OBJECTIVE

To investigate the effects of endothelin-1 (ET-1) overexpression on apoptosis of the rat pulmonary arterial microvascular smooth muscle cells (RPMC) in vitro.

METHODS

Primary RPMC obtained from the pulmonary artery and lung microvasculature were identified by immunofluorescence staining and electron microscope technique. The RPMC was transient transfected with the pMEXneo-ET1 and pCDNA5-FRT-TO-ET1-3'UTR plasmids as well as the empty vector respectively via lipofectamine. Flow cytometry was used to assess the cell cycle and apoptosis of RPMC. Akt and Caspase-3 expressions were detected by Western blot and real time RT-PCR.

RESULTS

The mRNA of ET(A) expression was significantly higher than that of ET(B) receptor in primary RPMC. Flow cytometry analysis revealed significantly reduced apoptosis in ET-1 transfected RPMC compared to that in vehicle transfected RPMC. Overexpression of ET-1 in RPMC also significantly increased the phosphorylation of Akt and reduced the cleaved Caspase-3 expression.

CONCLUSIONS

Overexpression of the ET-1 inhibited RPMC apoptosis and activated Akt/PKB-Caspase-3 signaling pathway, which might be responsible for ET-1 induced the pulmonary microvascular arteries remodeling.

The interaction between cicletanine (CIC) and atrial natriuretic factor (ANF) on vessels was studied using the isolated rat aorta as model. Contractions induced by endothelin (ET1), a vasoconstrictor peptide from vascular endothelial cells, and by phenylephrine (PE), an alpha 1-adrenoceptor agonist, were recorded isometrically on aortic rings the endothelium of which had deliberately been damaged. Both agonists produced a concentration-dependent contraction (ET1:EC50 1.8 nM, Emax 2.2 g; PE:EC50 30 nM, Emax 2.4 g) which was antagonized by a 30 min pretreatment with either CIC (100 microM) or ANF (1 nM). However, PE was more sensitive than ET1 to the inhibitory action of CIC or ANF. Moreover, during inhibition by ANF spasmodic contractions were observed with PE but not with ET1; this was not observed when the antagonist was CIC. The inhibitory effect produced by the combination of CIC and ANF was additive with ET1 whereas a potentiation was observed with PE. Thus, on the isolated rat aorta model the contraction induced by PE was more sensitive to the action of ANF than that induced by ET1, which indicates that the two antagonists have a different mechanism of action. A direct action of CIC on the alpha-adrenoceptor might account for the potentiation observed between ANF and CIC against PE.

Background: Power output considers all movement aspects of the game of football and could have meaningful impact for teams.

Purpose & methods: To assess inter-reliability of ten power meters designed for running; and as a descriptor of individual and team performance during a five-a-side football match. The work aimed to assess inter-device reliability of running power-meters combined with data analysis from intermittent running, along with descriptives of player work rate, gait and team performance during a small-sided game of football.

Methods: 10 different running power meters inter-reliability were on a treadmill at 8, 10, 12, and 16 km h^-1 for 60 s in a random order. Football players (N = 10) performed the Yo-Yo ET1 with the running power meters to determine participants' endurance capability, while assessing the ability to record metrics of gait and power output during intermittent running. Following a period of 7-days participants took part in a 20 min small-sided game of football wearing the running power meters to provide descriptors of work and gait.

Results: Good inter-device reliability for the power meters (CV 1.67, range 1.51-1.94 %) during continuous treadmill running were found. Overall mean ± SD results for Yo-Yo ET1 power output 263 ± 36W, power:weight 3.59 ± 0.34W∙kg^-1 significantly (p < 0.05) increased with successive stages, while ground-contact time 234 ± 17 ms, and vertical oscillation 90.7 ± 27 mm did not change (p > 0.05). Descriptive analysis of the small-sided game presented mean ± SD absolute and relative power outputs of 148 ± 44W and 1.98 ± 0.53W∙kg^-1, equating to 54 ± 21 %W_max and 74 ± 5%HR_max. Characteristics of gait included cadence 125 ± 22 rpm, ground contact time 266 ± 19 ms, and vertical oscillation 76.7 ± 7 mm. The winning team worked relatively harder than the losing team (53.3 ± 0.7 %W_max vs 46.7 ± 0.4 %W_max, p < 0.0001) with more time (398 s vs 141 s) spent above 70 %W_max.

