title: Acrolein generation stimulates hypercontraction in isolated human blood vessels.
abstract: Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202, USA. dj.conklin@louisville.edu
authors.forename: D J
authors.initials: DJ
authors.lastname: Conklin
authors.forename: A
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: H R
authors.initials: HR
authors.lastname: Cowley
authors.forename: G H
authors.initials: GH
authors.lastname: Johnson
authors.forename: R J
authors.initials: RJ
authors.lastname: Wiechmann
authors.forename: L M
authors.initials: LM
authors.lastname: Sayre
authors.forename: M B
authors.initials: MB
authors.lastname: Trent
authors.forename: P J
authors.initials: PJ
authors.lastname: Boor
mesh_terms: D000171:Acrolein / Q000378:metabolism / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000498:Allyl Compounds / Q000494:pharmacology; D000499:Allylamine / Q000494:pharmacology*; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012663:Semicarbazides / Q000494:pharmacology
chemical_list: D000498:Allyl Compounds; C090015:MDL 72274A; D011437:Propylamines; D012663:Semicarbazides; C010059:carbamylhydrazine; D000499:Allylamine; D000171:Acrolein; D006631:Amine Oxidase (Copper-Containing)