Effect of Particulate and Gaseous Pollutants on Spontaneous Arrhythmias in Aged Rats

Epidemiology studies suggest that exposure to air pollution increases the frequency of cardiac arrhythmias. A limitation of these studies is that it is difficult to link an increased risk of arrhythmias to a specific air pollutant. Animal exposure studies offer the opportunity to examine the effects of concentrated ambient fine particulate matter (PM), ultrafine PM, and copollutant gases separately. Male Fischer 344 rats, aged 18 mo, with implanted electrocardiograph (ECG) transmitters were used to determine the effects of PM on the frequency of arrhythmias. We found that old F344 rats had many spontaneous arrhythmias. An arrhythmia classification system was developed to quantify arrhythmia frequency. Arrhythmias were broadly grouped into two categories: premature beats and delayed beats. The rats were exposed to concentrated ambient PM (CAPS) or air for 4 h. The rats were exposed twice with a crossover design so each rat could serve as its own control. The CAPS concentrations were 160 μ g/m³ and 200 μ g/m³ for the first and second exposures, respectively. There was a significant increase in the frequency of irregular and delayed beats after exposure to CAPS. The same rats were subsequently exposed to laboratory-generated ultrafine carbon particles, to SO₂, or to air with a repeated crossover design. In these experiments there was no significant change in the frequency of any category of spontaneous arrhythmia following exposure to ultrafine carbon or SO₂. Thus, this study adds supporting evidence that acute exposure to elevated levels of ambient PM increases the frequency of cardiac arrhythmias.     

Angiotensin Antagonism in Patients with Heart Failure

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.     

Cardiac Oxidative Stress and Electrophysiological Changes in Rats Exposed to Concentrated Ambient Particles are Mediated by TRP-Dependent Pulmonary Reflexes

Previous studies suggest that, through the stimulation of pulmonarynervous endings, ambient particles modulate the autonomic toneon the heart leading to cardiac oxidant stress and dysfunction.In this paper we investigated the effect of blockade of vanilloidreceptor 1 (Transient Receptor Potential Vanilloid Receptor1 [TRPV1]) on concentrated ambient particles (CAPs)–inducedcardiac oxidative stress and dysfunction in a rat model of inhalationexposure. Capsazepine (CPZ), a selective antagonist of TRPV1,was given ip or as an aerosol immediately before exposure toCAPs. Control and CPZ-treated rats were exposed to filteredair or CAPs aerosols for 5 h using the Harvard Ambient ParticleConcentrator (mean PM_2.5 mass concentration: 218 ± 23µg/m³). At the end of the exposure we measured cardiacoxidative stress (in situ chemiluminescence [CL]), lipid peroxidation(thiobarbituric acid reactive substances [TBARS]), and tissueedema. Cardiac function was monitored throughout the exposure.CPZ (ip or aerosol) decreased CAPs-induced CL, lipid TBARS,and edema in the heart, indicating that blocking TRP receptors,systemically or locally, decreases heart CL. CAPs exposure ledto significant decreases in heart rate (CAPs 350 ± 32bpm, control: 370 ± 29), and in the length of the QT,RT, Pdur and Tpe intervals. These changes were observable immediatelyupon exposure and were maintained throughout the 5 h of CAPsinhalation. Changes in cardiac rhythm and electrocardiogrammorphology were prevented by CPZ. These data suggest that currentabnormalities in CAPs-exposed rats alter the action potentialsleading to changes in conduction velocity and ventricular repolarization,and that triggering of TRPV1-mediated autonomic reflexes inthe lung is essential for the observed changes in cardiac rhythms.     

ACE inhibitors,angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.     

