Secondhand Tobacco Smoke Impairs Rabbit Pulmonary Artery Endothelium-Dependent Relaxation

doi:10.1378/chest.120.6.2004

Chest

Volume 120, Issue 6, December 2001, Pages 2004-2012

https://doi.org/10.1378/chest.120.6.2004 Get rights and content

Objectives

To determine whether secondhand smoke (SHS) induces pulmonary artery endothelial dysfunction, and whether dietary l-arginine supplementation is preventive.

Background

SHS causes coronary and peripheral arterial endothelial dysfunction.

Methods

The effects of l-arginine supplementation (2.25% solution) and SHS (10 weeks) on pulmonary vascular reactivity were examined in 32 rabbits fed a normal diet. Endothelium-dependent relaxation of precontracted pulmonary artery segments was studied using acetylcholine and calcium ionophore. Endothelium-independent relaxation was studied using nitroglycerin. Endothelial and serum l-arginine levels were measured by chromatography. In eight SHS-exposed and in eight control rats, pulmonary artery nitric oxide synthase (NOS) activity and arginase activity were studied using the titrated arginine to citrulline conversion assay.

Results

SHS reduced maximal acetylcholine-induced (p = 0.04) and calcium ionophore-induced (p = 0.02) relaxation. l-Arginine increased maximal acetylcholine-induced (p = 0.047) vasodilation. SHS and l-arginine did not influence nitroglycerin-induced relaxation. SHS reduced endothelial l-arginine (p = 0.04) but not serum l-arginine. l-Arginine supplementation increased endothelial (p = 0.007) and serum l-arginine (p < 0.0005). Endothelium-dependent relaxation induced by acetylcholine and calcium ionophore varied directly with endothelial (r = 0.67, r = 0.67) and serum l-arginine (r = 0.43, r = 0.45), respectively. SHS reduced constitutive NOS activity (p = 0.03).

Conclusions

SHS reduces pulmonary artery endothelium-dependent relaxation by decreasing NOS activity and possibly by decreasing endothelial arginine content. l-Arginine supplementation increases serum and endothelial l-arginine stores and prevents SHS-induced endothelial dysfunction. l-Arginine may offset the deleterious effect of SHS on pulmonary arteries by substrate loading of the nitric oxide pathway.

Section snippets

Protocol

The study protocol was approved by the Committee for Animal Research of the University of California at San Francisco, and was performed in accordance with the recommendations of the American Association for Accreditation of Laboratory Animal Care. Rabbits ingested a standard rabbit chow diet throughout the study. Thirty-two rabbits were randomized in a two-by-two design (with SHS and long-term l-arginine as factors) into four groups: normal rabbits, SHS exposure, l-arginine exposure, and SHS/l

Animal Data

SHS and l-arginine did not influence body weight. l-Arginine ingestion by the two groups of arginine-supplemented animals was similar. SHS exposure reduced average food ingestion. l-Arginine supplementation did not affect food ingestion, but did block the SHS-induced reduction in food intake (Table 1).

SHS exposure markedly increased smoking-chamber carbon monoxide and particulate matter levels, and serum nicotine and cotinine levels. Neither SHS nor l-arginine affected levels of total

Discussion

This study demonstrates that (1) SHS reduces rodent conduit pulmonary artery endothelium-dependent relaxation, (2) SHS reduces rodent pulmonary artery endothelial constitutive nitric oxide activity, (3) a correlation between endothelial L-arginine content and endothelium-dependent relaxation exists, (4) SHS reduces endothelial L-arginine and long-term L-arginine supplementation increased endothelial L-arginine content, and (5) long-term L-arginine supplementation protects against SHS-induced

Conclusion

SHS exposure reduces rodent pulmonary artery endothelial NOS activity, lowers l-arginine content through a mechanism independent of l-arginase, and impairs pulmonary artery endothelium-dependent relaxation. Long-term dietary l-arginine supplementation increases serum and endothelial l-arginine content and prevents SHS-induced endothelial dysfunction. Although l-arginine supplementation addresses SHS-induced loss of substrate, the SHS-induced loss of NOS activity, if progressive, would not be

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Cited by (39)

