[Pain therapy in obstetrics]. / Schmerztherapie in der Geburtshilfe.

Labor pains can be stronger than pain caused by fractures and as a result of fear and stress can even have a negative effect on the course of parturition. A proportion of 75% of all women in labor use one or more supportive forms of analgesia to relieve labor pains. The procedures used range from supportive non-pharmacological measures, single intramuscular or intravenous analgesics and a prolonged inhalative analgesia up to highly efficient neuraxial blocks. Non-pharmacological interventions are considered to be generally safe but poorly effective. In contrast, pharmacological and invasive interventions are proven to be effective for analgesia but associated with potential side effects.

[Depression and heart failure - a twofold hazard? : Diagnosis, prognostic relevance and treatment of an underestimated comorbidity]. / Depression und Herzinsuffizienz ­ doppeltes Risiko? : Diagnostik, prognostische Bedeutung und Therapie einer unterschätzten Komorbidität.

Heart failure and depression are widespread diseases and of particular clinical and economic relevance. Compared with the general population depression is up to 5­times more common in patients with heart failure, with adverse effects on morbidity, mortality, quality of life and treatment costs. Depressive symptoms overlap with those of heart failure which renders diagnosis difficult. Simple screening tools, e. g. the two-item patient health questionnaire, help to recognize depression in the clinical routine. To date, there is no evidence that antidepressant pharmacotherapy improves mood and clinical outcomes in patients with heart failure and comorbid depression and antidepressant pharmacotherapy remains to be decided on a case by case basis; however, physical training, cognitive behavioral therapy and multidisciplinary comprehensive disease management improved symptoms and/or prognosis in a limited number of randomized studies.

I.V. APD421 (amisulpride) prevents postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) remain significant clinical problems for patients, especially nausea. The D2-antagonist droperidol was popular for prophylaxis until safety concerns limited its use. In early testing, APD421 (amisulpride for i.v. injection), a D2/D3-antagonist, has shown promising antiemetic efficacy at very low doses. We conducted a randomized, double-blind, dose-finding study to investigate APD421 in PONV prophylaxis. METHODS: Adult surgical patients with ≥2 Apfel risk factors for PONV undergoing surgery expected to last ≥1 h and receiving standard inhalation anaesthesia were randomized to receive placebo or one of three doses of APD421 (1, 5, or 20 mg) as a single i.v. administration at anaesthesia induction. The primary endpoint was PONV (vomiting/retching or antiemetic rescue) in the 24 h period after surgery. RESULTS: Two hundred and fifteen patients received study drug, 92% female and 60% with ≥3 risk factors. Groups were well balanced for baseline characteristics and risk factors. The PONV incidence was 37/54 [69%; 90% confidence interval (CI), 57-79%] in the placebo group; 28/58 (48%; 90% CI, 37-60%) with 1 mg APD421 (P=0.048); 20/50 (40%; 90% CI, 28-53%) with 5 mg (P=0.006); and 30/53 (57%; 90% CI, 44-68%) with 20 mg (P>0.1). APD421 at 5 mg also significantly improved vomiting, rescue medication use, and nausea rates. The safety profile of APD421 was similar to that of placebo at all doses, with no significant central nervous system (CNS) or cardiac side-effects. CONCLUSIONS: APD421 given i.v. before surgery is safe and effective at reducing PONV in moderate/high-risk adult surgical patients. The optimal dose tested was 5 mg.

Comorbid depression in heart failure.

Heart failure (HF) is highly prevalent and associated with adverse outcomes and high costs. Compared with the general population, depression is up to five times more common in HF patients. Comorbid depression increases morbidity and mortality risk and health-care expenditures even further and decreases quality of life. Possible, often interrelated, mediators of these effects include biological, behavioral, and psychosocial factors. Screening instruments such as the self-administered PHQ-2 facilitate detection of patients at risk. Although antidepressants may improve psychological well-being, no positive effects on hard clinical endpoints have been demonstrated to date.

Cytoskeletal role in protection of the failing heart by ß-adrenergic blockade.