Effect of particulate and gaseous pollutants on spontaneous arrhythmias in aged rats

Epidemiology studies suggest that exposure to air pollution increases the frequency of cardiac arrhythmias. A limitation of these studies is that it is difficult to link an increased risk of arrhythmias to a specific air pollutant. Animal exposure studies offer the opportunity to examine the effects of concentrated ambient fine particulate matter (PM), ultrafine PM, and copollutant gases separately. Male Fischer 344 rats, aged 18 mo, with implanted electrocardiograph (ECG) transmitters were used to determine the effects of PM on the frequency of arrhythmias. We found that old F344 rats had many spontaneous arrhythmias. An arrhythmia classification system was developed to quantify arrhythmia frequency. Arrhythmias were broadly grouped into two categories: premature beats and delayed beats. The rats were exposed to concentrated ambient PM (CAPS) or air for 4 h. The rats were exposed twice with a crossover design so each rat could serve as its own control. The CAPS concentrations were 160 microg/m(3) and 200 microg/m(3) for the first and second exposures, respectively. There was a significant increase in the frequency of irregular and delayed beats after exposure to CAPS. The same rats were subsequently exposed to laboratory-generated ultrafine carbon particles, to SO(2), or to air with a repeated crossover design. In these experiments there was no significant change in the frequency of any category of spontaneous arrhythmia following exposure to ultrafine carbon or SO(2). Thus, this study adds supporting evidence that acute exposure to elevated levels of ambient PM increases the frequency of cardiac arrhythmias.     

Role of chymase in vascular diseases and the efficacy of chymase inhibitor

In vascular tissues, angiotensin II is cleaved from angiotensin I by chymase and angiotensin converting enzyme (ACE). In the normal state, chymase is stored in mast cells and has no angiotensin II-forming activity, while chymase is activated immediately where mast cells have been activated by local stimuli. A clinical trial of an angiotensin receptor blocker (ARB) for preventing restenosis after percutaneous transluminal coronary angioplasty was successful, but that of an ACE inhibitor was not. After balloon injury in dog vessels, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an ARB were effective in preventing the vascular proliferation, but an ACE inhibitor was ineffective. In dog grafted veins, intimal area, chymase activity, and angiotensin II concentration were significantly increased after the operation, while they were significantly suppressed by a chymase inhibitor. However, the chymase inhibitor, unlike ACE inhibitor and ARB, did not affect blood pressure. These reports indicate that local angiotensin II production by chymase is involved only in the injured vessels. Therefore, a chymase inhibitor may be useful for preventing vascular disorders without affecting blood pressure.     

Cardiac and pulmonary oxidative stress in rats exposed to realistic emissions of source aerosols

In vivo chemiluminescence (CL) is a measure of reactive oxygen species in tissues. CL was used to assess pulmonary and cardiac responses to inhaled aerosols derived from aged emissions of three coal-fired power plants in the USA. Sprague-Dawley rats were exposed to either filtered air or: (1) primary emissions (P); (2) ozone oxidized emissions (PO); (3) oxidized emissions + secondary organic aerosol (SOA) (POS); (4) neutralized oxidized emissions + SOA (PONS); and (5) control scenarios: oxidized emissions + SOA in the absence of primary particles (OS), oxidized emissions alone (O), and SOA alone (S). Immediately after 6 hours of exposure, CL in the lung and heart was measured. Tissues were also assayed for thiobarbituric acid reactive substances (TBARS). Exposure to P or PO aerosols led to no changes compared to filtered air in lung or heart CL at any individual plant or when all data were combined. POS caused significant increases in lung CL and TBARS at only one plant, and not in combined data from all plants; PONS resulted in increased lung CL only when data from all plants were combined. Heart CL was also significantly increased with exposure to POS only when data from all plants were combined. PONS increased heart CL significantly in one plant with TBARS accumulation, but not in combined data. Exposure to O, OS, and S had no CL effects. Univariate analyses of individual measured components of the exposure atmospheres did not identify any component associated with increased CL. These data suggest that coal-fired power plant emissions combined with other atmospheric constituents produce limited pulmonary and cardiac oxidative stress.     

Acute renal failure during lisinopril and losartan therapy for proteinuria

The use of combined therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) for treatment of proteinuria has been gaining support. Limited data are available regarding this treatment in the pediatric population. This report describes a case of acute compromise of renal function associated with hypotension in a 7-year-old boy treated with the ACE inhibitor lisinopril and the ARB losartan. It emphasizes the need for close surveillance of renal function and blood pressure during such therapy even in patients with relative preservation of renal function. Further investigation into the utility and safety of dual therapy with an ACE inhibitor plus an ARB in pediatric patients is warranted. Key Words: renal failure, proteinuria, angiotensin-converting enzyme inhibitor, ACEI, angiotensin II receptor blocker, ARB.     

