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Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors.

Robertson S, Thomson AL, Carter R, Stott HR, Shaw CA, Hadoke PW, Newby DE, Miller MR, Gray GA - Part Fibre Toxicol (2014)

Bottom Line: Reperfusion injury was also increased in buffer perfused hearts isolated from rats instilled in vivo, excluding an effect dependent on continuous neurohumoral activation or systemic inflammatory mediators.Pulmonary diesel exhaust particulate increases blood pressure and has a profound adverse effect on the myocardium, resulting in tissue damage, but also increases vulnerability to ischemia-associated arrhythmia and reperfusion injury.These effects are mediated through activation of pulmonary TRPV1, the sympathetic nervous system and locally generated oxidative stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: BHF/ University Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK. gillian.gray@ed.ac.uk.

ABSTRACT

Background: Clinical studies have now confirmed the link between short-term exposure to elevated levels of air pollution and increased cardiovascular mortality, but the mechanisms are complex and not completely elucidated. The present study was designed to investigate the hypothesis that activation of pulmonary sensory receptors and the sympathetic nervous system underlies the influence of pulmonary exposure to diesel exhaust particulate on blood pressure, and on the myocardial response to ischemia and reperfusion.

Methods & results: 6 h after intratracheal instillation of diesel exhaust particulate (0.5 mg), myocardial ischemia and reperfusion was performed in anesthetised rats. Blood pressure, duration of ventricular arrhythmia, arrhythmia-associated death, tissue edema and reperfusion injury were all increased by diesel exhaust particulate exposure. Reperfusion injury was also increased in buffer perfused hearts isolated from rats instilled in vivo, excluding an effect dependent on continuous neurohumoral activation or systemic inflammatory mediators. Myocardial oxidant radical production, tissue apoptosis and necrosis were increased prior to ischemia, in the absence of recruited inflammatory cells. Intratracheal application of an antagonist of the vanilloid receptor TRPV1 (AMG 9810, 30 mg/kg) prevented enhancement of systolic blood pressure and arrhythmia in vivo, as well as basal and reperfusion-induced myocardial injury ex vivo. Systemic β1 adrenoreceptor antagonism with metoprolol (10 mg/kg) also blocked enhancement of myocardial oxidative stress and reperfusion injury.

Conclusions: Pulmonary diesel exhaust particulate increases blood pressure and has a profound adverse effect on the myocardium, resulting in tissue damage, but also increases vulnerability to ischemia-associated arrhythmia and reperfusion injury. These effects are mediated through activation of pulmonary TRPV1, the sympathetic nervous system and locally generated oxidative stress.

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β1 adrenoceptor blockade in vivo prevented the effects of intratracheal DEP on infarct size, myocardial oxidant stress, apoptosis, cell viability ex vivo. Infarct size was reduced in hearts isolated from DEP instilled (filled columns) compared to controls (open columns) rats when metoprolol was co-administered in vivo (10 mg/kg, i.p., hatched columns a), but not when metoprolol was present only in the perfusate ex vivo (10 μM, hatched column, (a) inset panel). The DEP-induced changes in oxygen-derived free radicals in the coronary perfusate, (electron paramagnetic resonance; EPR, b), number of apoptotic cells (TUNEL staining, c), and loss of cardiomyocyte viability (TTC staining, d) in the left ventricle (LV) were prevented when metoprolol (10 mg/kg, i.p., hatched columns) was administered in vivo at the time of instillation. Results are expressed as mean ± SEM (n = 6), **P < 0.01, ***P < 0.001 versus saline; ##P < 0.01, ###P < 0.001 versus DEP without metoprolol; two-way ANOVA followed by Bonferroni post-hoc test.
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Figure 4: β1 adrenoceptor blockade in vivo prevented the effects of intratracheal DEP on infarct size, myocardial oxidant stress, apoptosis, cell viability ex vivo. Infarct size was reduced in hearts isolated from DEP instilled (filled columns) compared to controls (open columns) rats when metoprolol was co-administered in vivo (10 mg/kg, i.p., hatched columns a), but not when metoprolol was present only in the perfusate ex vivo (10 μM, hatched column, (a) inset panel). The DEP-induced changes in oxygen-derived free radicals in the coronary perfusate, (electron paramagnetic resonance; EPR, b), number of apoptotic cells (TUNEL staining, c), and loss of cardiomyocyte viability (TTC staining, d) in the left ventricle (LV) were prevented when metoprolol (10 mg/kg, i.p., hatched columns) was administered in vivo at the time of instillation. Results are expressed as mean ± SEM (n = 6), **P < 0.01, ***P < 0.001 versus saline; ##P < 0.01, ###P < 0.001 versus DEP without metoprolol; two-way ANOVA followed by Bonferroni post-hoc test.

Mentions: The role of the sympathetic nervous system in mediating the effects of DEP was investigated by administration of the β1 adrenoreceptor selective antagonist, metoprolol (10 mg/kg i.p.), at the time of DEP instillation in vivo. In hearts isolated and buffer-perfused 6 h later, neither the baseline perfusion pressure nor the AAR after ischemia was influenced by prior in vivo β1 adrenoreceptor blockade (Additional file 1: Table S4). However, an influence of DEP on ex vivo reperfusion injury was absent in rats that had received metoprolol at the time of DEP instillation in vivo (Figure 4a). Hearts were not protected when metoprolol was added only to the perfusate ex vivo (Figure 4a, inset), confirming that protection occurs as a result of prevention of β1 adrenoreceptor activation in vivo. In vivo treatment with metoprolol was also effective in reducing DEP-associated oxygen free radical generation (P < 0.01, Figure 4b), apoptotic cell death (Figure 4c), and the corresponding reduction in cardiomyocyte viability prior to I/R (Figure 4d).


Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors.

