Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock

C. C. Wu, S. J. Chen, Csaba Szabo, C. Thiemermann, J. R. Vane

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 ± 4 mmHg (time 0, control) to 79 ± 9 mmHg at 180 min (P < 0.05, n = 10). The presser effect of noradrenaline (NA, 1 μg kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 ± 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the presser response to NA; indeed, at 180 min, the presser response returned to normal in aminoguanidine pretreated LPS-rats. 3. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractile responses elicited by NA (10-9-10-6 M). Pretreatment with aminoguanidine (15 mg kg-1, i.v., at 20 min prior to LPS) significantly prevented this LPS-induced hyporeactivity to NA ex vivo. 4. Endotoxaemia for 180 min resulted in a significant increase in iNOS activity in the lung from 0.6 ± 0.2 pmol mg-1 min-1 (control, n = 4) to 4.8 ± 0.3 pmol mg-1 min-1 (P < 0.05, n = 6). In LPS-rats treated with aminoguanidine, iNOS activity in the lung was attenuated by 44 ± 5% (n = 6, P < 0.05). Moreover, when added in vitro to lung homogenates obtained from LPS-rats, aminoguanidine and N(ω)-nitro-L-arginine methyl eater (L-NAME; 10-8 to 10-3 M) caused a concentration-dependent inhibition of iNOS activity (n = 3-6, IC50: 30 ± 12 and 11 ± 6 μM, respectively P > 0.05). In contrast, aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 ± 10 and 0.6 ± 0.1 μM, respectively, P < 0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME (maximal inhibition at 90 min and 30 min, respectively). 5. Treatment of conscious Swiss albino (T-O) mice with a high dose of endotoxin (60 mg kg-1, i.p.) resulted in a survival rate of only 8% at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75% (n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate (11%, n = 9). 6. Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine, or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock,

Original languageEnglish (US)
Pages (from-to)1666-1672
Number of pages7
JournalBritish Journal of Pharmacology
Volume114
Issue number8
StatePublished - 1995
Externally publishedYes

Fingerprint

Septic Shock
Rodentia
Shock
Protein Isoforms
Nitric Oxide Synthase
NG-Nitroarginine Methyl Ester
Arterial Pressure
Endotoxemia
Endotoxins
Vasoconstrictor Agents
Nitric Oxide Synthase Type II
pimagedine
Inhibitory Concentration 50
Blood Vessels
Lipopolysaccharides
Wistar Rats
Therapeutics
Heart Rate
Cytokines
Escherichia coli

Keywords

  • Aminoguanidine
  • Endotoxic shock
  • Nitric oxide
  • Nitric oxide synthase
  • Survival rate
  • Vascular hyporeactivity

ASJC Scopus subject areas

  • Pharmacology

Cite this

Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. / Wu, C. C.; Chen, S. J.; Szabo, Csaba; Thiemermann, C.; Vane, J. R.

In: British Journal of Pharmacology, Vol. 114, No. 8, 1995, p. 1666-1672.

Research output: Contribution to journalArticle

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abstract = "1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 ± 4 mmHg (time 0, control) to 79 ± 9 mmHg at 180 min (P < 0.05, n = 10). The presser effect of noradrenaline (NA, 1 μg kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 ± 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the presser response to NA; indeed, at 180 min, the presser response returned to normal in aminoguanidine pretreated LPS-rats. 3. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractile responses elicited by NA (10-9-10-6 M). Pretreatment with aminoguanidine (15 mg kg-1, i.v., at 20 min prior to LPS) significantly prevented this LPS-induced hyporeactivity to NA ex vivo. 4. Endotoxaemia for 180 min resulted in a significant increase in iNOS activity in the lung from 0.6 ± 0.2 pmol mg-1 min-1 (control, n = 4) to 4.8 ± 0.3 pmol mg-1 min-1 (P < 0.05, n = 6). In LPS-rats treated with aminoguanidine, iNOS activity in the lung was attenuated by 44 ± 5{\%} (n = 6, P < 0.05). Moreover, when added in vitro to lung homogenates obtained from LPS-rats, aminoguanidine and N(ω)-nitro-L-arginine methyl eater (L-NAME; 10-8 to 10-3 M) caused a concentration-dependent inhibition of iNOS activity (n = 3-6, IC50: 30 ± 12 and 11 ± 6 μM, respectively P > 0.05). In contrast, aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 ± 10 and 0.6 ± 0.1 μM, respectively, P < 0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME (maximal inhibition at 90 min and 30 min, respectively). 5. Treatment of conscious Swiss albino (T-O) mice with a high dose of endotoxin (60 mg kg-1, i.p.) resulted in a survival rate of only 8{\%} at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75{\%} (n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate (11{\%}, n = 9). 6. Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine, or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock,",
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T1 - Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock

AU - Wu, C. C.

