L Jin1, G Jagatheesan2, J Lynch3, L Guo2, D J Conklin4. 1. Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, USA; Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA; American Heart Association-Tobacco Regulation Center, University of Louisville, Louisville, KY, USA. 2. Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA; American Heart Association-Tobacco Regulation Center, University of Louisville, Louisville, KY, USA. 3. Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, USA; Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA; American Heart Association-Tobacco Regulation Center, University of Louisville, Louisville, KY, USA. 4. Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY, USA; Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA; American Heart Association-Tobacco Regulation Center, University of Louisville, Louisville, KY, USA. Electronic address: dj.conklin@louisville.edu.
Abstract
INTRODUCTION: Crotonaldehyde (CR) is an electrophilic α,β-unsaturated aldehyde present in foods and beverages and is a minor metabolite of 1,3-butadiene. CR is a product of incomplete combustion, and is at high levels in smoke of cigarettes and structural fires. Exposure to CR has been linked to cardiopulmonary toxicity and cardiovascular disease. OBJECTIVE: The purpose of this study was to examine the direct effects of CR in murine blood vessels (aorta and superior mesenteric artery, SMA) using an in vitro system. METHODS AND RESULTS: CR induced concentration-dependent (1-300 μM) relaxations (75-80%) in phenylephrine (PE) precontracted aorta and SMA. Because the SMA was 20× more sensitive to CR than aorta (SMA EC50 3.8 ± 0.5 μM; aorta EC50 76.0 ± 2.0 μM), mechanisms of CR relaxation were studied in SMA. The CR-induced relaxation at low concentrations (1-30 μM) was inhibited by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); 4) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); and, 5) by non-vasoactive level of nicotine (1 μM). Similarly, a TRPA1 agonist, allyl isothiocyanate (AITC; mustard oil), stimulated SMA relaxation dependent on TRPA1, endothelium, NO, and GC. Consistent with these mechanisms, TRPA1 was present in the SMA endothelium. CR, at higher concentrations (100-300 μM), induced tension oscillations (spasms) and irreversibly impaired contractility (a vasotoxic effect enhanced by impaired endothelium). CONCLUSIONS: CR relaxation depends on a functional endothelium and TRPA1, whereas vasotoxicity is enhanced by endothelium dysfunction. Thus, CR is both vasoactive and vasotoxic along a concentration continuum.
INTRODUCTION:Crotonaldehyde (CR) is an electrophilic α,β-unsaturated aldehyde present in foods and beverages and is a minor metabolite of 1,3-butadiene. CR is a product of incomplete combustion, and is at high levels in smoke of cigarettes and structural fires. Exposure to CR has been linked to cardiopulmonary toxicity and cardiovascular disease. OBJECTIVE: The purpose of this study was to examine the direct effects of CR in murine blood vessels (aorta and superior mesenteric artery, SMA) using an in vitro system. METHODS AND RESULTS:CR induced concentration-dependent (1-300 μM) relaxations (75-80%) in phenylephrine (PE) precontracted aorta and SMA. Because the SMA was 20× more sensitive to CR than aorta (SMA EC50 3.8 ± 0.5 μM; aorta EC50 76.0 ± 2.0 μM), mechanisms of CR relaxation were studied in SMA. The CR-induced relaxation at low concentrations (1-30 μM) was inhibited by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); 4) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); and, 5) by non-vasoactive level of nicotine (1 μM). Similarly, a TRPA1 agonist, allyl isothiocyanate (AITC; mustard oil), stimulated SMA relaxation dependent on TRPA1, endothelium, NO, and GC. Consistent with these mechanisms, TRPA1 was present in the SMA endothelium. CR, at higher concentrations (100-300 μM), induced tension oscillations (spasms) and irreversibly impaired contractility (a vasotoxic effect enhanced by impaired endothelium). CONCLUSIONS:CR relaxation depends on a functional endothelium and TRPA1, whereas vasotoxicity is enhanced by endothelium dysfunction. Thus, CR is both vasoactive and vasotoxic along a concentration continuum.
Authors: Daniel J Conklin; Petra Haberzettl; Ganapathy Jagatheesan; Shahid Baba; Michael L Merchant; Russell A Prough; Jessica D Williams; Sumanth D Prabhu; Aruni Bhatnagar Journal: Toxicol Appl Pharmacol Date: 2015-04-10 Impact factor: 4.219
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