Developmental Vasculotoxicity Associated with Inhibition of Semicarbazide-Sensitive Amine Oxidase

• Published in: Toxicology and applied pharmacology Vol. 155; no. 3; pp. 237 - 244
• Main Authors: Langford, S.D., Trent, M.B., Balakumaran, A., Boor, P.J.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.03.1999; Elsevier
• Subjects: Allyl Compounds - toxicity; Allylamine - analogs & derivatives; Allylamine - toxicity; Amine Oxidase (Copper-Containing) - antagonists & inhibitors; Animals; aorta; Aorta, Thoracic - drug effects; Aorta, Thoracic - enzymology; Aorta, Thoracic - growth & development; Aorta, Thoracic - pathology; Biological and medical sciences; Blood Vessels - drug effects; Blood Vessels - enzymology; Blood Vessels - growth & development; Blood Vessels - pathology; Chemical and industrial products toxicology. Toxic occupational diseases; collagen; Collagen - metabolism; developmental toxicity; elastin; Elastin - metabolism; Enzyme Inhibitors - toxicity; Lung - drug effects; Lung - enzymology; Lung - growth & development; lysyl oxidase; Male; Medical sciences; Monoamine Oxidase Inhibitors - toxicity; Propylamines - toxicity; Protein-Lysine 6-Oxidase - metabolism; Rats; Rats, Sprague-Dawley; semicarbazide-sensitive amine oxidase; Semicarbazides - toxicity; Toxicology; Various organic compounds; collagen; aorta; semicarbazide-sensitive amine oxidase; lysyl oxidase; developmental toxicity; elastin; Enzyme; Pathogenesis; Toxicity; Elastin; Enzyme inhibitor; Semicarbazides; Cardiovascular disease; Postnatal development; Amine oxidase (copper-containing); Vascular disease; Collagen; Oxidoreductases; Mechanism of action
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1998.8602

The endogenous substrate(s) and physiological function(s) of semicarbazide-sensitive amine oxidase (SSAO), a group of enzymes exhibiting highest activity in vascular smooth muscle cells of the mammalian aortic wall, remain undetermined. This study examines the pathophysiological effects in the thoracic aortic wall resulting from specificin vivoSSAO inhibition. Weanling Sprague–Dawley rats were treated acutely or chronically with either semicarbazide hydrochloride or the allylamine derivatives MDL-72274 or MDL-72145 (Marion Merrell Dow Research Institute, Cincinnati, OH). Treatment with these compounds produced acute (6 and 24 h) and chronic (21 day) lowering of SSAO activity in aorta and lung with little effect on the activity of the vital matrix-forming enzyme, lysyl oxidase, in aortas of chronically treated animals. Chronic SSAO inhibition produced lesions consisting of striking disorganization of elastin architecture within the aortic media accompanied by degenerative medial changes and metaplastic changes in vascular smooth muscle cells. No significant difference in the total weight of dry, lipid-extracted aortic elastin and collagen components were observed between chronically SSAO inhibited and control animals. However, the amount of mature elastin was lowered and mature collagen was raised in the aortas of animals treated chronically with semicarbazide. Descending thoracic aortic rings isolated from chronically SSAO-inhibited animals had larger cross-sectional diameters (i.e., exhibited dilation) when compared to corresponding rings from control animals. This study demonstrates that developmental toxicity, characterized by striking vascular lesions and dilated thoracic aortas, can result from specificin vivoSSAO inhibition, suggesting a role for SSAO in connective tissue matrix development and maintenance, and specifically in the development of normal elastin.