Allylamine and beta-aminopropionitrile induced aortic medial necrosis: mechanisms of synergism.

摘要

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 beta-aminopropionitrile, or betaAPN) 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 betaAPN 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 betaAPN; and (c) phenelzine sulphate (3 mg/kg/day, given 4 h prior to toxins), an inhibitor of SSAO and potentiator of betaAPN 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); (betaAPN, 1 g/kg/day) betaAPN + phenelzine (n = 8); betaAPN + semicarbazide (n = 8); betaAPN + L-cysteine (n = 8); (AA, 100 mg + betaAPN, 1 g/kg/day) AA + betaAPN + phenelzine (n = 9), AA + betaAPN + semicarbazide (n = 8); AA + betaAPN + 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 + betaAPN induced aortic lesions. Phenelzine + betaAPN caused no lesions, but when combined with AA + betaAPN, aortic lesions were intensified and included marked secondary degeneration of the vascular wall. Semicarbazide was found to completely obviate the vascular toxicity of AA + betaAPN. L-Cysteine feeding markedly decreased the incidence and severity of vascular lesions in AA + betaAPN 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 + betaAPN is primarily an AA effect. We postulate that some modulating influence of betaAPN (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.