Angiotensin II-receptor blockers: clinical relevance and therapeutic role.

The limitations of angiotensin-converting-enzyme (ACE) inhibitors and the role of angiotensin II-receptor blockers (ARBs) in the treatment of hypertension, heart failure, and diabetic nephropathy are discussed. Although ACE inhibitors are generally well tolerated, two important class-related adverse effects are cough, which is common, and angioedema, which is rare but serious. Cough and angioedema appear to be less frequent with ARBs than with ACE inhibitors. ARBs seem to be as capable as ACE inhibitors of producing renal dysfunction. ARBs may offer more complete inhibition of angiotensin II than ACE inhibitors. The mechanism of action is based on selective binding to angiotensin type 1 receptors. Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including ACE inhibitors. ARBs do not appear to have a greater clinical effect than ACE inhibitors in patients with heart failure. Some studies of combination ARB and ACE inhibitor therapy for heart failure indicate advantages of the combination over therapy with either class. ARBs may exert renal protective effects in diabetic nephropathy. ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.     

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.     

A novel therapeutic strategy against vascular disorders with chymase inhibitor

In vascular tissues, angiotensin II is potentially cleaved from angiotensin I by chymase and angiotensin converting enzyme (ACE). In the normal state, ACE regulates angiotensin II formation and plays a crucial role in the regulation of blood pressure, whereas chymase is stored in mast cells and has no angiotensin II-forming activity. Chymase is activated immediately upon its release into the extracellular matrix in vascular tissues after mast cells have been activated by local stimuli such as vessel injury by grafting or a balloon catheter. In dog grafted veins, vascular proliferation, chymase activity, angiotensin II concentration and mRNA levels of fibronectin, collagen I and collagen III were significantly increased after the operation, while they were significantly suppressed by a chymase inhibitor. A clinical trial of an angiotensin II receptor blocker (ARB) for preventing restenosis after percutaneous transluminal coronary angioplasty was successful, but that of an ACE inhibitor was not. After balloon injury in dog vessels, chymase activity was signifcantly increased in the injured artery, and a chymase inhibitor and an ARB were effective in preventing the vascular proliferation, but an ACE inhibitor was ineffective. On the other hand, a chymase inhibitor, unlike an ACE inhibitor and an ARB, did not affect blood pressure. These reports indicate that local angiotensin II production by chymase is involved only in the intimal hyperplasia seen in the injured vessels. Therefore, chymase inhibitors may be useful for preventing vascular disoders without affecting blood pressure.     

Angiotensin II receptor blockers in heart failure

Heart failure remains a significant cause of morbidity and mortality, despite major advances in therapy. Angiotensin II, the principal mediator of the renin-angiotensin system, exerts both short-term (e.g., hemodynamic, renal) and long-term (e.g., inflammation, cardiac remodeling) effects in the pathophysiology of cardiovascular disease. The effects of angiotensin II appear to be more completely inhibited by angiotensin II receptor blockers (ARBs), which act at the subtype 1 receptor level, than by angiotensin-converting enzyme (ACE) inhibitors because pathways other than that of ACE contribute to the generation of angiotensin II. Evidence demonstrates that ARBs, when added to conventional treatment for patients with heart failure, are associated with a reduction in morbidity and mortality as well as an improvement in quality of life. Clinical trials of ARB therapy indicate that these agents are generally well tolerated, both alone and in combination with other neurohormonal inhibitors. The current role of ARBs in heart failure is as an alternative for patients who cannot tolerate therapy with an ACE inhibitor. A number of ongoing clinical studies are likely to further define or expand the role of ARBs in the treatment of cardiovascular disease.     