Robertson S, Thomson AL, Carter R, Stott HR, Shaw CA, Hadoke PW, Newby DE, Miller MR, Gray GA - Part Fibre Toxicol (2014)

β1 adrenoceptor blockade in vivo prevented the effects of intratracheal DEP on infarct size, myocardial oxidant stress, apoptosis, cell viability ex vivo. Infarct size was reduced in hearts isolated from DEP instilled (filled columns) compared to controls (open columns) rats when metoprolol was co-administered in vivo (10 mg/kg, i.p., hatched columns a), but not when metoprolol was present only in the perfusate ex vivo (10 μM, hatched column, (a) inset panel). The DEP-induced changes in oxygen-derived free radicals in the coronary perfusate, (electron paramagnetic resonance; EPR, b), number of apoptotic cells (TUNEL staining, c), and loss of cardiomyocyte viability (TTC staining, d) in the left ventricle (LV) were prevented when metoprolol (10 mg/kg, i.p., hatched columns) was administered in vivo at the time of instillation. Results are expressed as mean ± SEM (n = 6), **P < 0.01, ***P < 0.001 versus saline; ##P < 0.01, ###P < 0.001 versus DEP without metoprolol; two-way ANOVA followed by Bonferroni post-hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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Figure 4: β1 adrenoceptor blockade in vivo prevented the effects of intratracheal DEP on infarct size, myocardial oxidant stress, apoptosis, cell viability ex vivo. Infarct size was reduced in hearts isolated from DEP instilled (filled columns) compared to controls (open columns) rats when metoprolol was co-administered in vivo (10 mg/kg, i.p., hatched columns a), but not when metoprolol was present only in the perfusate ex vivo (10 μM, hatched column, (a) inset panel). The DEP-induced changes in oxygen-derived free radicals in the coronary perfusate, (electron paramagnetic resonance; EPR, b), number of apoptotic cells (TUNEL staining, c), and loss of cardiomyocyte viability (TTC staining, d) in the left ventricle (LV) were prevented when metoprolol (10 mg/kg, i.p., hatched columns) was administered in vivo at the time of instillation. Results are expressed as mean ± SEM (n = 6), **P < 0.01, ***P < 0.001 versus saline; ##P < 0.01, ###P < 0.001 versus DEP without metoprolol; two-way ANOVA followed by Bonferroni post-hoc test.
Mentions: The role of the sympathetic nervous system in mediating the effects of DEP was investigated by administration of the β1 adrenoreceptor selective antagonist, metoprolol (10 mg/kg i.p.), at the time of DEP instillation in vivo. In hearts isolated and buffer-perfused 6 h later, neither the baseline perfusion pressure nor the AAR after ischemia was influenced by prior in vivo β1 adrenoreceptor blockade (Additional file 1: Table S4). However, an influence of DEP on ex vivo reperfusion injury was absent in rats that had received metoprolol at the time of DEP instillation in vivo (Figure 4a). Hearts were not protected when metoprolol was added only to the perfusate ex vivo (Figure 4a, inset), confirming that protection occurs as a result of prevention of β1 adrenoreceptor activation in vivo. In vivo treatment with metoprolol was also effective in reducing DEP-associated oxygen free radical generation (P < 0.01, Figure 4b), apoptotic cell death (Figure 4c), and the corresponding reduction in cardiomyocyte viability prior to I/R (Figure 4d).

Bottom Line: Reperfusion injury was also increased in buffer perfused hearts isolated from rats instilled in vivo, excluding an effect dependent on continuous neurohumoral activation or systemic inflammatory mediators.Pulmonary diesel exhaust particulate increases blood pressure and has a profound adverse effect on the myocardium, resulting in tissue damage, but also increases vulnerability to ischemia-associated arrhythmia and reperfusion injury.These effects are mediated through activation of pulmonary TRPV1, the sympathetic nervous system and locally generated oxidative stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: BHF/ University Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK. gillian.gray@ed.ac.uk.

ABSTRACT

Background: Clinical studies have now confirmed the link between short-term exposure to elevated levels of air pollution and increased cardiovascular mortality, but the mechanisms are complex and not completely elucidated. The present study was designed to investigate the hypothesis that activation of pulmonary sensory receptors and the sympathetic nervous system underlies the influence of pulmonary exposure to diesel exhaust particulate on blood pressure, and on the myocardial response to ischemia and reperfusion.

Methods & results: 6 h after intratracheal instillation of diesel exhaust particulate (0.5 mg), myocardial ischemia and reperfusion was performed in anesthetised rats. Blood pressure, duration of ventricular arrhythmia, arrhythmia-associated death, tissue edema and reperfusion injury were all increased by diesel exhaust particulate exposure. Reperfusion injury was also increased in buffer perfused hearts isolated from rats instilled in vivo, excluding an effect dependent on continuous neurohumoral activation or systemic inflammatory mediators. Myocardial oxidant radical production, tissue apoptosis and necrosis were increased prior to ischemia, in the absence of recruited inflammatory cells. Intratracheal application of an antagonist of the vanilloid receptor TRPV1 (AMG 9810, 30 mg/kg) prevented enhancement of systolic blood pressure and arrhythmia in vivo, as well as basal and reperfusion-induced myocardial injury ex vivo. Systemic β1 adrenoreceptor antagonism with metoprolol (10 mg/kg) also blocked enhancement of myocardial oxidative stress and reperfusion injury.

Conclusions: Pulmonary diesel exhaust particulate increases blood pressure and has a profound adverse effect on the myocardium, resulting in tissue damage, but also increases vulnerability to ischemia-associated arrhythmia and reperfusion injury. These effects are mediated through activation of pulmonary TRPV1, the sympathetic nervous system and locally generated oxidative stress.

Show MeSH
Related in: MedlinePlus