Significance: As such, the use of a running power-meter is a useful tool for comparing work rate and aspects of gait between team members while more research is required to investigate relative work rate (%W_max) within the field.

Keywords: Football; Match analysis; Power-meter.

OBJECTIVE

We recently demonstrated a protective effect of the farnesoid X receptor agonist obeticholic acid (OCA) in rat models of bleomycin-induced pulmonary fibrosis (PF). Aim of the present study was to investigate whether the positive effects of OCA treatment are apparent also on ongoing bleomycin-induced PF, i.e., after 2 weeks of bleomycin administration.

METHODS

Bleomycin-induced PF rats were treated 2 weeks after bleomycin administration with OCA or pirfenidone for two additional weeks. Pulmonary function test was performed at 2 and 4 weeks in all experimental groups. At the same time points, lung morphological features and mRNA expression profile of genes related to fibrosis, inflammation and epithelial-mesenchymal transition were also assessed.

RESULTS

After 2 weeks, bleomycin significantly increased the pressure at the airway opening (PAO), a functional parameter related to fibrosis-induced lung stiffness, and induced diffuse lung interstitium fibrosis, with upregulation of inflammation (IL1β, MCP1) and tissue remodeling (COL1A1, COL3A1, ET1, MMP7, PDGFa, αSMA, SNAI1) markers. At week four, a further increase of lung fibrosis and PAO was observed, accompanied by upregulation of extracellular matrix-related mRNA expression. OCA administration, even after the establishment of PF, significantly improved pulmonary function, normalizing PAO, and reverted the bleomycin-induced lung alterations, with significant reduction of markers of inflammation (CD206, COX2, HIF1, IL1β, MCP1), epithelial proliferation (CTGF, PDGFa) and fibrosis (COL1A1, COL3A1, ET1, FN1, MMPs, αSMA, SNAIs, TGFβ1, TIMPs). Results with OCA were similar or superior to those obtained with pirfenidone.

CONCLUSIONS

In conclusion, our results demonstrate a significant therapeutic effect of OCA in already established PF.

We characterized intrinsic deep level defects created in ion collision cascades which were produced by patterned implantation of single accelerated 2.0 MeV He and 600 keV H ions into n-type 4H-SiC epitaxial layers using a fast-scanning reduced-rate ion microbeam. The initial deep level transient spectroscopy measurement performed on as-grown material in the temperature range 150-700 K revealed the presence of only two electron traps, Z 1/2 (0.64 eV) and EH6/7 (1.84 eV) assigned to the two different charge state transitions of the isolated carbon vacancy, V C (=/0) and (0/+). C-V measurements of as-implanted samples revealed the increasing free carrier removal with larger ion fluence values, in particular at depth corresponding to a vicinity of the end of an ion range. The first DLTS measurement of as-implanted samples revealed formation of additional deep level defects labelled as ET1 (0.35 eV), ET2 (0.65 eV) and EH3 (1.06 eV) which were clearly distinguished from the presence of isolated carbon vacancies (Z 1/2 and EH6/7 defects) in increased concentrations after implantations either by He or H ions. Repeated C-V measurements showed that a partial net free-carrier recovery occurred in as-implanted samples upon the low-temperature annealing following the first DLTS measurement. The second DLTS measurement revealed the almost complete removal of ET2 defect and the partial removal of EH3 defect, while the concentrations of Z 1/2 and EH6/7 defects increased, due to the low temperature annealing up to 700 K accomplished during the first temperature scan. We concluded that the ET2 and EH3 defects: (i) act as majority carrier removal traps, (ii) exhibit a low thermal stability and (iii) can be related to the simple point-like defects introduced by light ion implantation, namely interstitials and/or complex of interstitials and vacancies in both carbon and silicon sub-lattices.

The Human Respiratory Tract Model of ICRP Publication 66 is used for calculations of dose in the extrathorathic (ET1) airways. Scaling for age and body size is included in determining the mass of the target tissue (basal cells) in ET1 but is not included in deriving the absorbed fraction for particulate radiation. For dose calculations, it has been assumed that all absorbed fractions for particulate radiation published in ICRP Publication 66 are independent of age and body size. Therefore, these absorbed fractions are applied to calculate specific effective energy values not only for the Reference Worker but also for non-adults with noses of different sizes. In this note changes to the size of the cylinder model of the anterior nose in ICRP 66 are made by varying the surface area, the cylinder radius, and the thickness of tissue beyond the target region (basal cell). The energy deposition (absorbed fractions) in the target region (basal cells) is calculated using the MCNP4B (Monte Carlo) code to study the effects of these changes on the predicted absorbed fractions within the cylinder model.

