#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Effects of flavoring compounds used in electronic cigarette refill liquids on endothelial and vascular function


Autoři: Gerald Wölkart aff001;  Alexander Kollau aff001;  Heike Stessel aff001;  Michael Russwurm aff002;  Doris Koesling aff002;  Astrid Schrammel aff001;  Kurt Schmidt aff001;  Bernd Mayer aff001
Působiště autorů: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Karl-Franzens-Universität Graz, Graz, Austria aff001;  Department of Pharmacology and Toxicology, Ruhr-Universität Bochum, Bochum, Germany aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222152

Souhrn

Electronic cigarette refill liquids are commercially provided with a wide variety of flavoring agents. A recent study suggested that several common flavors may scavenge nitric oxide (NO) and cause endothelial dysfunction. It was the aim of the present study to investigate the effects of these flavors on NO/cyclic GMP-mediated signaling and vascular relaxation. We tested the flavoring agents for effects on Ca2+-induced cGMP accumulation and NO synthase activation in cultured endothelial cells. NO scavenging was studied with NO-activated soluble guanylate cyclase and as NO release from a NO donor, measured with a NO electrode. Blood vessel function was studied with precontracted rat aortic rings in the absence and presence of acetylcholine or a NO donor. Cinnamaldehyde inhibited Ca2+-stimulated endothelial cGMP accumulation and NO synthase activation at ≥0.3 mM. Cinnamaldehyde and diacetyl inhibited NO-activated soluble guanylate cyclase with IC50 values of 0.56 (0.54–0.58) and 0.29 (0.24–0.36) mM, respectively, and caused moderate NO scavenging at 1 mM that was not mediated by superoxide anions. The other compounds did not scavenge NO at 1 mM. None of the flavorings interfered with acetylcholine-induced vascular relaxation, but they caused relaxation of pre-contracted aortas. The most potent compounds were eugenol and cinnamaldehyde with EC50 values of ~0.5 mM. Since the flavors did not affect endothelium-dependent vascular relaxation, NO scavenging by cinnamaldehyde and diacetyl does not result in impaired blood vessel function. Although not studied in vivo, the low potency of the compounds renders it unlikely that the observed effects are relevant to humans inhaling flavored vapor from electronic cigarettes.

Klíčová slova:

Biology and life sciences – Biochemistry – Neurochemistry – Neurochemicals – Nitric oxide – Neurotransmitters – Acetylcholine – Neuroscience – Psychology – Addiction – Nicotine addiction – Electronic cigarettes – Behavior – Habits – Smoking habits – Cell biology – Cellular types – Animal cells – Epithelial cells – Endothelial cells – Anatomy – Biological tissue – Epithelium – Body fluids – Blood – Plasma volume – Physiology – Social sciences – Medicine and health sciences – Mental health and psychiatry – Substance-related disorders – Smoking related disorders – Public and occupational health – Cardiovascular anatomy – Blood vessels – Pulmonology


Zdroje

1. Farsalinos KE, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: A systematic review. Ther Adv Drug Saf. 2014;5(2):67–86. doi: 10.1177/2042098614524430 25083263

2. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015;110:1352–6. doi: 10.1111/add.12942 25996087

3. LeBouf RF, Burns DA, Ranpara A, Attfield K, Zwack L, Stefaniak AB. Headspace analysis for screening of volatile organic compound profiles of electronic juice bulk material. Anal Bioanal Chem. 2018;410(23):5951–60. doi: 10.1007/s00216-018-1215-3 29974153

4. O’Connell G, Colard S, Cahours X, Pritchard JD. An assessment of indoor air quality before, during and after unrestricted use of E-cigarettes in a small room. Int J Environ Res Public Health. 2015;12(5):4889–907. doi: 10.3390/ijerph120504889 25955526

5. van Drooge BL, Marco E, Perez N, Grimalt JO. Influence of electronic cigarette vaping on the composition of indoor organic pollutants, particles, and exhaled breath of bystanders. Environ Sci Pollut Res. 2018:[Epub ahead of print]. doi: 10.1007/s11356-018-3975-x 30560536

6. Martuzevicius D, Prasauskas T, Setyan A, O’Connell G, Cahours X, Julien R, et al. Characterisation of the spatial and temporal dispersion differences between exhaled e-cigarette mist and cigarette smoke. Nicotine Tob Res. 2018:[Epub ahead of print].

