Developmental vasculotoxicity associated with inhibition of semicarbazide-sensitive amine oxidase

The endogenous substrate(s) and physiological function(s) of semicarbazide- sensitive amine oxidase (SSAO), a group of enzymes exhibiting highest activ ity in vascular smooth muscle cells of the mammalian aortic wall, remain un determined. This study examines the pathophysiological effects in the thora cic aortic wall resulting from specific in vivo SSAO inhibition. Weanling S prague-Dawley rats were treated acutely or chronically with either semicarb azide hydrochloride or the allylamine derivatives MDL-72274 or MDL-72145 (M arion Merrell Dow Research Institute, Cincinnati, OH). Treatment with these compounds produced acute (6 and 24 h) and chronic (21 day) lowering of SSA O activity in aorta and lung with little effect on the activity of the vita l matrix-forming enzyme, lysyl oxidase, in aortas of chronically treated an imals. Chronic SSAO inhibition produced lesions consisting of striking diso rganization of elastin architecture within the aortic media accompanied by degenerative medial changes and metaplastic changes in vascular smooth musc le cells. No significant difference in the total weight of dry, lipid-extra cted aortic elastin and collagen components were observed between chronical ly SSAO inhibited and control animals. However, the amount of mature elasti n was lowered and mature collagen was raised in the aortas of animals treat ed chronically with semicarbazide. Descending thoracic aortic rings isolate d from chronically SSAO-inhibited animals had larger cross-sectional diamet ers (i.e,, exhibited dilation) when compared to corresponding rings from co ntrol animals. This study demonstrates that developmental toxicity, charact erized by striking vascular lesions and dilated thoracic aortas, can result from specific in vivo SSAO inhibition, suggesting a role for SSAO in conne ctive tissue matrix development and maintenance, and specifically in the de velopment of normal elastin. (C) 1999 Academic Press.