Pyridazine derivatives, such as arylpiperazinylalkyl pyridazinones, display antinociceptive effects to thermal and chemical stimuli. Here, we extended our previous knowledge on the pharmacological profile of 4-amino-6-methyl-2-(3-(4-(4-methylcyclohexa-1,3-dien-1-yl)piperazin-1-yl)propyl)-5-vinylpyridazin-3(2H)-one, here referred as ET1, paving the way for the comprehension of its complete mechanism of action. To this aim, we have evaluated the mouse behavioural responses in several animal models of pain, the effect of ET1 in the murine model of zymosan-induced paw oedema and air-pouch, assessing the cytokines and the cellular phenotype and finally, an in vitro radioligand binding study was performed on a panel of 30 different receptors. In the formalin test, ET1 reduced both neurogenic and inflammatory phase of nociception induced by the aldehyde. Similarly, ET1 strongly reduced paw licking response in the capsaicin test, the abdominal stretching in the writhing test and the carrageenan-induced thermal hyperalgesia. ET1 also evoked a long-lasting reduction of thermal hyperalgesia. Furthermore, ET1 produced a long-lasting anti-inflammatory effect in the zymosan-induced mouse paw oedema and air-pouch through the selective inhibition of inflammatory monocytes recruitment and the modulation of IL-1β, IL-6, TNF-α and MCP-1. Binding experiments confirmed an inhibitory effect on adrenergic α_1A, α_1B and α_2A receptors subtypes and, for the first time, a moderate affinity was observed for the following receptors: histamine H₁, imidazoline I₂, sigma non-opioid intracellular receptor 1 and σ2. These results prompt ET1 as a potent analgesic and anti-inflammatory agent, and support the possibility that it may be suitable for clinical applications in a wide-range of inflammatory-based diseases.

Keywords: Arylpiperazinylalkyl pyridazinone; Hyperalgesia; Inflammation; Monocytes; Pain.

Prolonged vasoconstrictor-stimulated phospholipase C activity can induce arterial constriction, hypertension, and smooth muscle hypertrophy/hyperplasia. Arrestin proteins are recruited by agonist-occupied G protein-coupled receptors to terminate signaling and counteract changes in vascular tone. Here we determine whether the development of hypertension affects arrestin expression in resistance arteries and how such changes alter arterial contractile signaling and function. Arrestin2/3 expression was increased in mesenteric arteries of 12-wk-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) controls, while no differences in arrestin expression were observed between 6-wk-old SHR and WKY animals. In mesenteric artery myography experiments, high extracellular K(+)-stimulated contractions were increased in both 6- and 12-wk-old SHR animals. Concentration-response experiments for uridine 5'-triphosphate (UTP) acting through P2Y receptors displayed a leftward shift in 12-wk, but not 6-wk-old animals. Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals. Dual IP3/Ca(2+) imaging in mesenteric arterial cells showed that desensitization of UTP and endothelin-1 (ET1) responses was enhanced in 12-wk-old (but not 6-wk-old) SHR compared with WKY rats. siRNA-mediated depletion of arrestin2 for UTP and arrestin3 for ET1, reversed the desensitization of PLC signaling. In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction. Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.

We identified a compound in culture supernatants of Erwinia species, such as Erwinia amylovora, E. pyrifoliae, E. billingiae, E. tasmaniensis, E. persicina and E. rhapontici absorbing at 340 nm, which was associated before with the yellow pigment produced by E. amylovora on media containing copper ions. The compound was purified from E. tasmaniensis strain Et1/99 supernatants by chromatography on Dowex-1 and Dowex-50 columns and identified by HPLC/MS and NMR analysis as 6-thioguanine (6TG). Its signal at 167 Da matched with the expected molecular mass. By random mutagenesis with miniTn5, we obtained mutants defective in the genes for pyrimidine and purine metabolism. A specific gene cluster with ycf genes described by us before, absent in the corresponding region of Escherichia coli, was identified in the genome sequence of three Erwinia species and named tgs region for thioguanine synthesis. Clones of the tgs gene cluster promoted 6TG synthesis and secretion in E. coli, when the bacteria were grown in minimal medium supplemented with amino acids. 6TG was bacteriostatic for E. coli and Salmonella typhimurium strains, with cell growth resumed after prolonged incubation. Similar results were obtained with P. agglomerans strains. Bacteria from the genus Pectobacterium were barely and Rahnella or Gibbsiella species were not inhibited by 6TG. Adenine and guanine relieved the toxic effect of 6TG on E. coli. Non-producing strains were fully virulent on host plants. 6TG synthesis may help erwinias to interfere with growth of some microorganisms in the environment.

