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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{sub 2}O{sub 2} exposure (1 {mu}M-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 {mu}M), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca{sup 2+} to hypercontraction. Acrolein or allylamine but not H{sub 2}O{sub 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 MDLmore » 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca{sup 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.« less

Authors:
 [1];  [2];  [3];  [4];  [4];  [5];  [6];  [6]
  1. Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202 (United States) and Department of Biology, University of Wisconsin-Eau Claire, Eau Claire, WI 54701 (United States). E-mail: dj.conklin@louisville.edu
  2. Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202 (United States)
  3. Department of Biology, University of Wisconsin-Eau Claire, Eau Claire, WI 54701 (United States)
  4. Department of Cardiothoracic Surgery, Luther Hospital/Midelfort Clinic, Eau Claire, WI 54702 (United States)
  5. Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106 (United States)
  6. Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555-0609 (United States)
Publication Date:
OSTI Identifier:
20850502
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.009; PII: S0041-008X(06)00322-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACROLEIN; AORTA; ARTERIOSCLEROSIS; BIOLOGICAL STRESS; CALCIUM IONS; CORONARIES; GRAFTS; HYDROGEN PEROXIDE; HYPERTENSION; INFLAMMATION; ISOMERS; LIPIDS; METHYLAMINE; NORADRENALINE; OXIDASES; RATS; SENSITIVITY; SUBSTRATES; VEINS

Citation Formats

Conklin, D.J., Bhatnagar, A., Cowley, H.R., Johnson, G.H., Wiechmann, R.J., Sayre, L.M., Trent, M.B., and Boor, P.J. Acrolein generation stimulates hypercontraction in isolated human blood vessels. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.009.
Conklin, D.J., Bhatnagar, A., Cowley, H.R., Johnson, G.H., Wiechmann, R.J., Sayre, L.M., Trent, M.B., & Boor, P.J. Acrolein generation stimulates hypercontraction in isolated human blood vessels. United States. doi:10.1016/j.taap.2006.09.009.
Conklin, D.J., Bhatnagar, A., Cowley, H.R., Johnson, G.H., Wiechmann, R.J., Sayre, L.M., Trent, M.B., and Boor, P.J. Fri . "Acrolein generation stimulates hypercontraction in isolated human blood vessels". United States. doi:10.1016/j.taap.2006.09.009.
@article{osti_20850502,
title = {Acrolein generation stimulates hypercontraction in isolated human blood vessels},
author = {Conklin, D.J. and Bhatnagar, A. and Cowley, H.R. and Johnson, G.H. and Wiechmann, R.J. and Sayre, L.M. and Trent, M.B. and Boor, P.J.},
abstractNote = {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{sub 2}O{sub 2} exposure (1 {mu}M-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 {mu}M), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca{sup 2+} to hypercontraction. Acrolein or allylamine but not H{sub 2}O{sub 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{sup 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.},
doi = {10.1016/j.taap.2006.09.009},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}
  • The repair mode of DNA replication has been demonstrated in isolated nuclei from uv-irradiated human cells. Nuclei are incubated in a mixture containing (/sup 3/H)thymidine triphosphate and bromodeoxyuridine triphosphate in a 1:5 ratio. The /sup 3/H at the density of parental DNA in alkaline CsCl density gradients is then a measure of repair. In nuclei prepared from WI38 cells 30 min after irradiation, repair replication is uv-dependent and proceeds at approximately the in vivo rate for 5 min. Repair replication is reduced in irradiated nuclei or in nuclei prepared immediately after irradiation. It is Mg/sup 2 +/-dependent and stimulated bymore » added ATP and deoxyribonucleoside triphosphates. No repair replication is observed in nuclei from xeroderma pigmentosum (complementation group A) cells. However, upon addition of coliphage T4 endonuclease V, which specifically nicks DNA containing pyrimidine dimers, repair replication is observed in nuclei from irradiated xeroderma pigmentosum cells and is stimulated in WI38 nuclei. The reaction then persists for an hour and is dependent upon added ATP and deoxyribonucleoside triphosphates. The repair label is in stretches of roughly 35 nucleotides, as it is in intact cells. Added pancreatic DNase does not promote uv-dependent repair synthesis. Our results support the view that xeroderma pigmentosum (group A) cells are defective in the incision step of the DNA excision repair pathway, and demonstrate the utility of this system for probing DNA repair mechanisms.« less
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