Allylamine and β-aminopropionitrile induced aortic medial necrosis: Mechanisms of synergism

D. Kumar, M. B. Trent, P. J. Boor

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We have developed a model of aortic smooth muscle necrosis in adult Sprague Dawley rats by feeding them two vascular toxins (allylamine HCl, or AA, and β-aminopropionitrile, or βAPN) in concert for 10 days. Either toxin given alone does not cause aortic lesions. In order to shed light on the mechanism of the synergistic action of these two toxins we fed known modulators of AA or βAPN toxicity to rats concurrently with the two toxins. As modulators we used (a) semicarbazide (98 mg/kg/day, given 4 h prior to toxins), a known inhibitor of the vascular enzyme SSAO which metabolizes AA' (b) L-cysteine (1.5% in rat chow, beginning 3 days prior to toxins), which has been shown to reduce the toxic effects of βAPN; and (c) phenelzine sulphate (3 mg/kg/day, given 4 h prior to toxins), an inhibitor of SSAO and potentiator of βAPN toxicity. Rats were fed various combinations of the toxins and modulators by gavage: water (n = 8); (AA, 100 mg/kg/day) AA + phenelzine (n = 8); AA + semicarbazide (n = 8); AA + L-cysteine (n = 11); (βAPN, 1 g/kg/day) βAPN + phenelzine (n = 8); βAPN + semicarbazide (n = 8); βAPN + L-cysteine (n = 8); (AA, 100 mg + βAPN, 1 g/kg/day) AA + βAPN + phenelzine (n = 9), AA + βAPN + semicarbazide (n= 8); AA + βAPN+ L-cysteine (n = 12); phenelzine (3 mg/kg/day) (n = 4); semicarbazide (98 mg/kg/day) (n = 4) and L-cysteine (1.5% in rat chow) (n = 4). We found that phenelzine sulphate (a drug previously used in the treatment of hypertension) when given with AA reproduced the AA + βAPN induced aortic lesions. Phenelzine + βAPN caused no lesions, but when combined with AA + βAPN, aortic lesions were intensified and included marked secondary degeneration of the vascular wall. Semicarbazide was found to completely obviate the vascular toxicity of AA + βAPN. L-Cysteine feeding markedly decreased the incidence and severity of vascular lesions in AA + βAPN treated rats, but did not change the incidence or severity of heart lesions caused by AA alone. These data indicate that the synergistic necrotizing toxicity of AA + βAPN is primarily an AA effect. We postulate that some modulating influence of βAPN (or phenelzine) on tissue distribution, metabolism, or detoxification pathways of AA increases AA's acute vascular toxicity, whereas semicarbazide offers protection by inhibiting the initial deamination of AA to a highly reactive aldehyde.

Original languageEnglish (US)
Pages (from-to)107-115
Number of pages9
JournalToxicology
Volume125
Issue number2-3
DOIs
StatePublished - Feb 6 1998

Fingerprint

Aminopropionitrile
Allylamine
Phenelzine
Necrosis
Cysteine
Blood Vessels
Rats
Toxicity
Modulators
Detoxification
Deamination
Poisons
Incidence
Enzyme Inhibitors
Tissue Distribution
carbamylhydrazine
Metabolism
Aldehydes
Smooth Muscle
Sprague Dawley Rats

Keywords

  • β-Aminopropionitrile
  • Allylamine
  • Aortic smooth muscle
  • L- Cysteine
  • Phenelzine
  • Semicarbazide
  • Vascular media

ASJC Scopus subject areas

  • Toxicology

Cite this

Allylamine and β-aminopropionitrile induced aortic medial necrosis : Mechanisms of synergism. / Kumar, D.; Trent, M. B.; Boor, P. J.

In: Toxicology, Vol. 125, No. 2-3, 06.02.1998, p. 107-115.

Research output: Contribution to journalArticle

Kumar, D. ; Trent, M. B. ; Boor, P. J. / Allylamine and β-aminopropionitrile induced aortic medial necrosis : Mechanisms of synergism. In: Toxicology. 1998 ; Vol. 125, No. 2-3. pp. 107-115.
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T1 - Allylamine and β-aminopropionitrile induced aortic medial necrosis

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AU - Trent, M. B.

AU - Boor, P. J.

