Altered nitric oxide bioavailability contributes to diesel exhaust inhalation-induced cardiovascular dysfunction in man

Jeremy P Langrish, Jon Unosson, Jenny Bosson, Stefan Barath, Ala Muala, Scott Blackwell, Stefan Söderberg, Jamshid Pourazar, Ian L Megson, Andrew Treweeke, Thomas Sandström, David E Newby, Anders Blomberg, Nicholas L Mills, Jeremy P Langrish, Jon Unosson, Jenny Bosson, Stefan Barath, Ala Muala, Scott Blackwell, Stefan Söderberg, Jamshid Pourazar, Ian L Megson, Andrew Treweeke, Thomas Sandström, David E Newby, Anders Blomberg, Nicholas L Mills

Abstract

Background: Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects.

Methods and results: In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 μg/min) and sodium nitroprusside (SNP; 2 to 8 μg/min) in the presence of the NO clamp (NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) 8 μg/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous l-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L; P=0.006) despite similar l-NMMA-induced reductions in basal blood flow (-20.6±14.7% versus -21.1±14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, l-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air.

Conclusions: Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability.

Clinical trial registration: URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.

Figures

Figure 1.
Figure 1.
A, Forearm blood flow response during infusion of l‐NMMA (2‐way repeated measures ANOVA: P=0.559 for exposure). B, Forearm blood flow during infusion of the vasodilators acetylcholine and sodium nitroprusside (2‐way repeated measures ANOVA: P=0.209 and P=0.613, respectively, for exposure). Data expressed as mean±SEM. l‐NMMA indicates NG‐monomethyl‐l‐arginine; ANOVA, analysis of variance; SEM, standard error of the mean.
Figure 2.
Figure 2.
Changes in invasive mean arterial blood pressure, central arterial stiffness (PWV), cardiac index, and stroke volume following systemic infusion of l‐NMMA. Data expressed as mean±SEM and composite area under the curve with 2‐way repeated measures ANOVA for exposure. PWV indicates pulse‐wave velocity; l‐NMMA, NG‐monomethyl‐l‐arginine; SEM, standard error of the mean; ANOVA, analysis of variance.