Formation of a dense microtubule network that impedes cardiac contraction and intracellular transport occurs in severe pressure overload hypertrophy. This process is highly dynamic, since microtubule depolymerization causes striking improvement in contractile function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1 and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant myocardial microtubule-associated protein (MAP)4, which then decorates and stabilizes microtubules. This persistent phosphatase activation is dependent upon ongoing upstream activity of p21-activated kinase-1, or Pak1. Because cardiac ß-adrenergic activity is markedly and continuously increased in decompensated hypertrophy, and because ß-adrenergic activation of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on ß-adrenergic overdrive and thus could be reversed by ß-adrenergic blockade. The data in this study, which were designed to answer this question, show that such is the case; that is, ß(1)- (but not ß(2)-) adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network. These data were gathered in a feline model of severe right ventricular (RV) pressure overload hypertrophy in response to tight pulmonary artery banding (PAB) in which a stable, twofold increase in RV mass is reached by 2 wk after pressure overloading. After 2 wk of hypertrophy induction, these PAB cats during the following 2 wk either had no further treatment or had ß-adrenergic blockade. The pathological microtubule phenotype and the severe RV cellular contractile dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed in the treated (PAB ß-Blockade) cats. Thus these data provide both a specific etiology and a specific remedy for the abnormal microtubule network found in some forms of pathological cardiac hypertrophy.

Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy.

Increased activity of Ser/Thr protein phosphatases types 1 (PP1) and 2A (PP2A) during maladaptive cardiac hypertrophy contributes to cardiac dysfunction and eventual failure, partly through effects on calcium metabolism. A second maladaptive feature of pressure overload cardiac hypertrophy that instead leads to heart failure by interfering with cardiac contraction and intracellular transport is a dense microtubule network stabilized by decoration with microtubule-associated protein 4 (MAP4). In an earlier study we showed that the major determinant of MAP4-microtubule affinity, and thus microtubule network density and stability, is site-specific MAP4 dephosphorylation at Ser-924 and to a lesser extent at Ser-1056; this was found to be prominent in hypertrophied myocardium. Therefore, in seeking the etiology of this MAP4 dephosphorylation, we looked here at PP2A and PP1, as well as the upstream p21-activated kinase 1, in maladaptive pressure overload cardiac hypertrophy. The activity of each was increased persistently during maladaptive hypertrophy, and overexpression of PP2A or PP1 in normal hearts reproduced both the microtubule network phenotype and the dephosphorylation of MAP4 Ser-924 and Ser-1056 seen in hypertrophy. Given the major microtubule-based abnormalities of contractile and transport function in maladaptive hypertrophy, these findings constitute a second important mechanism for phosphatase-dependent pathology in the hypertrophied and failing heart.

Aging and susceptibility to toluene in rats: a pharmacokinetic, biomarker, and physiological approach.

Aging adults are a growing segment of the U.S. population and are likely to exhibit increased susceptibility to many environmental toxicants. However, there is little information on the susceptibility of the aged to toxicants. The toxicity of toluene has been well characterized in young adult rodents but there is little information in the aged. Three approaches were used: (1) pharmacokinetic (PK), (2) cardiac biomarkers, and (3) whole-animal physiology to assess whether aging increases susceptibility to toluene in the Brown Norway (BN) rat. Three life stages, young adult, middle aged, and aged (4, 12, and 24 mo, respectively), were administered toluene orally at doses of 0, 0.3, 0.65, or 1 g/kg and subjected to the following: terminated at 45 min or 4 h post dosing, and blood and brain toluene concentration were measured; terminated at 4 h post dosing, and biomarkers of cardiac function were measured; or monitor heart rate (HR), core temperature (Tc), and motor activity (MA) by radiotelemetry before and after dosing. Brain toluene concentration was significantly elevated in aged rats at 4 h after dosing with either 0.3 or 1 g/kg. Blood toluene concentrations were unaffected by age. There were various interactions between aging and toluene-induced effects on cardiac biomarkers. Most notably, toluene exposure led to reductions in mRNA markers for oxidative stress in aged but not younger animals. Toluene also produced a reduction in cardiac endothelin-1 in aged rats. Higher doses of toluene led to tachycardia, hypothermia, and a transient elevation in MA. Aged rats were less sensitive to the tachycardic effects of toluene but showed a prolonged hypothermic response. Elevated brain levels of toluene in aged rats may be attributed to their suppressed cardiovascular and respiratory responses. The expression of several cardiac biochemical markers of toluene exposure in the aged may also reflect differential susceptibility to this toxicant.

