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Contribution of endothelin-1 to the vascular effects of diesel exhaust inhalation in humans
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. (Division of Respiratory Medicine and Allergy)
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2009 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 54, no 4, 910-915 p.Article in journal (Refereed) Published
Abstract [en]

Diesel exhaust inhalation impairs vascular function, and, althoughthe underlying mechanism remains unclear, endothelin (ET) 1and NO are potential mediators. The aim of this study was toidentify whether diesel exhaust inhalation affects the vascularactions of ET-1 in humans. In a randomized, double-blind crossoverstudy, 13 healthy male volunteers were exposed to either filteredair or dilute diesel exhaust (331±13 µg/m3). Plasmaconcentrations of ET-1 and big-ET-1 were determined at baselineand throughout the 24-hour study period. Bilateral forearm bloodflow was measured 2 hours after the exposure during infusionof either ET-1 (5 pmol/min) or the ETA receptor antagonist,BQ-123 (10 nmol/min) alone and in combination with the ETB receptorantagonist, BQ-788 (1 nmol/min). Diesel exhaust exposure hadno effect on plasma ET-1 and big-ET-1 concentrations (P>0.05for both) or 24-hour mean blood pressure or heart rate (P>0.05for all). ET-1 infusion increased plasma ET-1 concentrationsby 58% (P<0.01) but caused vasoconstriction only after dieselexhaust exposure (–17% versus 2% after air; P<0.001).In contrast, diesel exhaust exposure reduced vasodilatationto isolated BQ-123 infusion (20% versus 59% after air; P<0.001)but had no effect on vasodilatation to combined BQ-123 and BQ-788administration (P>0.05). Diesel exhaust inhalation increasesvascular sensitivity to ET-1 and reduces vasodilatation to ETAreceptor antagonism despite unchanged plasma ET-1 concentrations.Given the tonic interaction between the ET and NO systems, weconclude that diesel exhaust inhalation alters vascular reactivityto ET-1 probably through its effects on NO bioavailability.

Place, publisher, year, edition, pages
Dallas, Tex.: The Association , 2009. Vol. 54, no 4, 910-915 p.
Keyword [en]
air pollution, particulate matter, endothelial function, endothelin receptor antagonists, ET-1, endothelin-1, blood pressure
National Category
Respiratory Medicine and Allergy
URN: urn:nbn:se:umu:diva-27792DOI: 10.1161/HYPERTENSIONAHA.109.135947OAI: diva2:277746
Available from: 2009-11-23 Created: 2009-11-20 Last updated: 2012-10-19Bibliographically approved
In thesis
1. Cardiovascular effects of diesel exhaust: mechanistic and interventional studies
Open this publication in new window or tab >>Cardiovascular effects of diesel exhaust: mechanistic and interventional studies
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Air pollution is associated with negative health effects. Exposure to combustion-derived particulate matter (PM) air pollution has been related to increased incidence of cardiovascular and respiratory morbidity and mortality, specifically in susceptible populations. Ambient particles, with a diameter of less than 2.5 mm, have been suggested to be the strongest contributor to these health effects. Diesel exhaust (DE) is a major source of small combustion-derived PM air pollution world wide. 

In healthy volunteers, exposure to DE, has been associated with airway inflammation and impaired vasomotor function and endogenous fibrinolysis.

The aims of this thesis were to further elucidate the underlying mechanisms to the reported cardiovascular effects following exposure to DE, with specific focus on endothelin-1 (ET-1). Additionally, the vascular effects of the major gaseous component of DE, nitrogen dioxide (NO2), were assessed together with the impact of an exhaust particle trap to reduce the observed negative vascular effects after DE exposure.

Methods: In all studies healthy, non-smoking male volunteers were included and exposed for one hour during intermittent exercise in a randomised double-blind crossover fashion. In studies I-III, subjects were exposed to DE at a particulate matter concentration of approximately 300 μg/m3 and filtered air, on two different occasions. In study V an additional exposure was employed, during which DE was filtered through an exhaust particle trap. In study IV subjects were exposed to nitrogen dioxide (NO2) at 4 ppm or filtered air.

In study I, thrombus formation and platelet activation were assessed using the Badimon ex vivo perfusion chamber and flow cytometry. Study II comprised the determination of arterial stiffness including pulse wave analysis and velocity.

In studies III-V, vascular assessment was performed using venous occlusion plethysmography. In studies IV and V, the vascular responses to intra-arterially infused endothelial-dependent and endothelial-independent vasodilatators were registered. In study III, vascular responses to intra-arterial infusion of Endothelin-1 (ET-1) and ET-1-receptor antagonists were assessed. Venous occlusion phlethysmography was in all cases performed 4-6 hours following exposures. Blood samples for markers of inflammation, coagulation and platelet activation were collected before and throughout the study periods in studies III and V.

Results: Exposure to DE increased ex vivo thrombus formation and arterial stiffness, in terms of augmentation index. DE inhalation impaired vasomotor function and endogenous fibrinolysis. The exhaust particle trap reduced the particle concentration by 98% and abolished the effects on vasomotor function, endogenous fibrinolysis and ex vivo thrombus formation. Plasma concentrations of ET-1 and its precursor big-ET-1 were unchanged following exposure. Dual endothelial receptor antagonism caused similar vasodilatation after both exposures, although vasodilatation to the endothelin-A receptor alone was blunted after DE exposure. ET-1 infusion induced vasoconstriction only following DE exposure. Exposure to nitrogen dioxide did not affect vascular function.

Conclusion: Inhalation of diesel exhaust in young healthy men impaired important and complementary aspects of vascular function in humans; regulation of vascular tone and endogenous fibrinolysis as well as increased ex vivo thrombus formation. The use of an exhaust particle trap significantly reduced particle emissions and abolished the DE-induced vascular and prothrombotic effects. The adverse vascular effects following DE exposure do not appear to be directly mediated through the endothelin system. Neither is NO2 suggested to be a major arbiter of the DE-induced cardiovascular responses. Arterial stiffness is a non-invasive and easily accessible method and could thus be employed to address vascular function in larger field studies. Taken together, this thesis has given further knowledge about the mechanisms underlying the DE-induced vascular effects.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 73 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1317
air pollution, diesel exhaust, nitrogen dioxide, endothelin-1, cardiovascular effects, exhaust particle trap
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
urn:nbn:se:umu:diva-27783 (URN)978-91-7264-868-5 (ISBN)
Public defence
2009-12-11, Sal E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2009-11-23 Created: 2009-11-19 Last updated: 2012-02-22Bibliographically approved

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