PM exposure leads to some of the same alterations in cardiac function and structure (reviewed in (Godleski 2006)) by mechanisms that seem to involve increases in ROS (Ghelfi 2008; Rhoden 2005). heart oxidative stress (CL, TBARs), and a shortening of the T-end to T-peak interval around the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. INTRODUCTION Ambient air pollution is a recognized risk factor for cardiovascular morbidity and mortality (Brook 2004). Short-term elevations in ambient particulate matter (PM) have been specifically implicated in the triggering of acute cardiovascular events including myocardial infarction (DIppoliti 2003; Peters 2001; Zanobetti and Schwartz 2005), ventricular arrhythmias (Dockery 2005; Peters 2000) (Rich 2005), heart failure exacerbations (Dominici 2006; Schwartz and Morris 1995), and ischemic stroke (Hong 2002; Tsai 2003; Wellenius 2005). The mechanisms underlying these observations are only partially comprehended. One important mechanistic pathway for cardiac health effects appears to be autonomic nervous system dysfunction. Short-term exposure to PM is associated with changes in heart rate variability (Creason 2001; Devlin 2003; Godleski 2000; Gold 2000; Holguin 2003; Liao 1999; Pope 1999), a quantitative, non-invasive marker of cardiac autonomic nervous system control. The changes reported in these studies are consistent with perturbations of both sympathetic and parasympathetic nervous system activity. We have previously shown that instillation exposure of rats to PM results in oxidant-dependent increases in both sympathetic and parasympathetic activity (Rhoden 2005), at least in part, by activation of pulmonary unmyelinated C-fibers (Ghelfi 2008). Cohort and panel studies have found that increases in the PM levels are associated not only with decreased heart rate variability and other cardiac outcomes, but also with changes in vascular parameters i.e. blood viscosity, increased blood pressure, and increase levels of thrombosis markers in circulation (reviewed in (Godleski 2006)). The mechanistic link between activation of pulmonary reflexes and these outcomes remains to be characterized. Angiotensin-II, the final active messenger of the reninCangiotensin system, has multiple biological actions including vasoconstriction, stimulation of myocytes, and facilitation of norepinephrine release from sympathetic neurons (Martin 2004). These actions are mediated through the binding of Angiotensin-II to Angiotensin-II type 1 receptors (AT1), which belong to the G protein coupled receptor (GPCR) superfamily (Martin 2004; Zisman 1998). Angiotensin-II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular tone (Brown and Vaughan 1998). Animal studies show that Angiotensin-II has effects on both limbs of the autonomic nervous system, simultaneously facilitating sympathetic activity and inhibiting vagal activity on the heart (Joy and Lowe 1970; Rechtman and Majewski 1993; Zimmerman 1993). Angiotensin-II increases the production of superoxide anion via stimulation of NAD(P)H oxidase, and the resulting oxidative stress has been postulated as an important mediator of Angiotensin-II signaling (Hanna 2002; Zhang 1999). Angiotensin-II also upregulates mRNA and protein expression of most NAD(P)H oxidase subunits (Rueckschloss 2002) and (Mollnau 2202). Thus angiotensin-II is a possible important link between the pulmonary and cardiovascular effects of PM. In this paper we investigated angiotensin-II involvement in the cardiotoxicity of PM by using inhibitors of its synthesis or binding. MATERIALS AND METHODS Adult Sprague Dawley rats were maintained and studied in accordance with the National Institutes of Health guidelines for the care and use of animals in research and all protocols were approved by the Harvard Medical Area Standing Committee on Animals. In a first.PM-Induced Cardiac Oxidative Stress Is Mediated by Autonomic Stimulation. and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. INTRODUCTION Ambient air pollution is a recognized risk factor for cardiovascular morbidity and mortality (Brook 2004). Short-term elevations in ambient particulate matter (PM) have been specifically implicated in the triggering of acute cardiovascular events including myocardial infarction (DIppoliti 2003; Peters 2001; Zanobetti and Schwartz 2005), ventricular arrhythmias (Dockery 2005; Peters 2000) (Rich 2005), heart