[Execution of analgesia and anesthesia procedures in obstetrics : Second revised recommendations of the German Society for Anesthesiology and Intensive Care Medicine and the Professional Association of German Anesthetists in cooperation with the German Society for Gynecology and Obstetrics]. / Durchführung von Analgesie- und Anästhesieverfahren in der Geburtshilfe : Zweite überarbeitete Empfehlungen der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und des Berufsverbandes Deutscher Anästhesisten in Zusammenarbeit mit der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe.

While guidelines represent systematically developed aids for decision-making on appropriate courses of action, recommendations should focus the attention of the medical profession on noteworthy circumstances which are in need of amendment. The new recommendations on the "Execution of analgesia and anesthesia procedures in obstetrics" of the German Society for Anesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin, DGAI) and the Professional Association of German Anesthetists (Berufsverband Deutscher Anästhesisten, BDA) in cooperation with the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) comprehensively fulfill these requirements. The new recommendations include not only revisions in the form of updating but also supplementations in the form of the new chapters "Initial care of newborns", "Postpartum hemorrhaging" and "Morbid obesity". In the following article relevant alterations to newly formulated or completely amended sections with consequences for the clinical practice will be discussed.

One-month diesel exhaust inhalation produces hypertensive gene expression pattern in healthy rats.

BACKGROUND: Exposure to diesel exhaust (DE) is linked to vasoconstriction, endothelial dysfunction, and myocardial ischemia in compromised individuals. OBJECTIVE: We hypothesized that DE inhalation would cause greater inflammation, hematologic alterations, and cardiac molecular impairment in spontaneously hypertensive (SH) rats than in healthy Wistar Kyoto (WKY) rats. METHODS AND RESULTS: Male rats (12-14 weeks of age) were exposed to air or DE from a 30-kW Deutz engine at 500 or 2,000 microg/m3, 4 hr/day, 5 days/week for 4 weeks. Neutrophilic influx was noted in the lung lavage fluid of both strains, but injury markers were minimally changed. Particle-laden macrophages were apparent histologically in DE-exposed rats. Lower baseline cardiac anti-oxidant enzyme activities were present in SH than in WKY rats; however, no DE effects were noted. Cardiac mitochondrial aconitase activity decreased after DE exposure in both strains. Electron microscopy indicated abnormalities in cardiac mitochondria of control SH but no DE effects. Gene expression profiling demonstrated alterations in 377 genes by DE in WKY but none in SH rats. The direction of DE-induced changes in WKY mimicked expression pattern of control SH rats without DE. Most genes affected by DE were down-regulated in WKY. The same genes were down-regulated in SH without DE producing a hypertensive-like expression pattern. The down-regulated genes included those that regulate compensatory response, matrix metabolism, mitochondrial function, and oxidative stress response. No up-regulation of inflammatory genes was noted. CONCLUSIONS: We provide the evidence that DE inhalation produces a hypertensive-like cardiac gene expression pattern associated with mitochondrial oxidative stress in healthy rats.

Differential pulmonary and cardiac effects of pulmonary exposure to a panel of particulate matter-associated metals.

Biological mechanisms underlying the association between particulate matter (PM) exposure and increased cardiovascular health effects are under investigation. Water-soluble metals reaching systemic circulation following pulmonary exposure are likely exerting a direct effect. However, it is unclear whether specific PM-associated metals may be driving this. We hypothesized that exposure to equimolar amounts of five individual PM-associated metals would cause differential pulmonary and cardiac effects. We exposed male WKY rats (14 weeks old) via a single intratracheal instillation (IT) to saline or 1 micromol/kg body weight of zinc, nickel, vanadium, copper, or iron in sulfate form. Responses were analyzed 4, 24, 48, or 96 h after exposure. Pulmonary effects were assessed by bronchoalveolar lavage fluid levels of total cells, macrophages, neutrophils, protein, albumin, and activities of lactate dehydrogenase, gamma-glutamyl transferase, and n-acetyl glucosaminidase. Copper induced earlier pulmonary injury/inflammation, while zinc and nickel produced later effects. Vanadium or iron exposure induced minimal pulmonary injury/inflammation. Zinc, nickel, or copper increased serum cholesterol, red blood cells, and white blood cells at different time points. IT of nickel and copper increased expression of metallothionein-1 (MT-1) in the lung. Zinc, nickel, vanadium, and iron increased hepatic MT-1 expression. No significant changes in zinc transporter-1 (ZnT-1) expression were noted in the lung or liver; however, zinc increased cardiac ZnT-1 at 24 h, indicating a possible zinc-specific cardiac effect. Nickel exposure induced an increase in cardiac ferritin 96 h after IT. This data set demonstrating metal-specific cardiotoxicity is important in linking metal-enriched anthropogenic PM sources with adverse health effects.

