title: The role of plasma semicarbazide-sensitive amine oxidase in allylamine and beta-aminopropionitrile cardiovascular toxicity: mechanisms of myocardial protection and aortic medial injury in rats.
abstract: Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (betaAPN) combined treatment (AA + betaAPN) results in myocardial protection from AA-induced subendocardial necrosis and a rapid and extensive aortic medial smooth muscle injury in rats. To determine the mechanisms of AA + betaAPN-induced vascular toxicity, cardiovascular parameters were monitored during a 10-day 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), betaAPN (1 g kg(-1) body weight), and AA + betaAPN for 10 days in metabolic cages. Plasma and urine samples were analyzed for blood urea nitrogen, CO2, creatinine, hematocrit, electrolytes (Na+, K+, Cl-), and osmolality. Heart and plasma semicarbazide-sensitive amine oxidase metabolic capacity (SSAO)was also measured following 1, 3 and 10 days of treatment. Following 10 day exposure to control or AA + betaAPN treatment, thoracic aortic rings (approximately 3 mm) were removed, and aortic reactivity to contractile and relaxant agonists was tested in vitro. In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating myocytes were exposed to various concentrations of AA and betaAPN or AA metabolites and betaAPN to test for synergism in vitro. Several of the changes in in vivo cardiovascular parameters were shared, both in direction and magnitude, between the AA + betaAPN and the AA alone or the betaAPN alone treatments. This 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 betaAPN alone effect and were not AA + betaAPN specific effects. Significant inhibition of plasma and heart SSAO metabolic capacity occurred in the betaAPN alone and the AA + betaAPN treatments, but not in the AA alone treatment. Aortic rings from AA + betaAPN treated rats were contracted significantly less than anatomically-matched control rat aortic rings by 100 mM potassium chloride or by 10 microM norepinephrine. BetaAPN offered substantial protection against AA cytotoxicity in cultured vascular smooth muscle cells and beating myocytes, but did not alter the cytotoxicity of AA metabolites (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined by the MTT viability assay. Overall, these data suggest that myocardial protection from AA injury that occurs in the combined AA + betaAPN 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.
authors.affiliation: Biology Department, University of Wisconsin-Eau Claire, 54702-4004, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Conklin
authors.forename: M B
authors.initials: MB
authors.lastname: Trent
authors.forename: P J
authors.initials: PJ
authors.lastname: Boor
mesh_terms: D000499:Allylamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000097:blood*; D000629:Aminopropionitrile / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004326:Drinking / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D000629:Aminopropionitrile; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing)