Altered Nitric Oxide Bioavailability Contributes to Diesel Exhaust Inhalation‐Induced Cardiovascular Dysfunction in Man

Abstract

BackgroundDiesel 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 ResultsIn 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 NG‐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.ConclusionsDiesel 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 RegistrationURL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.

Engine exhaust particulate and gas phase contributions to vascular toxicity

“…However, vasodilatory impairments induced by circulating components in the plasma were largely abrogated by removal of PM, moreso than the gases, consistent with numerous studies of PM-induced endothelial dysfunction. (Brook et al, 2002) (LeBlanc et al, 2010) (Langrish et al, 2013) (Mills et al, 2011) Epidemiological findings of traffic-derived pollution or proximity to roadways as more focused drivers of cardiovascular disease outcomes (Hoffmann et al, 2006) (Sarnat et al, 2008) may relate to the present findings, which show that the interaction of fresh gases and PM enhances systemic vascular toxicity compared to either component, alone.…”

A joint ERS/ATS policy statement: what constitutes an adverse health effect of air pollution? An analytical framework

“…Several air pollutants have been associated with impaired microvascular and conduit vascular function in human panel and controlled exposure studies, as well as in animal experiments [97–99]. Chronic endothelial dysfunction is an important biomarker that is both predictive of and causally related to cardiovascular diseases and events [100].…”

“…This probably occurs as a consequence of air pollution-mediated tissue oxidative stress and inflammation, reducing bioavailability of NO while potentiating vasoconstrictive mediators ( e.g. endothelin) and pathways [99]. The independent associations between endothelial dysfunction and heightened cardiovascular risk are all in the chronic timescale, and assume that a persistent impairment in vascular health is ongoing, which would indicate adversity as specified by consideration 5 (medical/functional significance) in table 1 and consideration 2 (relevance to a clinical condition) in table 2.…”

Environmental factors in cardiovascular disease

“…ROS, when present in excess, can alter cardiac and vascular function through the disruption of important redox-sensitive signalling pathways, the depletion of vasodilators (predominantly NO) and antioxidants, the perturbation of cellular mechanisms, and the oxidation of proteins and lipids. [123][124][125] These effects contribute to fibrosis, atherogenesis, metabolic dysfunction, and hypertension. Although studies in humans are limited to the measurement of surrogate markers of oxidative damage, both occupational and population-based cohort studies have produced reports of positive associations between exposure to particulate matter and markers of oxidation of proteins, lipids, and DNA in blood and urine.…”