7. Wei B, Goniewicz ML, O’Connor RJ, Travers MJ, Hyland AJ. Urinary metabolite levels of flame retardants in electronic cigarette users: A study using the data from NHANES 2013–2014. Int J Environ Res Public Health. 2018;15(2):E201. doi: 10.3390/ijerph15020201 29370113

8. Walele T, Bush J, Koch A, Savioz R, Martin C, O'Connell G. Evaluation of the safety profile of an electronic vapour product used for two years by smokers in a real-life setting. Regul Toxicol Pharmacol. 2018;92:226–38. doi: 10.1016/j.yrtph.2017.12.010 29248487

9. Polosa R, Morjaria JB, Caponnetto P, Caruso M, Campagna D, Amaradio MD, et al. Persisting long term benefits of smoking abstinence and reduction in asthmatic smokers who have switched to electronic cigarettes. Discov Med. 2016;21(114):99–108. 27011045.

10. Polosa R, Morjaria JB, Caponnetto P, Prosperini U, Russo C, Pennisi A, et al. Evidence for harm reduction in COPD smokers who switch to electronic cigarettes. Respir Res. 2016;17(1):166. doi: 10.1186/s12931-016-0481-x 27986085.

11. Kalkhoran S, Glantz SA. E-cigarettes and smoking cessation in real-world and clinical settings: A systematic review and meta-analysis. Lancet Respir Med. 2016;4(2):116–28. doi: 10.1016/S2213-2600(15)00521-4 26776875

12. Hajek P, Phillips-Waller A, Przulj D, Pesola F, Myers Smith K, Bisal N, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med. 2019:[Epub ahead of print]. Epub 2019/01/31. doi: 10.1056/NEJMoa1808779 30699054. 30699054

13. Johnson L, Ma Y, Fisher SL, Ramsey AT, Chen LS, Hartz SM, et al. E-cigarette usage Is associated with increased past-12-month quit attempts and successful smoking cessation in two US population-based surveys. Nicotine Tob Res. 2018:[Epub ahead of print].

14. Farsalinos K, Siakas G, Poulas K, Voudris V, Merakou K, Barbouni A. E-cigarette use is strongly associated with recent smoking cessation: an analysis of a representative population sample in Greece. Intern Emerg Med. 2019:[Epub ahead of print]. doi: 10.1007/s11739-018-02023-x 30637600

15. Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: A network meta-analysis. Circulation. 2014;129(1):28–41. doi: 10.1161/CIRCULATIONAHA.113.003961 24323793

16. Polosa R, Cibella F, Caponnetto P, Maglia M, Prosperini U, Russo C, et al. Health impact of E-cigarettes: A prospective 3.5-year study of regular daily users who have never smoked. Sci Rep. 2017;7(1):13825. doi: 10.1038/s41598-017-14043-2 29150612

17. Kapelewski CH, Vandenbergh DJ, Klein LC. Effect of monoamine oxidase inhibition on rewarding effects of nicotine in rodents. Curr Drug Abuse Rev. 2011;4(2):110–21. 21696345

18. Etter JF, Eissenberg T. Dependence levels in users of electronic cigarettes, nicotine gums and tobacco cigarettes. Drug Alcohol Depend. 2015;147:68–75. doi: 10.1016/j.drugalcdep.2014.12.007 25561385

19. Fagerström K. Determinants of tobacco use and renaming the FTND to the Fagerström test for cigarette dependence. Nicotine Tob Res. 2012;14(1):75–8. doi: 10.1093/ntr/ntr137 22025545

20. Simmons VN, Quinn GP, Harrell PT, Meltzer LR, Correa JB, Unrod M, et al. E-cigarette use in adults: A qualitative study of users’ perceptions and future use intentions. Addict Res Theory. 2016;24(4):313–21. doi: 10.3109/16066359.2016.1139700 27725794

21. Schneller LM, Bansal-Travers M, Goniewicz ML, McIntosh S, Ossip D, O’Connor RJ. Use of flavored electronic cigarette refill liquids among adults and youth in the US—results from wave 2 of the population assessment of tobacco and health study (2014–2015). PLoS ONE. 2018;13(8):e0202744. doi: 10.1371/journal.pone.0202744 30138412

