{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:58:49Z","timestamp":1790283529278,"version":"4.1.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,12,5]],"date-time":"2017-12-05T00:00:00Z","timestamp":1512432000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,12,5]],"date-time":"2017-12-05T00:00:00Z","timestamp":1512432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Maternal smoking with obligatory nicotine inhalation is associated with preterm delivery, low birth weight, fetal growth retardation and developmental defects. We tested the hypothesis that cigarette smoking-relevant nicotine inhalation during pregnancy impairs cardiovascular function and uterine hemodynamics with consequential fetal ischemia. Pregnant rats exposed to episodic inhaled nicotine via a novel lung alveolar region-targeted aerosol method produced nicotine pharmacokinetics resembling cigarette smoking in humans. This clinically relevant nicotine aerosol inhalation (NAI) induced transient reduction and irregular fluctuations in uterine artery blood flow associated with cardiac arrhythmia and high magnitude irregular fluctuations of systemic blood pressure. The arrhythmia included sinoatrial (SA) block, sinus arrest, 2\u00b0 and 3\u00b0 atrioventricular (A-V) block and supraventricular escape rhythm. These effects were blocked by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine. Resection of the ovarian nerve, which innervates uterine blood vessels, counteracted the NAI-induced reduction in uterine blood flow. We suggest that the rapid rise pattern of arterial blood nicotine concentration stimulates and then desensitizes autonomic nAChRs leading to disruptions of cardiac function as well as systemic and uterine hemodynamics that reduces uteroplacental blood flow, a mechanism underlying maternal smoking-associated pregnancy complications and developmental disorders. These findings challenge the safety of pure nicotine inhalation, i.e., E-cigarettes.<\/jats:p>","DOI":"10.1038\/s41598-017-17301-5","type":"journal-article","created":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T06:39:06Z","timestamp":1511937546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Inhaled nicotine equivalent to cigarette smoking disrupts systemic and uterine hemodynamics and induces cardiac arrhythmia in pregnant rats"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5165-347X","authenticated-orcid":false,"given":"Xuesi M.","family":"Shao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor E.","family":"L\u00f3pez-Vald\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack L.","family":"Feldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,5]]},"reference":[{"key":"17301_CR1","unstructured":"The Surgeon General. Charpter 9 Reproductive outcomes in The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. 459\u2013521 (U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2014)."},{"key":"17301_CR2","unstructured":"The Surgeon General. Charpter 8 Cardiovascular diseases in The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. 411\u2013458 (U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2014)."},{"key":"17301_CR3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S0033-0620(03)00079-3","volume":"46","author":"DM Burns","year":"2003","unstructured":"Burns, D. M. Epidemiology of smoking-induced cardiovascular disease. Prog. Cardiovasc. Dis. \n                           46, 11\u201329 (2003).","journal-title":"Prog. Cardiovasc. Dis."},{"key":"17301_CR4","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/0735-1097(95)00328-2","volume":"26","author":"RW Peters","year":"1995","unstructured":"Peters, R. W., Brooks, M. M., Todd, L., Liebson, P. R. & Wilhelmsen, L. Smoking cessation and arrhythmic death: the CAST experience. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. J. Am. Coll. Cardiol. \n                           26, 1287\u20131292 (1995).","journal-title":"J. Am. Coll. Cardiol."},{"key":"17301_CR5","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/S0033-0620(03)00087-2","volume":"46","author":"NL Benowitz","year":"2003","unstructured":"Benowitz, N. L. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog. Cardiovasc. Dis. \n                           46, 91\u2013111 (2003).","journal-title":"Prog. Cardiovasc. Dis."},{"key":"17301_CR6","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.yrtph.2013.07.008","volume":"67","author":"N Miura","year":"2013","unstructured":"Miura, N., Yuki, D., Minami, N., Kakehi, A. & Onozawa, M. Pharmacokinetic analysis of nicotine when using non-combustion inhaler type of tobacco product in Japanese adult male smokers. Regul. Toxicol. Pharmacol. \n                           67, 198\u2013205, https:\/\/doi.org\/10.1016\/j.yrtph.2013.07.008 (2013).","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"17301_CR7","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1002\/bdrb.20020","volume":"113","author":"RL Brent","year":"2004","unstructured":"Brent, R. L. Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents). Pediatrics \n                           113, 984\u2013995, https:\/\/doi.org\/10.1002\/bdrb.20020 (2004).","journal-title":"Pediatrics"},{"key":"17301_CR8","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s00213-006-0441-0","volume":"190","author":"SG Matta","year":"2007","unstructured":"Matta, S. G. et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl.) \n                           190, 269\u2013319, https:\/\/doi.org\/10.1007\/s00213-006-0441-0 (2007).","journal-title":"Psychopharmacology (Berl.)"},{"key":"17301_CR9","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1172\/JCI113227","volume":"80","author":"HC Porchet","year":"1987","unstructured":"Porchet, H. C., Benowitz, N. L., Sheiner, L. B. & Copeland, J. R. Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics. J. Clin. Invest. \n                           80, 1466\u20131471, https:\/\/doi.org\/10.1172\/JCI113227 (1987).","journal-title":"J. Clin. Invest."},{"key":"17301_CR10","unstructured":"The Surgeon General. Charpter 8 Reproductive and developmental effects in How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. A Report of the Surgeon General, 521\u2013644 (U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2010)."},{"key":"17301_CR11","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1093\/ntr\/nts261","volume":"15","author":"XM Shao","year":"2013","unstructured":"Shao, X. M. et al. Nicotine delivery to rats via lung alveolar region-targeted aerosol technology produces blood pharmacokinetics resembling human smoking. Nicotine Tob. Res. \n                           15, 1248\u20131258, https:\/\/doi.org\/10.1093\/ntr\/nts261 (2013).","journal-title":"Nicotine Tob. Res."},{"key":"17301_CR12","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/S1056-8719(00)00123-4","volume":"44","author":"R Tabrizchi","year":"2000","unstructured":"Tabrizchi, R. & Pugsley, M. K. Methods of blood flow measurement in the arterial circulatory system. J. Pharmacol. Toxicol. Methods \n                           44, 375\u2013384 (2000).","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"17301_CR13","unstructured":"EPA. Health Effects Test Guidelines: Acute Inhalation Toxicity. (The Office of Prevention, Pesticides and Toxic Substances, United States Environmental Protection Agency, 1998)."},{"key":"17301_CR14","unstructured":"OECD. OECD guidance document on acute inhalation toxicity testing in OECD Environment, Health and Safety Publications Series on Testing and Assessment 1\u201371 (The Environment, Health and Safety Division, Organization for Economic Co-operation and Development (OECD), 2009)."},{"key":"17301_CR15","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s002280050007","volume":"55","author":"E Lunell","year":"2000","unstructured":"Lunell, E., Molander, L., Ekberg, K. & Wahren, J. Site of nicotine absorption from a vapour inhaler\u2013comparison with cigarette smoking. Eur. J. Clin. Pharmacol. \n                           55, 737\u2013741, https:\/\/doi.org\/10.1007\/s002280050007 (2000).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"17301_CR16","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1124\/pr.57.1.3","volume":"57","author":"J Hukkanen","year":"2005","unstructured":"Hukkanen, J., Jacob, P. III & Benowitz, N. L. Metabolism and disposition kinetics of nicotine. Pharmacol. Rev. \n                           57, 79\u2013115, https:\/\/doi.org\/10.1124\/pr.57.1.3 (2005).","journal-title":"Pharmacol. Rev."},{"key":"17301_CR17","doi-asserted-by":"crossref","first-page":"R318","DOI":"10.1152\/ajpcell.1997.272.1.C318","volume":"272","author":"SM Hutchison","year":"1997","unstructured":"Hutchison, S. M., Tietz, A. E., Trostel, K. A. & Schramm, L. P. Uterine arterial vasoconstrictions mediated by ovarian nerves in virgin and postpartum rats. Am. J. Physiol. \n                           272, R318\u2013325 (1997).","journal-title":"Am. J. Physiol."},{"key":"17301_CR18","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1530\/jrf.0.0630163","volume":"63","author":"RE Hammer","year":"1981","unstructured":"Hammer, R. E., Goldman, H. & Mitchell, J. A. Effects of nicotine on uterine blood flow and intrauterine oxygen tension in the rat. J. Reprod. Fertil. \n                           63, 163\u2013168 (1981).","journal-title":"J. Reprod. Fertil."},{"issue":"Suppl 1","key":"17301_CR19","doi-asserted-by":"publisher","first-page":"S55","DOI":"10.1016\/S0301-2115(03)00173-8","volume":"110","author":"U Lang","year":"2003","unstructured":"Lang, U. et al. Uterine blood flow\u2013a determinant of fetal growth. Eur. J. Obstet. Gynecol. Reprod. Biol. \n                           110(Suppl 1), S55\u201361 (2003).","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"17301_CR20","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1161\/01.RES.83.12.1241","volume":"83","author":"RA Neff","year":"1998","unstructured":"Neff, R. A., Humphrey, J., Mihalevich, M. & Mendelowitz, D. Nicotine enhances presynaptic and postsynaptic glutamatergic neurotransmission to activate cardiac parasympathetic neurons. Circ. Res. \n                           83, 1241\u20131247 (1998).","journal-title":"Circ. Res."