A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy

Objective:Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB.Results:The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril).Conclusions:Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection.KEY WORDS: Angiotensin receptor blockers and angiotensin converting enzyme inhibitors, diabetes, diabetic nephropathy     

Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase

It had been believed that angiotensin II (Ang II) was produced by the renin-angiotensin system (RAS), which was established in the 1950's. After a while, people realized that the multiple functions of Ang II could not be explained by the conventional RAS. We have tried to determine the existence of the tissue Ang II generating system. At first, we found that vascular angiotensin-converting enzyme (ACE) was increased to generate local Ang II in the vessels of hypertension and was enhanced in lipid-loaded atherosclerosis, to respond to ACE inhibitor or Ang II antagonist (ARB). In both cases, Ang II production in vessels was independent from the systemic RAS that was estimated by the plasma renin activity. On the way to clarifying the roles of the vascular ACE, we noticed that vascular Ang II production was not completely suppressed by ACE inhibitor alone. This evidence led us to discover different types of chymase as a new Ang II producing enzyme. Now, we have obtained a strategy to distinguish the Ang II one by one, that is, circulating RAS derived, tissue ACE derived, and chymase derived. It is essential to understand not only the intracellular mechanisms of Ang II but also the process of Ang II productions in each disease to show accurate indications of the effectiveness of ACE inhibitor, ARB, and chymase inhibitor.     

The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.     

Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

BACKGROUND AND PURPOSE: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. EXPERIMENTAL APPROACH: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. KEY RESULTS: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. CONCLUSION AND IMPLICATION: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.     

Differential gene expression associated with inflammation and blood pressure regulation induced by concentrated ambient particle exposure

Epidemiological studies have indicated that exposure to particle matter (PM) increased the risk of respiratory and cardiovascular morbidity and mortality. It is suggested that PM smaller than 2.5 μm in aerodynamic diameter (PM_2.5) may contribute to these responses. However, the molecular mechanism is still unknown. To elucidate the changes in molecular level, we investigated the gene expression profile of concentrated ambient particles (CAPs)-exposed rats. Aged F344 rats were exposed with CAPs (594 μg/m³) or clean air 4?h per day for 3 days, and lung and heart tissues were then excised for DNA microarray analysis. Expression profiles related to inflammation and blood pressure regulation revealed differential expression of 7 genes in the lung and that of 3 genes in the heart ventricle. According to the complement activation-associated genes, complement factor B (Bf), complement component 2 and 4a (C4a), and C1 inhibitor genes were up-regulated in CAPs-exposed rat lung. Bf and C4a genes were also up-regulated in the heart. These suggest the treated animal ready for production of these proteins when activation of complement cascade is required. Pro-inflammatory cytokine, interleukin-1β, was also up-regulated in CAPs-exposed rat lung. Gene related with blood pressure regulation (angiotensin I converting enzyme) was also up-regulated in CAPs-exposed rat lung. Negative regulator of blood pressure (neuropeptide Y) was down-regulated in CAPs-exposed rat heart. These results indicate that CAPs may affect respiratory and cardiovascular organs by activation of inflammatory responses and disintegration of blood pressure regulation in early stage of CAPs exposure.     

Potentiation by enalaprilat of fenoldopam-evoked natriuresis is due to blockade of intrarenal production of angiotensin-II in rats

We have previously shown that the natriuretic response to DA-1 receptor agonist fenoldopam is markedly potentiated by angiotensin converting enzyme inhibitor captopril. Since inhibition of angiotensin converting enzyme can lead to decreased production of angiotensin-II and increased levels of kinins (e.g., bradykinin), it is likely that both of these mechanisms might be involved in this phenomenon. However, it is not known whether and to what degree the accumulation of kinins contributes to the overall potentiation of natriuretic response to fenoldopam seen during angiotensin converting enzyme inhibition. In the present study, we have examined the effect of angiotensin converting enzyme inhibitor enalaprilat and angiotensin-II receptor antagonist losartan as well as bradykinin-2 receptor antagonist HOE 140 on fenoldopam-induced natriuresis. Intravenous infusion of fenoldopam (1 g/kg/min) for 30 min produced significant increases in urine output and urinary sodium excretion without causing any changes in glomerular filtration rate, renal blood flow and mean arterial blood pressure, a phenomenon suggestive of a direct tubular site of action. In animals treated with either the angiotensin converting enzyme inhibitor enalaprilat or angiotensin-II receptor antagonist losartan, the diuretic and natriuretic effects of fenoldopam were potentiated to a similar degree. Whereas no significant changes in glomerular filtration rate occurred when fenoldopam alone was given to control rats, in animals treated with either enalaprilat or losartan, fenoldopam produced a modest but significant increase in glomerular filtration rate. In a separate group of animals, the effects of bradykinin-2 receptor antagonist HOE 140 on potentiation of fenoldopam-induced natriuresis by enalaprilat was examined. It was found that the magnitude of changes in urine output, sodium excretion and glomerular filtration rate in animals receiving pretreatment with both enalaprilat and HOE 140 were similar to those with enalaprilat pretreatment alone. These findings suggest that the potentiation of natriuretic response to fenoldopam by enalaprilat is solely due to blockade of angiotensin-II production and kinins do not appear to contribute to this phenomenon.Abbreviations DA Dopamine - JG Juxtaglomerular - Ang II Angiotensin II - ACE Angiotensin converting enzyme     

