Amine metabolism: A novel path to coronary artery vasospasm

Citation
Dj. Conklin et al., Amine metabolism: A novel path to coronary artery vasospasm, TOX APPL PH, 175(2), 2001, pp. 149-159
Citations number
48
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN journal
0041008X → ACNP
Volume
175
Issue
2
Year of publication
2001
Pages
149 - 159
Database
ISI
SICI code
0041-008X(20010901)175:2<149:AMANPT>2.0.ZU;2-J
Abstract
We hypothesized that allylamine (AA) induces subendocardial necrosis in mam mals via coronary artery (CA) vasospasm. Additionally, AA toxicity is likel y dependent on the enzyme semicarbazide-sensitive amine oxidase (SSAO), whi ch is highly expressed in the aorta of rats and humans. We tested whether A A or acrolein (1, 10, 100, and 1000 muM), a highly reactive product of AA m etabolism by SSAO, could contract CA or thoracic aorta (TA) in vitro and if the AA effects involved SSAO. AA or acrolein produced a similar pattern of responses in both CA and TA rings at 100 and 1000 muM, including (1) incre ased basal tension, (2) enhanced agonist-induced contraction (hypercontract ility or vasospasm), (3) remarkable, agonist-induced slow wave vasomotion ( vasospasm), and (4) irreversible reduction in vessel contractility after I mM exposure. Endothelium-dependent acetylcholine-induced relaxation was not altered during vasospasm in either vessel. Pretreatment with the SSAO inhi bitor semicarbazide (1 mM; 10 min) prevented or significantly reduced the m ajority, of AA's effects in both CA and TA rings and inhibited 100% of the SSAO activity present in rat TA and human CA and TA. We propose a two-step model for AA induction of CA vasospasm and resultant myocardial necrosis: ( 1) metabolism of AA to acrolein by coronary arterial SSAO activity and (2) acrolein induction of CA vasospasm independent of endothelial injury-a nove l path. (C) 2001 Academic Press.