OBJECTIVE

To investigate whether inhalation of ethyl pyruvate (EP) encapsulated with poly(ethylene glycol)-block-lactide/glycolide copolymer nanoparticles (EP-NPs) can prevent the development of shunt-flow-induced hyperkinetic pulmonary arterial hypertension (PAH) in a rat model.

METHODS

Rats were separated into five groups: blank (ie, no treatment after shunt flow), normal control (ie, no shunt flow or treatment), EP-NP instillation, EP-only instillation, and vehicle. The animals received intratracheal instillation of EP-NPs or other treatments immediately after a shunt flow, and treatment continued weekly until the end of the experiment. Hemodynamic data were recorded, pulmonary arterial remodeling was assessed, and levels of inflammatory mediators and ET1 expression in the lung and serum were analyzed. In addition, retention of EP in the lungs of rats in the EP-NP and EP-only groups was measured using high-performance liquid chromatography.

RESULTS

After 12 weeks, hemodynamic abnormalities and pulmonary arterial remodeling were improved in the EP-NP instillation group, compared with the blank, EP-only, and vehicle groups (P<0.05). In addition, the EP-NP group showed significantly decreased levels of HMGB1, IL-6, TNFα, reactive oxygen species, and ET1 in the lung during PAH development (P<0.05). Furthermore, EP-NP instillation was associated with reduced serum levels of inflammatory factors and ET1. High-performance liquid-chromatography measurement indicated that EP retention was greater in the lungs of the EP-NP group than in the EP-only group.

CONCLUSIONS

EP-NP instillation attenuated inflammation and prevented pulmonary arterial remodeling during the development of PAH induced by shunt flow. In the future, EP-NP delivery into the lung might provide a novel approach for preventing PAH.

Early functional evaluation after non-complicated acute myocardial infarction (AMI) is widely recommended because of its prognostic value in the short term. In fact it seems to have a prognostic value within 15-20 days of the AMI, but in this period the patient is particularly controlled and is often still hospitalized. To evaluate the real significance of an early functional evaluation within 10 days of the AMI (mean 8.6 days +/- 1.2) as compared to an identical functional evaluation performed at 3 weeks after AMI (mean 20.16 days +/- 5.38) 25 patients with uncomplicated myocardial infarction were studied. Significant statistical differences were found between the first (ET1) and second (ET2) functional evaluations: they concern the maximal heart rate reached (P less than 0.001), the maximal pressure-rate product (P less than 0.05), the percentage increment of heart rate (P less than 0.01) and the total work performed (P less than 0.001). Agreement between ET1 and ET2 was found in 19 cases; 12 patients showed markers of ischaemia both at ET1 and ET2, while seven were free from ischaemia at both times. In six cases a disagreement between ET1 and ET2 was found: in particular, three cases had ischaemic ET1 and nonischaemic ET2; the reverse was seen in the other three. During follow-up (mean 215.4 days +/- 85.5), the total number of new events (reinfarctions, angina or surgery) among the 25 patients was eight; none occurred within the first 30 days after the AMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal response being approximately 65% of the maximal response to isoproterenol. ET-1 induced a positive inotropic effect over the concentration range below 10(-9) M, at which ET-3 did not produce a positive inotropic effect, but the maximal response to ET-1 was equivalent to or slightly lower than that of ET-3. The nonselective ET receptor antagonist PD 145065 effectively antagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10(-5) M. PD 145065 decreased the positive inotropic effect induced by ET1 at lower concentrations (< 10(-9) M) but it did not affect the main portion of the concentration-response curve for the positive inotropic effect, i.e., the effect induced by high concentrations >> 10(-9) M) of ET-1. PD 145065 antagonized also the positive inotropic effect of sarafotoxin S6c. PD 145065 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [125Iuc]ET-3 with high affinity but they scarcely affected the [125I]ET-1 binding. These findings indicate that different subtypes of the ET receptor are responsible for the induction of the positive inotropic effect of ET-3 and ET-1. ET receptors involved in the production of the positive inotropic effect in the rabbit ventricular myocardium have pharmacological characteristics that are different from those of conventional ET receptors originally classified based on the pharmacological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by ETB receptors that are inhibitable with RES-701-1. ETA2 receptors that are resistant to ETA selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle.