Systemic translocation of (70)zinc: kinetics following intratracheal instillation in rats.

Mechanisms of particulate matter (PM)-induced cardiotoxicity are not fully understood. Direct translocation of PM-associated metals, including zinc, may mediate this effect. We hypothesized that following a single intratracheal instillation (IT), zinc directly translocates outside of the lungs, reaching the heart. To test this, we used high resolution magnetic sector field inductively coupled plasma mass spectrometry to measure levels of five stable isotopes of zinc ((64)Zn, (66)Zn, (67)Zn, (68)Zn, (70)Zn), and copper in lungs, plasma, heart, liver, spleen, and kidney of male Wistar Kyoto rats (13 weeks old, 250-300 g), 1, 4, 24, and 48 h following a single IT or oral gavage of saline or 0.7 micromol/rat (70)Zn, using a solution enriched with 76.6% (70)Zn. Natural abundance of (70)Zn is 0.62%, making it an easily detectable tracer following exposure. In IT rats, lung (70)Zn was highest 1 h post IT and declined by 48 h. Liver endogenous zinc was increased 24 and 48 h post IT. (70)Zn was detected in all extrapulmonary organs, with levels higher following IT than following gavage. Heart (70)Zn was highest 48 h post IT. Liver, spleen and kidney (70)Zn peaked 4 h following gavage, and 24 h following IT. (70)Zn IT exposure elicited changes in copper homeostasis in all tissues. IT instilled (70)Zn translocates from lungs into systemic circulation. Route of exposure affects (70)Zn translocation kinetics. Our data suggests that following pulmonary exposure, zinc accumulation and subsequent changes in normal metal homeostasis in the heart and other organs could induce cardiovascular injury.

Transcatheter closure of patent foramen ovale, atrial septal defect and left atrial appendage.

Intracardiac defects such as atrial septal defect (ASD) and patent foramen ovale (PFO) are common forms of congenital intracardiac apertures which can be successfully closed percutaneously. Since the initial description of an atrial septal defect closure device in the mid 1970s by King and Mills, transcatheter closure of atrial septal defects and patent foramen ovale using various devices has now become an established practice in many centers. The left atrial appendage is a trabeculated remnant of the embryonic left atrium. This is an important source of emboli related to atrial fibrillation. Closure of the left atrial appendage is designed to reduce the risk of stroke in patients with atrial fibrillation. This article reviews the current indications and latest developments in catheter closure of PFO, ASD and left atrial appendage.

The role of particulate matter-associated zinc in cardiac injury in rats.

BACKGROUND: Exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity; however, causative components are unknown. Zinc is a major element detected at high levels in urban air. OBJECTIVE: We investigated the role of PM-associated zinc in cardiac injury. METHODS: We repeatedly exposed 12- to 14-week-old male Wistar Kyoto rats intratracheally (1x/week for 8 or 16 weeks) to a) saline (control); b) PM having no soluble zinc (Mount St. Helens ash, MSH); or c) whole-combustion PM suspension containing 14.5 microg/mg of water-soluble zinc at high dose (PM-HD) and d ) low dose (PM-LD), e) the aqueous fraction of this suspension (14.5 microg/mg of soluble zinc) (PM-L), or f ) zinc sulfate (rats exposed for 8 weeks received double the concentration of all PM components of rats exposed for 16 weeks). RESULTS: Pulmonary inflammation was apparent in all exposure groups when compared with saline (8 weeks > 16 weeks). PM with or without zinc, or with zinc alone caused small increases in focal subepicardial inflammation, degeneration, and fibrosis. Lesions were not detected in controls at 8 weeks but were noted at 16 weeks. We analyzed mitochondrial DNA damage using quantitative polymerase chain reaction and found that all groups except MSH caused varying degrees of damage relative to control. Total cardiac aconitase activity was inhibited in rats receiving soluble zinc. Expression array analysis of heart tissue revealed modest changes in mRNA for genes involved in signaling, ion channels function, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulation in zinc but not in MSH-exposed rats. CONCLUSION: These results suggest that water-soluble PM-associated zinc may be one of the causal components involved in PM cardiac effects.