References

    1. Anderson HR, Ponce de Leon A, Bland JM, Bower JS, Strachan DP. Air pollution and daily mortality in London: 1987–92. BMJ. 1996; 312:665-669
    1. Dockery D, Pope C, Xu X, Spengler J, Ware J, Fay M, Ferris B, Speizer F. An association between air pollution and mortality in six U.S. cities. N Engl J Med. 1993; 329:1753-1759
    1. Miller K, Siscovick D, Sheppard L, Shepherd K, Sullivan J, Anderson G, Kaufman J. Long‐term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med. 2007; 356:447-458
    1. Pope C, Burnett R, Thun M, Calle E, Krewski D, Ito K, Thurston G. Lung cancer, cardiopulmonary mortality, and long‐term exposure to fine particulate air pollution. JAMA. 2002; 287:1132-1141
    1. Peters A, von Klot S, Heier M, Trentinaglia I, Hörmann A, Wichmann H, Löwel H. Exposure to traffic and the onset of myocardial infarction. N Engl J Med. 2004; 351:1721-1730
    1. Mills N, Törnqvist H, Robinson S, Gonzales M, Darnley K, MacNee W, Boon N, Donaldson K, Blomberg A, Sandström T, Newby D. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation. 2005; 112:3930-3936
    1. Brook R, Brook J, Urch B, Vincent R, Rajagopalan S, Silverman F. Inhalation of fine particulate air pollution and ozone causes acute arterial vasoconstriction in healthy adults. Circulation. 2002; 105:1534-1536
    1. Urch B, Silverman F, Corey P, Brook JR, Lukic KZ, Rajagopalan S, Brook RD. Acute blood pressure responses in healthy adults during controlled air pollution exposures. Environ Health Perspect. 2005; 113:1052-1055
    1. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, and risk of cardiovascular events in patients with coronary heart disease. Circulation. 2001; 104:2673-2678
    1. Nightingale J, Maggs R, Cullinan P, Donnelly L, Rogers D, Kinnersley R, Chung KF, Barnes P, Ashmore M, Newman‐Taylor A. Airway inflammation after controlled exposure to diesel exhaust particulates. Am J Respir Crit Care Med. 2000; 162:161-166
    1. Salvi S, Blomberg A, Rudell B, Kelly F, Sandström T, Holgate S, Frew A. Acute inflammatory responses in the airways and peripheral blood after short‐term exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med. 1999; 159:702-709
    1. Baulig A, Garlatti M, Bonvallot V, Marchand A, Barouki R, Marano F, Baeza‐Squiban A. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Am J Physiol Lung Cell Moll Physiol. 2003; 285:L671-L679
    1. Behndig A, Mudway I, Brown J, Stenfors N, Helleday R, Duggan S, Wilson S, Boman C, Cassee F, Frew A, Kelly F, Sandström T, Blomberg A. Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans. Eur Respir J. 2006; 27:359-365
    1. Nemmar A, Hoet PH, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, Vanbilloen H, Mortelmans L, Nemery B. Passage of inhaled particles into the blood circulation in humans. Circulation. 2002; 105:411-414
    1. Nemmar A, Hoylaerts M, Hoet P, Nemery B. Possible mechanisms of the cardiovascular effects of inhaled particles: systemic translocation and prothrombotic effects. Toxicol Lett. 2004; 149:243-253
    1. Lum H, Roebuck K. Oxidant stress and endothelial dysfunction. Am J Physiol Cell Physiol. 2001; 280:719-741
    1. Ikeda M, Watarai K, Suzuki M, Ito T, Yamasaki H, Sagai M, Tomita T. Mechanism of pathophysiological effects of diesel exhaust particles on endothelial cells. Environ Toxicol Pharmacol. 1998; 6:117-123
    1. Moncada S, Higgs A. The l‐arginine‐nitric oxide pathway. N Engl J Med. 1993; 329:2002-2012
    1. Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002; 105:546-549
    1. Nurkiewicz TR, Porter DW, Hubbs AF, Stone S, Chen BT, Frazer DG, Boegehold MA, Castranova V. Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling. Toxicol Sci. 2009; 110:191-203
    1. Rudell B, Ledin M, Hammarstrom U, Sternberg N, Lundback B, Sandström T. Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust. Occup Environ Med. 1996; 53:658-662
    1. Langrish JP, Lundback M, Mills NL, Johnston NR, Webb DJ, Sandstrom T, Blomberg A, Newby DE. Contribution of endothelin 1 to the vascular effects of diesel exhaust inhalation in humans. Hypertension. 2009; 54:910-915
    1. Wilkinson I, Webb D. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol. 2001; 52:631-646
    1. Japp AG, Cruden NL, Amer DA, Li VK, Goudie EB, Johnston NR, Sharma S, Neilson I, Webb DJ, Megson IL, Flapan AD, Newby DE. Vascular effects of apelin in vivo in man. J Am Coll Cardiol. 2008; 52:908-913
    1. Stroes ES, Luscher TF, de Groot FG, Koomans HA, Rabelink TJ. Cyclosporin a increases nitric oxide activity in vivo. Hypertension. 1997; 29:570-575
    1. Haynes WG, Noon JP, Walker BR, Webb DJ. l‐NMMA increases blood pressure in man. Lancet. 1993; 342:931-932
    1. Blackwell S, O'Reilly DS, Talwar DK. HPLC analysis of asymmetric dimethylarginine (ADMA) and related arginine metabolites in human plasma using a novel non‐endogenous internal standard. Clin Chim Acta. 2009; 401:14-19
    1. Nagababu E, Rifkind JM. Measurement of plasma nitrite by chemiluminescence without interference of S‐, N‐nitroso and nitrated species. Free Radic Biol Med. 2007; 42:1146-1154
    1. Petrie JR, Ueda S, Morris AD, Murray LS, Elliott HL, Connell JM. How reproducible is bilateral forearm plethysmography? Br J Clin Pharmacol. 1998; 45:131-139
    1. Newby D, Wright R, Labinjoh C, Ludlam C, Fox K, Boon N, Webb D. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation. 1999; 99:1411-1415