failure exacerbations (Dominici 2006; Schwartz and Morris 1995), and ischemic stroke (Hong 2002; Tsai 2003; Wellenius 2005). The mechanisms underlying these observations are only partially understood. One important mechanistic pathway for cardiac health effects appears to be autonomic nervous system dysfunction. Short-term exposure to PM is associated with changes in heart rate variability (Creason 2001; Devlin 2003; Godleski 2000; Gold 2000; Holguin 2003; Liao 1999; Pope 1999), a quantitative, non-invasive marker of cardiac autonomic nervous system control. The changes reported in Bilobalide these studies are consistent with perturbations of both sympathetic and parasympathetic nervous system activity. We have previously shown that instillation exposure of rats to PM results in oxidant-dependent increases in both sympathetic and parasympathetic activity (Rhoden 2005), at least in part, by activation of pulmonary unmyelinated C-fibers (Ghelfi 2008). Cohort and panel studies have found that increases in the PM levels are associated not only with decreased heart rate variability and other cardiac outcomes, but also with changes in vascular parameters i.e. blood viscosity, increased blood pressure, and increase levels of thrombosis markers in circulation (reviewed in (Godleski 2006)). The mechanistic link between activation of pulmonary reflexes and these outcomes remains to be characterized. Angiotensin-II, the final active messenger of the reninCangiotensin system, has multiple biological actions including vasoconstriction, stimulation of myocytes, and facilitation of norepinephrine release from sympathetic neurons (Martin 2004). These actions are mediated through the binding of Angiotensin-II to Angiotensin-II type 1 receptors (AT1), which belong to the G protein coupled receptor (GPCR) superfamily (Martin 2004; Zisman 1998). Angiotensin-II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular firmness (Brown and Vaughan 1998). Animal studies show that Angiotensin-II offers effects on both limbs of the autonomic nervous system, simultaneously facilitating sympathetic activity and inhibiting vagal activity within the heart (Joy and Lowe 1970; Rechtman and Majewski 1993; Zimmerman 1993). Angiotensin-II increases the production of superoxide anion via activation of NAD(P)H oxidase, and the producing oxidative stress has been postulated as an important mediator of Angiotensin-II signaling (Hanna 2002; Zhang 1999). Angiotensin-II also upregulates mRNA and protein expression of most NAD(P)H oxidase subunits (Rueckschloss 2002) and (Mollnau 2202). Therefore angiotensin-II is definitely a possible important link between the pulmonary and cardiovascular effects of PM. With this paper we investigated angiotensin-II involvement in the cardiotoxicity of PM by using inhibitors of its synthesis or binding. MATERIALS AND METHODS Adult Sprague Dawley rats were maintained and analyzed in accordance with the National Institutes of Health recommendations for the care and use of animals in study and.2003;40:76sC80s. TBARs), and a shortening of the T-end to T-peak interval within the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results display that ambient good particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. Intro Ambient air pollution is a recognized risk element for cardiovascular morbidity and mortality (Brook 2004). Short-term elevations in ambient particulate P1-Cdc21 matter (PM) have been specifically implicated in the triggering of acute cardiovascular events including myocardial infarction (DIppoliti 2003; Peters 2001; Zanobetti and Schwartz 2005), ventricular arrhythmias (Dockery 2005; Peters 2000) (High 2005), heart failure exacerbations (Dominici 2006; Schwartz and Morris 1995), and ischemic stroke (Hong 2002; Tsai 2003; Wellenius 2005). The mechanisms underlying these observations are only partially recognized. One important mechanistic pathway for cardiac health effects appears to be autonomic nervous system dysfunction. Short-term exposure to PM is associated with changes in heart rate variability (Creason 2001; Devlin 2003; Godleski 2000; Platinum 2000; Holguin 2003; Liao 1999; Pope 1999), a quantitative, non-invasive marker of cardiac autonomic nervous system control. The changes reported in these studies are consistent with perturbations of both sympathetic and parasympathetic nervous system activity. We have