Subchronic inhalation of zinc sulfate induces cardiac changes in healthy rats.

Zinc is a common metal in most ambient particulate matter (PM), and has been proposed to be a causative component in PM-induced adverse cardiovascular health effects. Zinc is also an essential metal and has the potential to induce many physiological and nonphysiological changes. Most toxicological studies employ high levels of zinc. We hypothesized that subchronic inhalation of environmentally relevant levels of zinc would cause cardiac changes in healthy rats. To address this, healthy male WKY rats (12 weeks age) were exposed via nose only inhalation to filtered air or 10, 30 or 100 microg/m(3) of aerosolized zinc sulfate (ZnSO(4)), 5 h/day, 3 days/week for 16 weeks. Necropsies occurred 48 h after the last exposure to ensure effects were due to chronic exposure rather than the last exposure. No significant changes were observed in neutrophil or macrophage count, total lavageable cells, or enzyme activity levels (lactate dehydrogenase, n-acetyl beta-D-glucosaminidase, gamma-glutamyl transferase) in bronchoalveolar lavage fluid, indicating minimal pulmonary effect. In the heart, cytosolic glutathione peroxidase activity decreased, while mitochondrial ferritin levels increased and succinate dehydrogenase activity decreased, suggesting a mitochondria-specific effect. Although no cardiac pathology was seen, cardiac gene array analysis indicated small changes in genes involved in cell signaling, a pattern concordant with known zinc effects. These data indicate that inhalation of zinc at environmentally relevant levels induces cardiac effects. While changes are small in healthy rats, these may be especially relevant in individuals with pre-existent cardiovascular disease.

Systemic translocation of particulate matter-associated metals following a single intratracheal instillation in rats.

Respirable ambient particulate matter (PM) exposure has been associated with an increased risk of cardiovascular disease. Direct translocation of PM-associated metals from the lungs into systemic circulation may be partly responsible. We measured elemental content of lungs, plasma, heart, and liver of healthy male WKY rats (12-15 weeks old) 4 or 24 h following a single intratracheal (IT) instillation of saline or 8.33 mg/kg of oil combustion PM (HP-12) containing a variety of transition metals with differing water and acid solubility. Tissues were digested with a combination of quaternary acid, amine, and nitric acid and analyzed using inductively coupled plasma-atomic emission spectroscopy. Lung levels of metals were lower at 24 h than at 4 h. Metals with high water solubility and relatively high concentration in HP-12 were increased in extrapulmonary organs. Water-soluble nonessential metals, like vanadium and nickel, were increased in plasma, hearts, and livers of exposed animals at both time points. Exposure-related small increases in essential metals, like zinc and manganese, were also noted in extrapulmonary tissues at both time points. Lead, with low water solubility but high acid solubility, was detected in liver only at 24-h postinstillation. Elements with low water or acid solubility, like silicon and aluminum, were not detected in extrapulmonary tissues despite decreased levels in the lung suggesting mucociliary clearance. We have shown that HP-12-associated metals translocate to systemic circulation and extrapulmonary organs following IT exposure. This translocation is dependent upon their relative levels and water solubility. Thus, following inhalation, PM-associated metals deposited in the lung may be released into systemic circulation at different rates depending on their water/acid solubility, thereby providing a means by which metals may elicit direct extrapulmonary effects.

Cardiopulmonary responses of Wistar Kyoto, spontaneously hypertensive, and stroke-prone spontaneously hypertensive rats to particulate matter (PM) exposure.