},{"key":"17301_CR21","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.neuropharm.2006.03.001","volume":"51","author":"H Kamendi","year":"2006","unstructured":"Kamendi, H. et al. Prenatal nicotine exposure alters the nicotinic receptor subtypes that modulate excitation of parasympathetic cardiac neurons in the nucleus ambiguus from primarily alpha3beta2 and\/or alpha6betaX to alpha3beta4. Neuropharmacology \n                           51, 60\u201366, https:\/\/doi.org\/10.1016\/j.neuropharm.2006.03.001 (2006).","journal-title":"Neuropharmacology"},{"key":"17301_CR22","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.1523\/JNEUROSCI.20-13-05076.2000","volume":"20","author":"S Bibevski","year":"2000","unstructured":"Bibevski, S., Zhou, Y., McIntosh, J. M., Zigmond, R. E. & Dunlap, M. E. Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J. Neurosci. \n                           20, 5076\u20135082 (2000).","journal-title":"J. Neurosci."},{"key":"17301_CR23","unstructured":"The Surgeon General. Chapter 3 Chemistry and toxicology of cigarette smoke and biomarkers of exposure and harm in How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. A Report of the Surgeon General 27\u2013102 (U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2010)."},{"key":"17301_CR24","doi-asserted-by":"publisher","first-page":"H2091","DOI":"10.1152\/ajpheart.00371.2003","volume":"285","author":"H Hayashi","year":"2003","unstructured":"Hayashi, H. et al. Age-related sensitivity to nicotine for inducible atrial tachycardia and atrial fibrillation. Am. J. physiol. Heart and circulatory physiology \n                           285, H2091\u20132098, https:\/\/doi.org\/10.1152\/ajpheart.00371.2003 (2003).","journal-title":"Heart and circulatory physiology"},{"key":"17301_CR25","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1161\/01.CIR.102.10.1165","volume":"102","author":"H Wang","year":"2000","unstructured":"Wang, H. et al. Nicotine is a potent blocker of the cardiac A-type K(+) channels. Effects on cloned Kv4.3 channels and native transient outward current. Circulation \n                           102, 1165\u20131171 (2000).","journal-title":"Circulation"},{"key":"17301_CR26","first-page":"H1081","volume":"277","author":"HZ Wang","year":"1999","unstructured":"Wang, H. Z., Shi, H., Liao, S. J. & Wang, Z. Inactivation gating determines nicotine blockade of human HERG channels. Am. J. Physiol. \n                           277, H1081\u20131088 (1999).","journal-title":"Am. J. Physiol."},{"key":"17301_CR27","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1177\/107424849700200407","volume":"2","author":"MC Mehta","year":"1997","unstructured":"Mehta, M. C., Jain, A. C., Mehta, A. & Billie, M. Cardiac Arrhythmias Following Intravenous Nicotine: Experimental Study in Dogs. J. Cardiovasc. Pharmacol. Ther. \n                           2, 291\u2013298 (1997).","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"17301_CR28","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/0014-2999(88)90298-1","volume":"146","author":"KW Barron","year":"1988","unstructured":"Barron, K. W., Heesch, C. M., Fleming, B. P., Chien, C. Y. & Diana, J. N. Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat. Eur. J. Pharmacol. \n                           146, 237\u2013245 (1988).","journal-title":"Eur. J. Pharmacol."},{"key":"17301_CR29","unstructured":"Hinds, W. C. Aerosol Technology: properties, behavior, and measurement of airborne particles. 2nd edn, (John Wiley & Sons, Inc., 1999)."},{"key":"17301_CR30","first-page":"299","volume":"17","author":"CJ Drost","year":"1978","unstructured":"Drost, C. J. Vessel Diameter-Independent Volume Flow Measurements Using Ultrasound. Proceedings San Diego Biomedical Symposium \n                           17, 299\u2013302 (1978).","journal-title":"Proceedings San Diego Biomedical Symposium"},{"key":"17301_CR31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3109\/00207458708985942","volume":"34","author":"X Shao","year":"1987","unstructured":"Shao, X. & Chen, P. X. Normalized auto- and cross-covariance functions for neuronal spike train analysis. Int. J. Neurosci. \n                           34, 85\u201395 (1987).","journal-title":"Int. J. Neurosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17301-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17301-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17301-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T10:13:10Z","timestamp":1671790390000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17301-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,5]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["17301"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-17301-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/195099","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,5]]},"assertion":[{"value":"1 September 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"16974"}}