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N2 - We have developed a model of aortic smooth muscle necrosis in adult Sprague Dawley rats by feeding them two vascular toxins (allylamine HCl, or AA, and β-aminopropionitrile, or βAPN) in concert for 10 days. Either toxin given alone does not cause aortic lesions. In order to shed light on the mechanism of the synergistic action of these two toxins we fed known modulators of AA or βAPN toxicity to rats concurrently with the two toxins. As modulators we used (a) semicarbazide (98 mg/kg/day, given 4 h prior to toxins), a known inhibitor of the vascular enzyme SSAO which metabolizes AA' (b) L-cysteine (1.5% in rat chow, beginning 3 days prior to toxins), which has been shown to reduce the toxic effects of βAPN; and (c) phenelzine sulphate (3 mg/kg/day, given 4 h prior to toxins), an inhibitor of SSAO and potentiator of βAPN toxicity. Rats were fed various combinations of the toxins and modulators by gavage: water (n = 8); (AA, 100 mg/kg/day) AA + phenelzine (n = 8); AA + semicarbazide (n = 8); AA + L-cysteine (n = 11); (βAPN, 1 g/kg/day) βAPN + phenelzine (n = 8); βAPN + semicarbazide (n = 8); βAPN + L-cysteine (n = 8); (AA, 100 mg + βAPN, 1 g/kg/day) AA + βAPN + phenelzine (n = 9), AA + βAPN + semicarbazide (n= 8); AA + βAPN+ L-cysteine (n = 12); phenelzine (3 mg/kg/day) (n = 4); semicarbazide (98 mg/kg/day) (n = 4) and L-cysteine (1.5% in rat chow) (n = 4). We found that phenelzine sulphate (a drug previously used in the treatment of hypertension) when given with AA reproduced the AA + βAPN induced aortic lesions. Phenelzine + βAPN caused no lesions, but when combined with AA + βAPN, aortic lesions were intensified and included marked secondary degeneration of the vascular wall. Semicarbazide was found to completely obviate the vascular toxicity of AA + βAPN. L-Cysteine feeding markedly decreased the incidence and severity of vascular lesions in AA + βAPN treated rats, but did not change the incidence or severity of heart lesions caused by AA alone. These data indicate that the synergistic necrotizing toxicity of AA + βAPN is primarily an AA effect. We postulate that some modulating influence of βAPN (or phenelzine) on tissue distribution, metabolism, or detoxification pathways of AA increases AA's acute vascular toxicity, whereas semicarbazide offers protection by inhibiting the initial deamination of AA to a highly reactive aldehyde.

AB - We have developed a model of aortic smooth muscle necrosis in adult Sprague Dawley rats by feeding them two vascular toxins (allylamine HCl, or AA, and β-aminopropionitrile, or βAPN) in concert for 10 days. Either toxin given alone does not cause aortic lesions. In order to shed light on the mechanism of the synergistic action of these two toxins we fed known modulators of AA or βAPN toxicity to rats concurrently with the two toxins. As modulators we used (a) semicarbazide (98 mg/kg/day, given 4 h prior to toxins), a known inhibitor of the vascular enzyme SSAO which metabolizes AA' (b) L-cysteine (1.5% in rat chow, beginning 3 days prior to toxins), which has been shown to reduce the toxic effects of βAPN; and (c) phenelzine sulphate (3 mg/kg/day, given 4 h prior to toxins), an inhibitor of SSAO and potentiator of βAPN toxicity. Rats were fed various combinations of the toxins and modulators by gavage: water (n = 8); (AA, 100 mg/kg/day) AA + phenelzine (n = 8); AA + semicarbazide (n = 8); AA + L-cysteine (n = 11); (βAPN, 1 g/kg/day) βAPN + phenelzine (n = 8); βAPN + semicarbazide (n = 8); βAPN + L-cysteine (n = 8); (AA, 100 mg + βAPN, 1 g/kg/day) AA + βAPN + phenelzine (n = 9), AA + βAPN + semicarbazide (n= 8); AA + βAPN+ L-cysteine (n = 12); phenelzine (3 mg/kg/day) (n = 4); semicarbazide (98 mg/kg/day) (n = 4) and L-cysteine (1.5% in rat chow) (n = 4). We found that phenelzine sulphate (a drug previously used in the treatment of hypertension) when given with AA reproduced the AA + βAPN induced aortic lesions. Phenelzine + βAPN caused no lesions, but when combined with AA + βAPN, aortic lesions were intensified and included marked secondary degeneration of the vascular wall. Semicarbazide was found to completely obviate the vascular toxicity of AA + βAPN. L-Cysteine feeding markedly decreased the incidence and severity of vascular lesions in AA + βAPN treated rats, but did not change the incidence or severity of heart lesions caused by AA alone. These data indicate that the synergistic necrotizing toxicity of AA + βAPN is primarily an AA effect. We postulate that some modulating influence of βAPN (or phenelzine) on tissue distribution, metabolism, or detoxification pathways of AA increases AA's acute vascular toxicity, whereas semicarbazide offers protection by inhibiting the initial deamination of AA to a highly reactive aldehyde.

KW - β-Aminopropionitrile

KW - Allylamine

KW - Aortic smooth muscle

KW - L- Cysteine

KW - Phenelzine

KW - Semicarbazide

KW - Vascular media

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