Controlled Exposures of Healthy and Asthmatic Volunteers to Concentrated Ambient Fine Particles in Los Angeles

Information about health effects from controlled exposure to particulate matter (PM) air pollution is relatively limited but potentially critical in urban locations such as Los Angeles, where abundant mobile sources generate combustion-related particles. Nonsmoking healthy (n = 12) and asthmatic (n = 12) volunteers, age 18-45 yr, were exposed to concentrated ambient particulates (CAP) in the fine (PM 2.5) size range at an average concentration of 174 µg/m 3 (range 99-224), and to filtered air (FA). Exposures used a two-stage Harvard virtual-impactor concentrator and whole-body chamber and lasted 2 h with alternating rest-exercise periods. Neither group showed significant (p < .05) changes in spirometry or routine hematologic measurements attributable to CAP exposure, relative to FA. Both groups showed CAP-related decreases of columnar cells in postexposure induced sputum, slight changes in certain mediators of blood coagulability and systemic inflammation, and modest increases in parasympathetic stimulation of heart rate variability. Systolic blood pressure decreased in asthmatics and increased in healthy subjects during CAP exposure relative to FA. Cardiovascular (but not respiratory) symptoms increased slightly with CAP in both groups. In summary, the urban fine PM exposures elicited different biologic endpoints with statistically significant differences between CAP and FA. The observed changes in blood inflammation and heart-rate variability were consistent with systemic (rather than respiratory) effects reported from other laboratory and epidemiologic studies. Further studies involving other biologic endpoints, PM size modes, and risk factors will be needed to clarify these results.     

Comparative electrocardiographic,autonomic and systemic inflammatory responses to soy biodiesel and petroleum diesel emissions in rats

Abstract

Context: Biodiesel fuel represents an alternative to high particulate matter (PM)-emitting petroleum-based diesel fuels, yet uncertainty remains regarding potential biodiesel combustion emission health impacts.

Objective: The purpose of this study was to compare cardiovascular responses to pure and blended biodiesel fuel emissions relative to petroleum diesel exhaust (DE).

Materials and methods: Spontaneously hypertensive rats were exposed for 4?h per day for four days via whole body inhalation to combustion emissions (based on PM concentrations 50, 150 or 500?μg/m³ or filtered air) from pure (B100) or blended (B20) soy biodiesel, or to pure petroleum DE (B0). Electrocardiogram (ECG) and heart rate variability (HRV, an index of autonomic balance) were monitored before, during and after exposure while pulmonary and systemic inflammation were assessed one day after the final exposure. ECG and HRV data and inflammatory data were statistically analyzed using a linear mixed model for repeated measures and an analysis of variance, respectively.

Results: B100 and B0, but not B20, increased HRV during all exposure days at the highest concentration indicating increased parasympathetic tone. Electrocardiographic data were mixed. B100 and B0, but not B20, caused significant changes in one or more of the following: serum C-reactive protein, total protein, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, and blood urea nitrogen (BUN) and plasma angiotensin converting enzyme (ACE) and fibrinogen.

Discussion and conclusions: Although responses to emissions from all fuels were mixed and relatively mild, some findings point to a reduced cardiovascular impact of blended biodiesel fuel emissions.