701270-00004
Garvin, Paul J. ; Niehoff, Michael L. ; Robinson, Sandra M. ; Mistry, Bhargav ; Esterl, Robert M ; Heisler, Tracy ; Combs, Connie ; Berson, Andrew ; Solomon, Harvey ; Salinas-Madrigal, Luis. / Renoprotective effects of the 21-aminosteroid U74389G in ischemia- reperfusion injury and cold storage preservation. In: Transplantation. 1997 ; Vol. 63, No. 2. pp. 194-201.
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abstract = "Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A- nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C- U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01±1.1 mg{\%} vs. 3.32±0.96 mg{\%}; ischemic control creatinine clearance = 0.069±0.03 ml/min vs. 0.206±0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5±10.0 vs. ischemic controls = 296.8±81.4; P=0.02). In Model 3 graft survivals were 100{\%}, 0{\%}, and 60{\%} respectively. Peak Cr and BUN (mg{\%}) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59±0.63 vs. Group C = 12.8±1.01; Group A BUN = 64.1±2.73 vs. Group C = 104.9±12.21)-however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15±0.3 vs. Group C = 2.10±0.06; Group A BUN = 27.0±6.0 vs. Group C = 31.1±6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.",
author = "Garvin, {Paul J.} and Niehoff, {Michael L.} and Robinson, {Sandra M.} and Bhargav Mistry and Esterl, {Robert M} and Tracy Heisler and Connie Combs and Andrew Berson and Harvey Solomon and Luis Salinas-Madrigal",
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T1 - Renoprotective effects of the 21-aminosteroid U74389G in ischemia- reperfusion injury and cold storage preservation

AU - Garvin, Paul J.

AU - Niehoff, Michael L.

AU - Robinson, Sandra M.

AU - Mistry, Bhargav

AU - Esterl, Robert M

AU - Heisler, Tracy

AU - Combs, Connie

AU - Berson, Andrew

AU - Solomon, Harvey

AU - Salinas-Madrigal, Luis

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N2 - Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A- nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C- U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01±1.1 mg% vs. 3.32±0.96 mg%; ischemic control creatinine clearance = 0.069±0.03 ml/min vs. 0.206±0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5±10.0 vs. ischemic controls = 296.8±81.4; P=0.02). In Model 3 graft survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59±0.63 vs. Group C = 12.8±1.01; Group A BUN = 64.1±2.73 vs. Group C = 104.9±12.21)-however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15±0.3 vs. Group C = 2.10±0.06; Group A BUN = 27.0±6.0 vs. Group C = 31.1±6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.

AB - Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A- nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C- U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01±1.1 mg% vs. 3.32±0.96 mg%; ischemic control creatinine clearance = 0.069±0.03 ml/min vs. 0.206±0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5±10.0 vs. ischemic controls = 296.8±81.4; P=0.02). In Model 3 graft survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59±0.63 vs. Group C = 12.8±1.01; Group A BUN = 64.1±2.73 vs. Group C = 104.9±12.21)-however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15±0.3 vs. Group C = 2.10±0.06; Group A BUN = 27.0±6.0 vs. Group C = 31.1±6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.

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