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2020, American Journal of the Medical Sciences
Citation Excerpt :
FeNO has not been well characterized in COPD because there are many factors that affect it. Studies have shown that smoking can inhibit the expression of eNOS and iNOS and reduce the production of NO.41,42 However, many oxides in smoke will react with NO and increase the consumption of NO. The influence of smoking on FeNO persists for at least 24 hours; however, FeNO levels can gradually recover after an individual quits smoking.43,44 Therefore, FeNO in smokers is lower than that in nonsmokers.45
Fraction of exhaled nitric oxide (FeNO) is a noninvasive indicator of eosinophilic airway inflammation and has been used for the diagnosis and treatment of asthma. The levels of FeNO are controversial in patients with stable chronic obstructive pulmonary disease (COPD). Accordingly, this study aimed to assess FeNO levels in patients with stable COPD.
A search of the Medline, Embase, Web of Science, ClinicalTrials.gov and The Cochrane Library databases was performed in August 2019. The literature search was restricted to articles published in English. Studies were included if they reported data addressing FeNO levels in patients with stable COPD and healthy controls. Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis.
A total of 19 studies were included. Analysis revealed that FeNO levels in patients with stable COPD were higher than those in the healthy control group (mean difference [MD] 2.49 [95% confidence interval {CI} 0.99-4.00]; P < 0.05), those in nonsmoking patients with stable COPD were higher than those in the healthy control group (MD 5.04 [95% CI 2.19-7.89]; P < 0.05) and those in smoking patients with stable COPD were not higher than those in the healthy control group (MD 0.30 [95% CI −2.81 to 3.41]; P = 0.85). FeNO measured using a chemiluminescence analyzer in nonsmoking patients with stable COPD was higher than those in the healthy control group (MD 4.84 [95% CI 1.83-7.86]; P < 0.05).
Findings suggested that FeNO levels in patients with stable COPD were elevated, and that smokers exhibited decreased levels.
Benfotiamine attenuates nicotine and uric acid-induced vascular endothelial dysfunction in the rat
2008, Pharmacological Research
The study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in nicotine and uric acid-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg kg⁻¹ day⁻¹, i.p., 4 weeks) and uric acid (150 mg kg⁻¹ day⁻¹, i.p., 3 weeks) were administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy (SEM) of thoracic aorta. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of nicotine and uric acid produced VED by impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic concentration of nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine and uric acid produced oxidative stress, which was assessed in terms of increase in serum TBARS and aortic superoxide generation. However, treatment with benfotiamine (70 mg kg⁻¹ day⁻¹, p.o.) or atorvastatin (30 mg kg⁻¹ day⁻¹ p.o., a standard agent) markedly prevented nicotine and uric acid-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that benfotiamine reduces the oxidative stress and consequently improves the integrity of vascular endothelium and enhances the generation of nitric oxide to prevent nicotine and uric acid-induced experimental VED.
Parental smoking and lung function in healthy children and adolescents
2007, Archivos de Bronconeumologia
Continúa la controversia sobre el efecto del tabaquismo pasivo en los no fumadores. El efecto del tabaquismo de los padres sobre la función pulmonar de los hijos presenta gran variabilidad entre diferentes zonas geográficas, fuente del tabaquismo pasivo y sexos. El objetivo del presente estudio ha sido valorar el efecto del tabaquismo de los padres sobre la función pulmonar de sus hijos.
Hemos llevado a cabo un estudio transversal en una muestra de la población de niños y adolescentes sanos de 6 a 18 años de Galicia, seleccionada mediante un muestreo bietápico en racimos y estratificada por sexo y edad.
Alrededor del 56% de los niños estaban expuestos al humo del tabaco de alguno de sus padres. Los niños de padres fumadores presentaban un 40% más de riesgo de reducción del flujo espiratorio forzado al 75% de la capacidad vital forzada (FEF_75%), y un 30% de reducción del FEF_25-75%. Los niños cuyas madres eran fumadoras tenían un 30% más de riesgo de reducción del volumen espiratorio forzado en el primer segundo, y un 40% de reducción del FEF_50%. El incremento de riesgo de reducción del FEF_75% fue del 60%. El hecho de que fumaran ambos progenitores no pareció incrementar el riesgo de función pulmonar reducida.
El tabaquismo parental tiene un importante efecto sobre la función pulmonar de niños y adolescentes. Tanto el tabaquismo materno como el paterno influyen decisivamente. El hecho de que este efecto sea independiente del crecimiento del niño y que el efecto obstructivo se localice fundamentalmente en la vía aérea distal parece confirmar la hipótesis de que este efecto se produce después del nacimiento.
The debate continues on the effect of passive smoking on nonsmokers. The effect of parental smoking on the lung function of children varies considerably according to geographic area, source of passive smoking, and sex. The objective of this study was to evaluate the effect of parental smoking on the lung function of children.
A cross-sectional study was performed on a sample of the population of healthy children and adolescents between 6 and 18 years of age in Galicia. Subjects were selected by means of 2-stage cluster sampling grouped by sex and age.
Approximately 56% of the children were exposed to the tobacco smoke of one of their parents. Children whose fathers were smokers presented a 40% higher risk of reduced forced expiratory flow at75% of forced vital capacity (FEF_75%) and a 30% higher risk of reduced FEF_25%-75%. Children whose mothers were smokers presented a 30% higher risk of reduced forced expiratory volume in the first second and a 40% higher risk of reduced FEF_50%. There was a 60% increase in risk of reduced FEF_75%. The fact that both parents smoked did not appear to increase the risk of reduced lung function.
Parental smoking has a considerable effect on the lung function of children and adolescents. Smoking by either the mother or the father has a decisive influence. The fact that this effect is independent of the growth of the child and that the obstructive effect is located principally in the distal airways appears to confirm the hypothesis that this effect is produced after birth.
Genetic polymorphisms in arginase I and II and childhood asthma and atopy
2006, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Environmental tobacco smoke is a stimulus for airway inflammation41 that might magnify genetic effects that influence this pathway. In addition to effects on inflammatory cells, smoking can decrease endothelial NOS activity in smooth muscle,42 which, if occurring in the airway, would result in decreased bronchodilatory NO. Because arginase activity depletes arginine, leading to decreased substrate for endothelial NOS, there could be a synergistic decrease in NO production. There may also be synergism on the basis of airway remodeling, which both smoking and arginase activity can promote.43
A recent microarray study implicated arginase I (ARG1) and arginase II (ARG2) in mouse allergic asthma models and human asthma.
To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk.
We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of ARG1 and 4 SNPs of ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif).
ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One ARG2 SNP was related to the number of positive skin tests (P = .027).
Variation in arginase genes may contribute to asthma and atopy in children.
Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers
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Remnant cholesterol associates with hypertension beyond low-density lipoprotein cholesterol among the general US adult population
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View all citing articles on Scopus