22. Russell C, McKeganey N, Dickson T, Nides M. Changing patterns of first e-cigarette flavor used and current flavors used by 20,836 adult frequent e-cigarette users in the USA. Harm Reduct J. 2018;15(1). doi: 10.1186/s12954-018-0238-6 29954412

23. Brass DM, Palmer SM. Models of toxicity of diacetyl and alternative diones. Toxicology. 2017;388:15–20. doi: 10.1016/j.tox.2017.02.011 28232124

24. Behar RZ, Luo W, Lin SC, Wang Y, Valle J, Pankow JF, et al. Distribution, quantification and toxicity of cinnamaldehyde in electronic cigarette refill fluids and aerosols. Tob Control. 2016;25(Suppl 2):ii94–ii102. Epub 2016/09/17. doi: 10.1136/tobaccocontrol-2016-053224 27633763; PubMed Central PMCID: PMC5503843.

25. Fetterman JL, Weisbrod RM, Feng B, Bastin R, Tuttle ST, Holbrook M, et al. Flavorings in tobacco products induce endothelial cell dysfunction. Arterioscler Thromb Vasc Biol. 2018;38(7):1607–15. Epub 2018/06/16. doi: 10.1161/ATVBAHA.118.311156 29903732; PubMed Central PMCID: PMC6023725.

26. Schmidt K, Mayer B, Kukovetz WR. Effect of calcium on endothelium-derived relaxing factor formation and cGMP levels in endothelial cells. Eur J Pharmacol. 1989;170:157–66. doi: 10.1016/0014-2999(89)90536-0 2559853

27. Schmidt K, Werner-Felmayer G, Mayer B, Werner ER. Preferential inhibition of inducible nitric oxide synthase in intact cells by the 4-amino analogue of tetrahydrobiopterin. Eur J Biochem. 1999;259(1–2):25–31. doi: 10.1046/j.1432-1327.1999.00003.x 9914471

28. Russwurm M, Koesling D. Purification and characterization of NO-sensitive guanylyl cyclase. Methods Enzymol. 2005;396:492–501. doi: 10.1016/S0076-6879(05)96041-2 16291256

29. Mayer B, Klatt P, Werner ER, Schmidt K. Kinetics and mechanism of tetrahydrobiopterin-induced oxidation of nitric oxide. J Biol Chem. 1995;270:655–9. doi: 10.1074/jbc.270.2.655 7529763

30. Wölkart G, Schrammel A, Koyani CN, Scheruebel S, Zorn-Pauly K, Malle E, et al. Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca2+currents. Br J Pharmacol. 2017;174(20):3640–53. doi: 10.1111/bph.13967 28768052

31. Friedman M, Kozukue N, Harden LA. Cinnamaldehyde content in foods determined by gas chromatography-mass spectrometry. J Agric Food Chem. 2000;48(11):5702–9. Epub 2000/11/23. doi: 10.1021/jf000585g 11087542.

32. Broillet M, Randin O, Chatton J. Photoactivation and calcium sensitivity of the fluorescent NO indicator 4,5-diaminofluorescein (DAF-2): implications for cellular NO imaging. FEBS Lett. 2001;491(3):227–32. Epub 2001/03/10. doi: 10.1016/s0014-5793(01)02206-2 11240132.

33. Jourd'heuil D. Increased nitric oxide-dependent nitrosylation of 4,5-diaminofluorescein by oxidants: implications for the measurement of intracellular nitric oxide. Free Radic Biol Med. 2002;33(5):676–84. Epub 2002/09/05. doi: 10.1016/s0891-5849(02)00955-3 12208354.

34. Balcerczyk A, Soszynski M, Bartosz G. On the specificity of 4-amino-5-methylamino-2′,7′- difluorofluorescein as a probe for nitric oxide. Free Rad Biol Med. 2005;39:327–35. doi: 10.1016/j.freeradbiomed.2005.03.017 15993331

35. Vanhoutte PM, Shimokawa H, Tang EHC, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiologica. 2009;196(2):193–222. doi: 10.1111/j.1748-1716.2009.01964.x 19220204

36. Boulanger CM. Highlight on endothelial activation and beyond. Arterioscler Thromb Vasc Biol. 2018;38:e198–e201. doi: 10.1161/ATVBAHA.118.312054 30571176

37. Wang F, Pu C, Zhou P, Wang P, Liang D, Wang Q, et al. Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2. Cell Physiol Biochem. 2015;36(1):315–24. Epub 2015/05/15. doi: 10.1159/000374074 25967970.