In the present work, Sr_0.9-x-y-zCa_0.1In₂O₄:(xEu³⁺, yTm³⁺, zTb³⁺) particles were synthesized by the ultrasonic spray pyrolysis (USP) method to obtain a single-phase white phosphorus formed by six different cations in solution within the lattice (superstructure). The samples were also structurally and morphologically characterized by X-ray diffraction (XRD) techniques and by field emission scanning electron microscopy (FE-SEM). The photoluminescent behavior and the characteristics of the emitted colors were studied by the variation in the co-doping of the rare earth elements. The Sr_0.9Ca_0.1In₂O₄ sample showed a near blue color emission, but all co-doped samples showed emission in white with very close chromaticity coordinates to the standard white (x = 0.33 and y = 0.33). The Tm³⁺ → Tb³⁺ (ET1), Tm³⁺ → Eu³⁺ (ET2) and Tb³⁺ → Eu³⁺ (ET3) Energy Transfers were proposed and are considered necessary for adjusting and controlling the desired color properties.

This study was aimed to assess the diagnostic value of laboratory markers of endothelial lesions in patients with unstable angina (UA). Plasma levels of CRP, homocysteine, endothelin-1 (ET1), and pregnancy-associated plasma protein (pAPP-A) were measured by an ultrasensitive method in 51 patients. They were followed up for 4 months to evaluate the clinical picture of CHD and dynamics of laboratory parameters. The hospitalized patients with UA had elevated baseline levels of CRP (5.02+-3.35 mg/ml) during the entire study period. PAPP-A and homocysteine levels were significantly decreased (p<0.05 and p<0.0 respectively). Patients with deteriorated clinical picture of CHD had significantly elevated ET1 levels (p<0.05) both on day 1 and 4 months later It is concluded that ET1 levels increase in patients with UA and severe prognostically unfavourable CHD.

Cold temperatures are associated with increased prevalence of hypertension. Cold exposure increases endothelin-1 (ET1) production. The purpose of this study is to determine whether upregulation of ET1 contributes to cold-induced hypertension (CIH). In vivo RNAi silencing of the ET1 gene was achieved by adeno-associated virus 2 (AAV2) delivery of ET1 short-hairpin small interfering RNA (ET1-shRNA). Four groups of male rats were used. Three groups were given AAV.ET1-shRNA, AAV.SC-shRNA (scrambled shRNA), and phosphate-buffered saline (PBS), respectively, before exposure to a moderately cold environment (6.7 ± 2°C), while the last group was given PBS and kept at room temperature (warm, 24 ± 2°C) and served as a control. We found that systolic blood pressure of the PBS-treated and SC-shRNA-treated groups increased significantly within 2 weeks of exposure to cold, reached a peak level (145 ± 4.8 mmHg) by 6 weeks, and remained elevated thereafter. By contrast, blood pressure of the ET1-shRNA-treated group did not increase, suggesting that silencing of ET1 prevented the development of CIH. Animals were euthanized after 10 weeks of exposure to cold. Cold exposure significantly increased the left ventricle (LV) surface area and LV weight in cold-exposed rats, suggesting LV hypertrophy. Superoxide production in the heart was increased by cold exposure. Interestingly, ET1-shRNA prevented cold-induced superoxide production and cardiac hypertrophy. ELISA assay indicated that ET1-shRNA abolished the cold-induced upregulation of ET1 levels, indicating effective silencing of ET1. In conclusion, upregulation of ET1 plays a critical role in the pathogenesis of CIH and cardiac hypertrophy. AAV delivery of ET1-shRNA is an effective therapeutic strategy for cold-related cardiovascular disease.