Humans with underlying cardiovascular disease, including stroke, are more susceptible to ambient particulate matter (PM)-induced morbidity and mortality. We hypothesized that stroke-prone spontaneously hypertensive rats (SHRSP) would be more susceptible than healthy Wistar Kyoto (WKY) rats to PM-induced cardiac oxidative stress and pulmonary injury. We further postulated that PM-induced injury would be greater in SHRSP than in spontaneously hypertensive rats (SHR) based on the greater disease severity in SHRSP than SHR. First, male WKY and SHRSP were intratracheally (IT) instilled with saline or 1.11, 3.33, or 8.33 mg/kg of oil combustion PM and responses were analyzed 4 or 24 h later. Second, SHR and SHRSP were IT instilled with saline or 3.33 or 8.33 mg/kg of the same PM and responses were analyzed 24 h later. Pulmonary injury and inflammation were assessed in bronchoalveolar lavage fluid (BALF) and cardiac markers in cytosolic and mitochondrial fractions. BALF neutrophilic inflammatory response was induced similarly in all strains following PM exposure. BALF protein leakage, gamma-glutamyl transferase, and N-acetylglucosaminidase activities, but not lactate dehydrogenase activity, were exacerbated in SHRSP compared to WKY or SHR. Pulmonary cytosolic and cardiac mitochondrial ferritin levels decreased, and cardiac cytosolic superoxide dismutase (SOD) activity increased in SHRSP only. Pulmonary SOD activity decreased in WKY and SHRSP. Cardiac mitochondrial isocitrate dehydrogenase (ICDH) activity decreased in PM-exposed WKY and SHR; control levels were lower in SHRSP than SHR or WKY. In summary, strain-related differences exist in pulmonary protein leakage and oxidative stress markers. PM-induced changes in cardiac oxidative stress sensitive enzymes are small, and appear only slightly exacerbated in SHRSP compared to WKY or SHR. Multiple biological markers may be differentially affected by PM in genetic models of cardiovascular diseases. Preexisting cardiovascular disease may influence susceptibility to PM pulmonary and cardiac health effects in a disease-specific manner.

Intensive Care in a Patient with Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis (TEN) is a serious adverse drug reaction with high lethality, which usually requires intensive-medical care. A 44-year-old man developed generalized exanthema with increasing exfoliation and mucosal involvement after taking allopurinol, ibuprofen, and etoricoxib. The clinical diagnosis of TEN was histologically confirmed. Prednisolone therapy with 3 mg/kg body weight (BW) was not able to prevent further progress to finally 80% of the body surface, and infliximab 5 mg/kg BW was given as a single dose. This prevented further progression of the TEN. Despite marked improvement in skin findings, the ICU stay was prolonged by a complex analgosedation, transient kidney failure, volume management, positioning therapy, and vegetatively impeded weaning. Moreover, there was colonization with multiresistant bacteria (MRSA and VRE). Nonetheless, the patient could be restored to health and was released after four weeks. Infliximab seems to be effective in the treatment of TEN, especially in cases of rapid progression. Moreover, patients with TEN are difficult to handle in intensive-medical care, whereby attention should especially be paid to sufficient pain therapy, and the positioning of the patient is a particular challenge.

Vascular and cardiac impairments in rats inhaling ozone and diesel exhaust particles.

BACKGROUND: Mechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants are unknown. OBJECTIVE: We sought to determine whether episodic exposure of rats to ozone or diesel exhaust particles (DEP) causes differential cardiovascular impairments that are exacerbated by ozone plus DEP. METHODS AND RESULTS: Male Wistar Kyoto rats (10-12 weeks of age) were exposed to air, ozone (0.4 ppm), DEP (2.1 mg/m(3)), or ozone (0.38 ppm) + DEP (2.2 mg/m(3)) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP (1.9 mg/m(3)) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1), thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids (DEP > ozone). The combined effect of ozone and DEP exposure was less pronounced than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute) caused mild changes in the aorta. CONCLUSIONS: In animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers of vascular impairments in the aorta, with the loss of phospholipid fatty acids in myocardial mitochondria. We conclude that there is a possible role of oxidized lipids and protein through LOX-1 and/or RAGE signaling.