38. Momtaz S, Hassani S, Khan F, Ziaee M, Abdollahi M. Cinnamon, a promising prospect towards Alzheimer's disease. Pharmacol Res. 2018;130:241–58. Epub 2017/12/21. doi: 10.1016/j.phrs.2017.12.011 29258915.

39. Vasconcelos NG, Croda J, Simionatto S. Antibacterial mechanisms of cinnamon and its constituents: A review. Microb Pathog. 2018;120:198–203. Epub 2018/04/28. doi: 10.1016/j.micpath.2018.04.036 29702210.

40. Dorri M, Hashemitabar S, Hosseinzadeh H. Cinnamon (Cinnamomum zeylanicum) as an antidote or a protective agent against natural or chemical toxicities: a review. Drug Chem Toxicol. 2018;41(3):338–51. Epub 2018/01/11. doi: 10.1080/01480545.2017.1417995 PubMed 29319361. 29319361

41. Xue YL, Shi HX, Murad F, Bian K. Vasodilatory effects of cinnamaldehyde and its mechanism of action in the rat aorta. Vasc Health Risk Manag. 2011;7:273–80. Epub 2011/05/24. doi: 10.2147/VHRM.S15429 21603596; PubMed Central PMCID: PMC3096507.

42. Raffai G, Kim B, Park S, Khang G, Lee D, Vanhoutte PM. Cinnamaldehyde and cinnamaldehyde-containing micelles induce relaxation of isolated porcine coronary arteries: role of nitric oxide and calcium. Int J Nanomedicine. 2014;9:2557–66. Epub 2014/06/07. doi: 10.2147/IJN.S56578 24904214; PubMed Central PMCID: PMC4039418.

43. Sun L, Liu LN, Li JC, Lv YZ, Zong SB, Zhou J, et al. The essential oil from the twigs of Cinnamomum cassia Presl inhibits oxytocin-induced uterine contraction in vitro and in vivo. J Ethnopharmacol. 2017;206:107–14. Epub 2017/05/24. doi: 10.1016/j.jep.2017.05.023 28532683.

44. Pozsgai G, Bodkin JV, Graepel R, Bevan S, Andersson DA, Brain SD. Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo. Cardiovasc Res. 2010;87(4):760–8. Epub 2010/05/06. doi: 10.1093/cvr/cvq118 20442136.

45. Farsalinos KE, Romagna G, Allifranchini E, Ripamonti E, Bocchietto E, Todeschi S, et al. Comparison of the cytotoxic potential of cigarette smoke and electronic cigarette vapour extract on cultured myocardial cells. Int J Environ Res Public Health. 2013;10(10):5146–62. Epub 2013/10/19. doi: 10.3390/ijerph10105146 24135821; PubMed Central PMCID: PMC3823305.

46. Omaiye EE, McWhirter KJ, Luo W, Tierney PA, Pankow JF, Talbot P. High concentrations of flavor chemicals are present in electronic cigarette refill fluids. Sci Rep. 2019;9(1):2468. Epub 2019/02/23. doi: 10.1038/s41598-019-39550-2 30792477.

47. Barboza JN, da Silva Maia Bezerra Filho C, Silva RO, Medeiros JVR, de Sousa DP. An overview on the anti-inflammatory potential and antioxidant profile of eugenol. Oxid Med Cell Longev. 2018;2018:3957262. Epub 2018/11/15. doi: 10.1155/2018/3957262 30425782; PubMed Central PMCID: PMC6217746.

48. Damiani CE, Rossoni LV, Vassallo DV. Vasorelaxant effects of eugenol on rat thoracic aorta. Vascul Pharmacol. 2003;40(1):59–66. Epub 2003/03/21. 12646411.

49. Interaminense LF, Juca DM, Magalhaes PJ, Leal-Cardoso JH, Duarte GP, Lahlou S. Pharmacological evidence of calcium-channel blockade by essential oil of Ocimum gratissimum and its main constituent, eugenol, in isolated aortic rings from DOCA-salt hypertensive rats. Fundam Clin Pharmacol. 2007;21(5):497–506. Epub 2007/09/18. doi: 10.1111/j.1472-8206.2007.00514.x 17868202.