BACKGROUND

Subarachnoid hemorrhage (SAH) frequently leads to prolonged cerebral vasospasm resulting in vascular pathology due to endothelial cell ischemia and neuronal hypoxia. Posthemorrhagic vasospasm can be counteracted by the administration of phosphoramidon, which blocks the endothelin converting enzyme (ECE) responsible for the conversion of big endothelin into a fully active ET1 peptide. The aim of the study was to determine the effect of chronic vasospasm after SAH on angiogenesis and the effect on this process of endothelin-1, the main causative factor in vasospasm.

METHODS

Male Wistar rats were examined. Seven days after cannulation of the cisterna magna, blood was administered to induce SAH. The ECE inhibitor phosphoramidon was administered in a dose of 40 nmol in 50 microl of cerebrospinal fluid three times: 20 min before SAH, 60 min after SAH, and 24 hours after SAH. The brains were removed 48 hours later for histological evaluation. The vascular surface density was measured in cerebral hemisphere sections (at the level of the dorsal part of the hippocampus) and brainstem sections (1/2 of the pons).

CONCLUSIONS

Increased angiogenesis was observed in the cerebral hemispheres after SAH. The administration of phosphoramidon inhibits angiogenesis in cerebral hemispheres after SAH.

Blood perfusion was always lower in tumor tissues as compared with that in surrounding normal tissues which lead to inadequate nanomedicine delivery to tumors. Inspired by the upregulation of both endothelin-1 (ET1) and its ETA receptor in tumor tissues and the crucial contribution of ET1-ETA receptor signaling to maintain myogenic tone of tumor vessels, we supposed that inhibition of ET1-ETA receptor signaling might selectively improve tumor perfusion and help deliver nanomedicine to tumors. Using human U87 MG glioblastomas with abundant vessels as the tumor model, immunofluorescence staining demonstrated that ETA receptor was overexpressed by in glioblastomas tissues compared with normal brain tissues. A single administration of ETA receptor antagonist BQ123 at the dose of 0.5 mg/kg could effectively improve tumor perfusion which was evidenced by in vivo photoacoustic imaging. Additionally, a single treatment of BQ123 could significantly improve the accumulation of nanoparticles (NPs) around 115 nm in tumors with a more homogeneous distribution pattern by in vivo imaging, ex vivo imaging as well as in vivo distribution experiments. Furthermore, BQ123 successfully increased the therapeutic benefits of paclitaxel-loaded NPs and significantly elongated the survival time of orthotropic glioblastomas-bearing animal models. In summary, the present study provided a new strategy to selectively improve tumor perfusion and therefore benefit nanomedicine delivery for tumor therapy. As ET1-ETA receptor signaling was upregulated in a variety of tumors, this strategy might open a new avenue for tumor treatment.

OBJECTIVE

To evaluate the effect of high thoracic epidural analgesia (HTEA) in congestive heart failure (CHF).

METHODS

Rat model of CHF.

METHODS

Harbin Medical University, Harbin, Heilongjiang, China.

METHODS

One hundred thirty-five rats.

METHODS

HTEA involved 5 times daily injections of 0.1% lidocaine at the T3-T4 level.

RESULTS

The authors examined myocardial norepinephrine (NE), angiotensin II (Ang II), endothelin-1 (ET1), and tumor necrosis factor-α (TNF-α) concentrations 2, 4, and 6 weeks after the start of HTEA. They also examined histologic changes in heart tissue and myocardial expression of apoptosis-inducing factor (AIF) and poly (ADP-ribose) polymerase (PARP). Sham rats were used as a control. In the time course, myocardial NE, Ang II, ET1, and TNF-α concentrations were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Similarly, PARP and AIF protein expression levels were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Microscopy revealed pronounced damage to myocardial cell structures in the CHF group; this damage clearly was reduced in the HTEA group. In addition, cardiac function evaluation indicated treatment with HTEA resulted in similar heart function as animals that did not have surgically induced CHF.

CONCLUSIONS

The findings suggest that HTEA induces changes in sympathetic nervous system, renin-angiotensin system, endothelial, and inflammatory process activity involved in CHF.

Endothelial dysfunction was observed in patients with chronic renal failure (CRF). Endothelial cells produce a lot of factors among them endothelin and nitric oxide. The aim of this study was to evaluate the plasma/serum and urine levels of edothelin 1 (ET 1) and nitric oxide (NO) in children with CRF treated conservatively. 52 children (23 girls and 29 boys) aged 2-20 years (mean 13.19 years) were enrolled into the study. Patients were divided into 2 groups according to the creatinine level: group I--children with CRF and creatinine level below 265.2 micromol/l, group II CRF children with creatinine level above 265.2 micromol/l. We evaluated serum and urine metabolites of NO (nitrates + nitrites).