previously demonstrated that instillation exposure of rats to PM results in oxidant-dependent raises in both sympathetic and parasympathetic activity (Rhoden 2005), at least in part, by activation of pulmonary unmyelinated C-fibers (Ghelfi 2008). Cohort and panel studies have found that raises in the PM levels are associated not only with decreased heart rate variability and additional cardiac results, but also with changes in vascular guidelines i.e. blood viscosity, increased blood pressure, and increase levels of thrombosis markers in blood circulation (examined in (Godleski 2006)). The mechanistic link between activation of pulmonary reflexes and these results remains to be characterized. Angiotensin-II, the final active messenger of the reninCangiotensin system, offers multiple biological actions including vasoconstriction, activation of myocytes, and facilitation of norepinephrine launch from sympathetic neurons (Martin 2004). These actions are mediated through the binding of Angiotensin-II to Angiotensin-II type 1 receptors (AT1), which belong to the G protein coupled receptor (GPCR) superfamily (Martin 2004; Zisman 1998). Angiotensin-II interacts with the sympathetic nervous system both peripherally and centrally to increase vascular firmness (Brown and Vaughan 1998). Animal studies show that Angiotensin-II offers effects on both limbs of the autonomic nervous system, simultaneously facilitating sympathetic activity and inhibiting vagal activity within the heart (Joy and Lowe 1970; Rechtman and Majewski 1993; Zimmerman 1993). Angiotensin-II increases the production of superoxide anion via activation of NAD(P)H oxidase, and the producing oxidative stress has been postulated as an important mediator of Angiotensin-II signaling (Hanna 2002; Zhang 1999). Angiotensin-II also upregulates mRNA and protein expression of most NAD(P)H oxidase subunits (Rueckschloss 2002) and (Mollnau 2202). Therefore angiotensin-II is definitely a possible important link between the pulmonary and cardiovascular effects of PM. With this paper we investigated angiotensin-II involvement in the cardiotoxicity of PM by using inhibitors of its synthesis or binding. MATERIALS AND METHODS Adult Sprague Dawley rats were maintained and analyzed in accordance with the National Institutes of Health recommendations for the care and use of animals in research and all protocols were authorized by the Harvard Medical Area Standing up Committee on Animals. In an initial set of tests, a complete of 80 unrestrained, mindful pets had been open once for 5 hours to either great PM or filtered atmosphere. By the end from the publicity the pets had been examined for oxidative tension measure by chemiluminescence (CL) and lipid peroxidation assessed by thiobarbituric acidity reactive chemicals (TBARS), as referred to below. Bloodstream examples were taken up to measure angiotensin-II and creatinine amounts in plasma also. A complete of 14 exposures, each on the different day, had been run over an interval of six months. In another series of tests yet another 8 rats had been open for 5 hours to either great PM (Hats) or filtered atmosphere (sham). A complete of 11 exposures were performed more than a 4-month period repeatedly. Rats had been housed on the Harvard College of Public Wellness.Angiotensin II-induced superoxide anion era in individual vascular endothelial cells: function of membrane-bound NADH-/NADPH-oxidases. to boosts in angiotensin above the PM-only level. PM publicity also resulted in significant boosts in center oxidative Bilobalide tension (CL, TBARs), and a shortening from the T-end to T-peak period in the ECG which were avoided by treatment with both ACE inhibitor and ARB. These outcomes present that ambient great particles can boost plasma degrees of angiotensin-II and recommend a job from the renin-angiotensin program in the introduction of particle-related severe cardiac events. Launch Ambient polluting of the environment is an established risk aspect for cardiovascular morbidity and mortality (Brook 2004). Short-term elevations in ambient particulate matter (PM) have already been particularly implicated in the triggering Bilobalide of severe cardiovascular occasions including myocardial infarction (DIppoliti 2003; Peters 2001; Zanobetti and Schwartz 2005), ventricular arrhythmias (Dockery 2005; Peters 2000) (Affluent 2005), center failing exacerbations (Dominici 2006; Schwartz and Morris 1995), and ischemic heart stroke (Hong 2002; Tsai 2003; Wellenius 2005). The systems root these observations are just partially grasped. One essential mechanistic pathway for cardiac wellness effects is apparently autonomic anxious program dysfunction. Short-term contact with PM is connected with adjustments in heartrate variability (Creason 2001; Devlin 2003; Godleski 2000; Yellow metal 2000; Holguin 2003; Liao 1999; Pope 1999), a quantitative, noninvasive marker of cardiac autonomic anxious program control. The adjustments reported in these research are in keeping with perturbations of both sympathetic and parasympathetic anxious program activity. We’ve previously proven that instillation publicity of rats to PM leads to oxidant-dependent boosts in both sympathetic and parasympathetic activity (Rhoden 2005), at least partly, by activation of pulmonary unmyelinated C-fibers (Ghelfi 2008). Cohort and -panel studies have discovered that boosts in the PM amounts are associated not merely with decreased heartrate variability and various other cardiac final results, but also with adjustments in vascular variables i.e. bloodstream viscosity, increased blood circulation pressure, and boost degrees of thrombosis markers in blood flow (evaluated in (Godleski 2006)). The mechanistic hyperlink between activation of pulmonary reflexes and these final results remains to become characterized. Angiotensin-II, the ultimate active messenger from the reninCangiotensin program, provides multiple biological activities including vasoconstriction, excitement of myocytes, and facilitation of norepinephrine discharge from sympathetic neurons (Martin 2004). These activities are mediated through the binding of Angiotensin-II to Angiotensin-II type 1 receptors (AT1), which participate in the G proteins combined receptor (GPCR) superfamily (Martin 2004; Zisman 1998). Angiotensin-II interacts using the sympathetic anxious program both peripherally and centrally to improve vascular shade (Dark brown and Vaughan 1998). Pet studies also show that Angiotensin-II provides results on both limbs from the autonomic anxious program, concurrently facilitating sympathetic activity and inhibiting vagal activity in the center (Pleasure and Lowe 1970; Rechtman and Majewski 1993; Zimmerman 1993). Angiotensin-II escalates the creation of superoxide anion via excitement of NAD(P)H oxidase, as well as the ensuing oxidative stress continues to be postulated as a significant mediator of Angiotensin-II signaling (Hanna 2002; Zhang 1999). Angiotensin-II also upregulates mRNA and proteins expression of all NAD(P)H oxidase subunits (Rueckschloss 2002) and (Mollnau 2202). Therefore angiotensin-II can be a possible essential link between your pulmonary and cardiovascular ramifications of PM. With this paper we looked into angiotensin-II participation in the cardiotoxicity of PM through the use of inhibitors of its synthesis or binding. Components AND Strategies Adult Sprague Dawley rats had been maintained and researched relative to the Country wide Institutes of Wellness recommendations for the treatment and usage of pets in research and everything protocols had been authorized by the Harvard Medical Region Standing up Committee on Pets. In an initial set of tests, a complete of 80 unrestrained, mindful pets.[PMC free content] [PubMed] [Google Scholar]Liao D, Creason J, Timid C, Williams R, W R, Zweidinger R. using the ACE inhibitor reduced angiotensin focus, whereas ARB treatment resulted in raises in angiotensin above the PM-only level. PM publicity also resulted in significant raises in center oxidative tension (CL, TBARs), and a shortening from the T-end to T-peak period for the ECG which were avoided by treatment with both ACE inhibitor and ARB. These outcomes display that ambient good particles can boost plasma degrees of angiotensin-II and recommend a job from the renin-angiotensin program in the introduction of particle-related severe cardiac events. Intro Ambient polluting of the environment is an established risk element for cardiovascular morbidity and mortality (Brook 2004). Short-term elevations in ambient particulate matter (PM) have already been particularly implicated in the triggering of severe cardiovascular occasions including myocardial infarction (DIppoliti 2003; Peters 2001; Zanobetti and Schwartz 2005), ventricular arrhythmias (Dockery 2005; Peters 2000) (Affluent 2005), center failing exacerbations (Dominici 2006; Schwartz and Morris 1995), and ischemic heart stroke (Hong 2002; Tsai 2003; Wellenius 2005). The systems root these observations are just partially realized. One essential mechanistic pathway for cardiac wellness effects is apparently autonomic anxious program dysfunction. Short-term contact with PM is connected with adjustments in heartrate variability (Creason 2001; Devlin 2003; Godleski 2000; Yellow metal 2000; Holguin 2003; Liao 1999; Pope 1999), a quantitative, noninvasive marker of cardiac autonomic anxious program control. The adjustments reported in these research are in keeping with perturbations of both sympathetic and parasympathetic anxious program activity. We’ve previously demonstrated that instillation publicity of rats to PM leads to oxidant-dependent raises in both sympathetic and parasympathetic activity (Rhoden 2005), at least partly, by activation of pulmonary unmyelinated C-fibers (Ghelfi 2008). Cohort and -panel studies have discovered that raises in the PM amounts are associated not merely with decreased heartrate variability and additional cardiac results, but also with adjustments in vascular guidelines i.e. bloodstream viscosity, increased blood circulation pressure, and boost degrees of thrombosis markers in blood flow (evaluated in (Godleski 2006)). The mechanistic hyperlink between activation of pulmonary reflexes and these results remains to become characterized. Angiotensin-II, the ultimate active messenger from the reninCangiotensin program, offers multiple biological activities including vasoconstriction, excitement of myocytes, and facilitation of norepinephrine launch from sympathetic neurons (Martin 2004). These activities are mediated through the binding of Angiotensin-II to Angiotensin-II type 1 receptors (AT1), which participate in the G proteins combined receptor (GPCR) superfamily (Martin 2004; Zisman 1998). Angiotensin-II interacts using the sympathetic anxious program both peripherally and centrally to improve vascular shade (Dark brown and Vaughan 1998). Pet studies also show that Angiotensin-II offers results on both limbs from the autonomic anxious program, concurrently facilitating sympathetic activity and inhibiting vagal activity for the center (Pleasure and Lowe 1970; Rechtman and Majewski 1993; Zimmerman 1993). Angiotensin-II escalates the creation of superoxide anion via excitement of NAD(P)H oxidase, as well as the ensuing oxidative stress continues to Bilobalide be postulated as a significant mediator of Angiotensin-II signaling (Hanna 2002; Zhang 1999). Angiotensin-II also upregulates mRNA and proteins expression of all NAD(P)H oxidase subunits (Rueckschloss 2002) and (Mollnau 2202). Hence angiotensin-II is normally a possible essential link between your pulmonary and cardiovascular ramifications of PM. Within this paper we looked into angiotensin-II participation in the cardiotoxicity of PM through the use of inhibitors of its synthesis or binding. Components AND Strategies Adult Sprague Dawley rats had been maintained and examined relative to the Country wide Institutes of Wellness suggestions for the treatment and usage of pets in research and everything protocols had been accepted by the Harvard Medical Region Position Committee on Pets. In an initial set of tests, a complete of 80 unrestrained, mindful pets had been shown once for 5 hours to either great PM or filtered surroundings. By the end from the publicity the pets had been examined for oxidative tension measure by chemiluminescence (CL) and lipid peroxidation assessed by thiobarbituric acidity reactive chemicals (TBARS), as defined below. Blood examples had been also taken up to measure angiotensin-II and creatinine amounts in plasma. A complete of 14 exposures, each on the different day, had been run over an interval of six months. In another series of tests yet another 8 rats had been shown for 5 hours to either great PM (Hats) or filtered surroundings (sham). A complete of 11 exposures had been performed repeatedly more than a 4-month period. Rats had been housed on the Harvard College of Public Wellness animal facility through the 7-14 times between one publicity and the various other. During each publicity we utilized radio telemetry to record the electrocardiogram (ECG) and evaluated cardiac function. In both tests,.