AU - Chen, S. J.

AU - Szabo, Csaba

AU - Thiemermann, C.

AU - Vane, J. R.

PY - 1995

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N2 - 1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 ± 4 mmHg (time 0, control) to 79 ± 9 mmHg at 180 min (P < 0.05, n = 10). The presser effect of noradrenaline (NA, 1 μg kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 ± 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the presser response to NA; indeed, at 180 min, the presser response returned to normal in aminoguanidine pretreated LPS-rats. 3. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractile responses elicited by NA (10-9-10-6 M). Pretreatment with aminoguanidine (15 mg kg-1, i.v., at 20 min prior to LPS) significantly prevented this LPS-induced hyporeactivity to NA ex vivo. 4. Endotoxaemia for 180 min resulted in a significant increase in iNOS activity in the lung from 0.6 ± 0.2 pmol mg-1 min-1 (control, n = 4) to 4.8 ± 0.3 pmol mg-1 min-1 (P < 0.05, n = 6). In LPS-rats treated with aminoguanidine, iNOS activity in the lung was attenuated by 44 ± 5% (n = 6, P < 0.05). Moreover, when added in vitro to lung homogenates obtained from LPS-rats, aminoguanidine and N(ω)-nitro-L-arginine methyl eater (L-NAME; 10-8 to 10-3 M) caused a concentration-dependent inhibition of iNOS activity (n = 3-6, IC50: 30 ± 12 and 11 ± 6 μM, respectively P > 0.05). In contrast, aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 ± 10 and 0.6 ± 0.1 μM, respectively, P < 0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME (maximal inhibition at 90 min and 30 min, respectively). 5. Treatment of conscious Swiss albino (T-O) mice with a high dose of endotoxin (60 mg kg-1, i.p.) resulted in a survival rate of only 8% at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75% (n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate (11%, n = 9). 6. Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine, or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock,

AB - 1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 ± 4 mmHg (time 0, control) to 79 ± 9 mmHg at 180 min (P < 0.05, n = 10). The presser effect of noradrenaline (NA, 1 μg kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 ± 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the presser response to NA; indeed, at 180 min, the presser response returned to normal in aminoguanidine pretreated LPS-rats. 3. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractile responses elicited by NA (10-9-10-6 M). Pretreatment with aminoguanidine (15 mg kg-1, i.v., at 20 min prior to LPS) significantly prevented this LPS-induced hyporeactivity to NA ex vivo. 4. Endotoxaemia for 180 min resulted in a significant increase in iNOS activity in the lung from 0.6 ± 0.2 pmol mg-1 min-1 (control, n = 4) to 4.8 ± 0.3 pmol mg-1 min-1 (P < 0.05, n = 6). In LPS-rats treated with aminoguanidine, iNOS activity in the lung was attenuated by 44 ± 5% (n = 6, P < 0.05). Moreover, when added in vitro to lung homogenates obtained from LPS-rats, aminoguanidine and N(ω)-nitro-L-arginine methyl eater (L-NAME; 10-8 to 10-3 M) caused a concentration-dependent inhibition of iNOS activity (n = 3-6, IC50: 30 ± 12 and 11 ± 6 μM, respectively P > 0.05). In contrast, aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 ± 10 and 0.6 ± 0.1 μM, respectively, P < 0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME (maximal inhibition at 90 min and 30 min, respectively). 5. Treatment of conscious Swiss albino (T-O) mice with a high dose of endotoxin (60 mg kg-1, i.p.) resulted in a survival rate of only 8% at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75% (n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate (11%, n = 9). 6. Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine, or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock,

KW - Aminoguanidine

KW - Endotoxic shock

KW - Nitric oxide

KW - Nitric oxide synthase

KW - Survival rate

KW - Vascular hyporeactivity

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