The role of plasma semicarbazide-sensitive amine oxidase in allylamine andbeta-aminopropionitrile cardiovascular toxicity: mechanisms of myocardial protection and aortic medial injury in rats

Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (beta APN) comb ined treatment (AA + beta APN) results in myocardial protection from AA-ind uced subendocardial necrosis and a rapid and extensive aortic medial smooth muscle injury in rats. To determine the mechanisms of AA + beta APN-induce d vascular toxicity, cardiovascular parameters were monitored during a 10-d ay exposure by gavage in male Sprague-Dawley rats (180-200 g). Water intake and urine output were measured in rats treated with water, AA (100 mg kg(- 1) body weight), beta APN (1 g kg(-1) body weight), and AA + beta APN for 1 0 days in metabolic cages. Plasma and urine samples were analyzed for blood urea nitrogen, CO2, creatinine, hematocrit, electrolytes (Na+, K+, Cl-), a nd osmolality. Heart and plasma semicarbazide-sensitive amine oxidase metab olic capacity (SSAO)was also measured following 1, 3 and 10 days of treatme nt. Following 10 day exposure to control or AA + beta APN treatment, thorac ic aortic rings (similar to 3 mm) were removed, and aortic reactivity to co ntractile and relaxant agonists was tested in vitro. In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating myocytes were e xposed to various concentrations of AA and beta APN or AA metabolites and b eta APN to test for synergism in vitro. Several of the changes in in vivo c ardiovascular parameters were shared, both in direction and magnitude, betw een the AA + beta APN and the AA alone or the beta APN alone treatments. Th is suggests that these effects (e.g. increased water intake and urine flow, decreased hematocrit, decreased heart and plasma SSAO metabolic capacity) were dependent on an AA alone or a beta APN alone effect and were not AA beta APN specific effects. Significant inhibition of plasma and heart SSAO metabolic capacity occurred in the beta APN alone and the AA + beta APN tre atments, but not in the AA alone treatment. Aortic rings from AA + beta APN treated rats were contracted significantly less than anatomically-matched control rat aortic rings by 100 mM potassium chloride or by 10 mu M norepin ephrine. beta APN offered substantial protection against AA cytotoxicity in cultured vascular smooth muscle cells and beating myocytes, but did not al ter the cytotoxicity of AA metabolites (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined by the MTT viability assay. Ove rall, these data suggest that myocardial protection from AA injury that occ urs in the combined AA + beta APN treatment is likely due to inhibition of plasma SSAO. This may result in an increase in the AA dose accumulation and metabolism in the aorta leading to the severe aortic medial injury. (C) 19 99 Elsevier Science Ireland Ltd. All rights reserved.