50. Lahlou S, Interaminense LF, Magalhaes PJ, Leal-Cardoso JH, Duarte GP. Cardiovascular effects of eugenol, a phenolic compound present in many plant essential oils, in normotensive rats. J Cardiovasc Pharmacol. 2004;43(2):250–7. Epub 2004/01/13. doi: 10.1097/00005344-200402000-00013 14716213.

51. Peixoto-Neves D, Wang Q, Leal-Cardoso JH, Rossoni LV, Jaggar JH. Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels. Br J Pharmacol. 2015;172(14):3484–94. Epub 2015/04/03. doi: 10.1111/bph.13156 25832173; PubMed Central PMCID: PMC4507154.

52. Soares PM, Lima RF, de Freitas Pires A, Souza EP, Assreuy AM, Criddle DN. Effects of anethole and structural analogues on the contractility of rat isolated aorta: Involvement of voltage-dependent Ca2+-channels. Life Sci. 2007;81(13):1085–93. Epub 2007/09/18. doi: 10.1016/j.lfs.2007.08.027 17869309.

53. Raffai G, Khang G, Vanhoutte PM. Vanillin and vanillin analogs relax porcine coronary and basilar arteries by inhibiting L-type Ca2+ channels. J Pharmacol Exp Ther. 2015;352(1):14–22. Epub 2014/10/26. doi: 10.1124/jpet.114.217935 25344384.

54. Cheang WS, Lam MY, Wong WT, Tian XY, Lau CW, Zhu Z, et al. Menthol relaxes rat aortae, mesenteric and coronary arteries by inhibiting calcium influx. Eur J Pharmacol. 2013;702(1–3):79–84. Epub 2013/02/06. doi: 10.1016/j.ejphar.2013.01.028 23380688.

55. Johnson CD, Melanaphy D, Purse A, Stokesberry SA, Dickson P, Zholos AV. Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone. Am J Physiol Heart Circ Physiol. 2009;296(6):H1868–77. Epub 2009/04/14. doi: 10.1152/ajpheart.01112.2008 19363131; PubMed Central PMCID: PMC2716108.

56. Silva DF, de Almeida MM, Chaves CG, Braz AL, Gomes MA, Pinho-da-Silva L, et al. TRPM8 channel activation induced by monoterpenoid rotundifolone underlies mesenteric artery relaxation. PLoS One. 2015;10(11):e0143171. Epub 2015/11/26. doi: 10.1371/journal.pone.0143171 26599698; PubMed Central PMCID: PMC4657920.

57. Schweitzer KS, Chen SX, Law S, Van Demark M, Poirier C, Justice MJ, et al. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures. Am J Physiol. 2015;309(2):L175–L87. doi: 10.1152/ajplung.00411.2014 25979079

58. Putzhammer R, Doppler C, Jakschitz T, Heinz K, Förste J, Danzl K, et al. Vapours of US and EU market leader electronic cigarette brands and liquids are cytotoxic for human vascular endothelial cells. PLoS ONE. 2016;11(6). doi: 10.1371/journal.pone.0157337 27351725

59. Carnevale R, Sciarretta S, Violi F, Nocella C, Loffredo L, Perri L, et al. Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function. Chest. 2016;150:606–6012. doi: 10.1016/j.chest.2016.04.012 27108682

60. Yuan JH, Dieter MP, Bucher JR, Jameson CW. Toxicokinetics of cinnamaldehyde in F344 rats. Food Chem Toxicol. 1992;30(12):997–1004. Epub 1992/12/01. doi: 10.1016/0278-6915(92)90109-x 1473801.

61. Zhao H, Xie Y, Yang Q, Cao Y, Tu H, Cao W, et al. Pharmacokinetic study of cinnamaldehyde in rats by GC-MS after oral and intravenous administration. J Pharm Biomed Anal. 2014;89:150–7. Epub 2013/12/03. doi: 10.1016/j.jpba.2013.10.044 24291110.


Článek vyšel v časopise

PLOS One


2019 Číslo 9
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

plice
INSIGHTS from European Respiratory Congress
nový kurz

Současné pohledy na riziko v parodontologii
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií
Autoři: prof. MUDr. Petr Němec, Ph.D.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#