    1. Barath S, Mills N, Törnqvist H, Lucking A, Langrish J, Söderberg S, Boman C, Westerholm R, Löndahl J, Donaldson K, Sandström T, Newby D, Blomberg A. Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions. Part Fibre Toxicol. 2010; 7:19.
    1. Cirino G, Fiorucci S, Sessa WC. Endothelial nitric oxide synthase: the cinderella of inflammation? Trend Pharmacol Sci. 2003; 24:91-95
    1. Kang WS, Tamarkin FJ, Wheeler MA, Weiss RM. Rapid up‐regulation of endothelial nitric‐oxide synthase in a mouse model of Escherichia coli lipopolysaccharide‐induced bladder inflammation. J Pharmacol Exp Ther. 2004; 310:452-458
    1. Bai N, Kido T, Kavanagh TJ, Kaufman JD, Rosenfeld ME, van Breemen C, van Eeden SF. Exposure to diesel exhaust up‐regulates inos expression in ApoE knockout mice. Toxicol Appl Pharmacol. 2011; 255:184-192
    1. Bai N, Kido T, Suzuki H, Yang G, Kavanagh TJ, Kaufman JD, Rosenfeld ME, van Breemen C, Eeden SF. Changes in atherosclerotic plaques induced by inhalation of diesel exhaust. Atherosclerosis. 2011; 216:299-306
    1. Miller MR, Borthwick SJ, Shaw CA, McLean SG, McClure D, Mills NL, Duffin R, Donaldson K, Megson IL, Hadoke PW, Newby DE. Direct impairment of vascular function by diesel exhaust particulate through reduced bioavailability of endothelium‐derived nitric oxide induced by superoxide free radicals. Environ Health Perspect. 2009; 117:611-616
    1. Knuckles TL, Lund AK, Lucas SN, Campen MJ. Diesel exhaust exposure enhances venoconstriction via uncoupling of eNOS. Toxicol Appl Pharmacol. 2008; 230:346-351
    1. Knuckles TL, Buntz JG, Paffett M, Channell M, Harmon M, Cherng T, Lucas SN, McDonald JD, Kanagy NL, Campen MJ. Formation of vascular S‐nitrosothiols and plasma nitrates/nitrites following inhalation of diesel emissions. J Toxicol Environ Health A. 2011; 74:828-837
    1. Munzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J. 2010; 31:2741-2748
    1. Brook RD, Rajagopalan S, Pope CA, III, Brook JR, Bhatnagar A, Diez‐Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC, Jr, Whitsel L, Kaufman JD. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation. 2010; 121:2331-2378
    1. Moller P, Loft S. Oxidative damage to DNA and lipids as biomarkers of exposure to air pollution. Environ Health Perspect. 2010; 118:1126-1136
    1. Castillo L, Beaumier L, Ajami AM, Young VR. Whole body nitric oxide synthesis in healthy men determined from [15N] arginine‐to‐[15N]citrulline labeling. Proc Natl Acad Sci USA. 1996; 93:11460-11465
    1. Wu G, Morris SM., Jr Arginine metabolism: nitric oxide and beyond. Biochem J. 1998; 336:1-17
    1. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium‐dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992; 340:1430-1432
    1. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990; 86:228-234
    1. Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid‐lowering medication. Lancet. 1995; 346:467-471
    1. Gamboa A, Shibao C, Diedrich A, Choi L, Pohar B, Jordan J, Paranjape S, Farley G, Biaggioni I. Contribution of endothelial nitric oxide to blood pressure in humans. Hypertension. 2007; 49:170-177
    1. Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens. 1993; 11:1375-1380
    1. Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Modder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J. 2006; 27:1699-1705
    1. Stewart AD, Millasseau SC, Kearney MT, Ritter JM, Chowienczyk PJ. Effects of inhibition of basal nitric oxide synthesis on carotid‐femoral pulse wave velocity and augmentation index in humans. Hypertension. 2003; 42:915-918
    1. Wilkinson IB, MacCallum H, Cockcroft JR, Webb DJ. Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br J Clin Pharmacol. 2002; 53:189-192
    1. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard‐Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial‐dependent flow‐mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol. 2002; 39:257-265
    1. Luksha L, Agewall S, Kublickiene K. Endothelium‐derived hyperpolarizing factor in vascular physiology and cardiovascular disease. Atherosclerosis. 2009; 202:330-344
    1. Tomioka H, Hattori Y, Fukao M, Sato A, Liu M, Sakuma I, Kitabatake A, Kanno M. Relaxation in different‐sized rat blood vessels mediated by endothelium‐derived hyperpolarizing factor: importance of processes mediating precontractions. J Vasc Res. 1999; 36:311-320
    1. Brook RD, Urch B, Dvonch JT, Bard RL, Speck M, Keeler G, Morishita M, Marsik FJ, Kamal AS, Kaciroti N, Harkema J, Corey P, Silverman F, Gold DR, Wellenius G, Mittleman MA, Rajagopalan S, Brook JR. Insights into the mechanisms and mediators of the effects of air pollution exposure on blood pressure and vascular function in healthy humans. Hypertension. 2009; 54:659-667
    1. Auchincloss AH, Roux AV, Dvonch JT, Brown PL, Barr RG, Daviglus ML, Goff DC, Kaufman JD, O'Neill MS. Associations between recent exposure to ambient fine particulate matter and blood pressure in the multi‐ethnic study of atherosclerosis (MESA). Environ Health Perspect. 2008; 116:486-491
    1. Gold D, Litonjua A, Schwartz J, Lovett E, Larson A, Nearing B, Allen G, Verrier M, Cherry R, Verrier R. Ambient pollution and heart rate variability. Circulation. 2000; 101:1267-1273

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