Dr. Hutchison was supported in part by a fellowship from the R.

Samuel McLaughlin Foundation, Toronto, Ontario, Canada.

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Laboratory and Animal InvestigationsSecondhand Tobacco Smoke Impairs Rabbit Pulmonary Artery Endothelium-Dependent Relaxation

Objectives

Background

Methods

Results

Conclusions

Section snippets

Protocol

Animal Data

Discussion

Conclusion

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Am J Clin Nutr

Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans

Circulation

Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension

Br J Pharmacol

Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man

J Physiol (Lond)

Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans

Circulation

Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats

J Physiol (Lond)

Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults

Circulation

Passive smoking is associated with impaired endothelium-dependent dilation in healthy young adults

N Engl J Med

Chronic dietary L-arginine prevents endothelial dysfunction secondary to environmental tobacco smoke in normocholesterolemic rabbits

Hypertension

Changes in the structure and mechanical properties of pulmonary arteries of rats exposed to cigarette smoke

Am Rev Respir Dis

Hemodynamic and gas exchange responses to infusion of acetylcholine and inhalation of nitric oxide in patients with chronic obstructive lung disease and pulmonary hypertension

Am Rev Respir Dis

Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension

Circulation

Laboratory and Animal Investigations
Secondhand Tobacco Smoke Impairs Rabbit Pulmonary Artery Endothelium-Dependent Relaxation