CONCLUSIONS

in children with chronic renal failure elevated level of ET1 and enhanced excretion of ET1 were observed. Decreased plasma and urine NOx levels were found in CRF children. The disorders are connected with progression of renal failure.

Preincubation with physiological concentrations of insulin affects contractile reactivity of isolated smooth muscle cells. We studied the effects of insulin on intact aortic rings of Wistar rats preincubated 1-2 h with 240 pM (I1) and 960 pM (I2) insulin with and without NO synthesis inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME). Resting force was tripled by 0.1 mM L-NAME in control (C) and I1 groups, but not in I2 groups. I1 treatment decreased the tachyphylaxis to two successive 1 microM arginine vasopressin (AVP) stimulations. Single contractions elicited by 1 microM AVP, 1 microM angiotensin II (AngII), or 0.01 microM endothelin (ET1) were not affected by insulin preincubation in either maximal force (Fmax) or relaxation times. L-NAME enhanced Fmax of AngII contractions by about 75% in C, 120% in I1, and 74% in I2 groups; accordingly, it augmented the final steady-state force in C and I1 but not in I2. Similarly, L-NAME increased Fmax (30-40%) of AVP and ET1 contractions in C and I1 groups but failed to do so in contractions of I2 group. Results obtained with 10 microM indomethacin suggest that this is due to insulin stimulation of prostacyclin effects.

The rate of passage (ROP) in the gastrointestinal tract (GIT) influences the exposure time of food to the digestion and absorption processes. Consequently, ROP affects the efficiency of nutrient utilization and energy from the diet. This study aimed to determine the physiological parameters that characterize the digestive response, such as first appearance time (FAT), ROP, mean retention time (MRT) and transit time (TT) in adult Japanese quail (Coturnix coturnix japonica), and to evaluate the effects of sex, apparent metabolizable energy corrected for nitrogen balance (AMEn) content in the diet and different types of markers on these parameters. In the first trial, we investigated the effects of sex and AMEn level (high- and low-energy diet) on the FAT parameter. Thirty-two male and 32 female Japanese quail were randomly allocated to 8 battery cages and assigned to 4 treatments in a 2 × 2 factorial design with 4 replicates of 4 birds for each treatment. To determine the FAT, ferric oxide (1%) was added to the diet, and the excreta of the quail was monitored until the first appearance of the marker. The results indicated significant differences (P < 0.05) in the FAT between males (100 min) and females (56 min), regardless of the AMEn content. In the second trial, thirty-two 32-week-old female Japanese quail in the laying phase were assigned to four treatments in a 2 × 2 factorial design, in which the main independent variables were type of marker (Cr or Ti) and AMEn level (high- and low-energy diets). In order to determine ROP (<em>ET1</em>%), MRT and TT (<em>ET1</em>00%), the markers (0.5%: Cr2O3 and 0.5%: TiO2) were added to the diets, and the excreta were collected for 750 min. The excretion times for 1% (<em>ET1</em>%), 25% (ET25%), 50% (ET50%), 75% (ET75%) and 100% (<em>ET1</em>00%) were estimated using cumulative excretion curves. No effect was detected for the AMEn level (P > 0.05); however, the effect of different marker types was significant (P < 0.05). This difference increased with time and <em>ET1</em>00% was estimated to occur at 59 min. The ROP was estimated to be 68 min. The TT was estimated to be 540 min using Cr and 599 min using Ti, with an average MRT value of 0930 h. Taken together, our findings support the hypothesis that Japanese quail digestion through the GIT can be dynamic and differ based on sex or marker type.

Keywords: coturnix quail; markers; mean retention time; metabolizable energy; passage rate.

OBJECTIVE

To investigate the role of endothelin on nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX2) enzyme inhibitors-induced effects on the gastric mucosa.

METHODS

This study was carried out in the Department of Pharmacology Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey during the period January to December 2002. In the first group a cyclooxygenase-1 (COX1) and COX2 enzyme inhibitor, indomethacin (25 mg/kg, subcutaneous injection (s.c), n=7), a selective COX2 enzyme inhibitor, NS398 (10 mg/kg, s.c) and normal saline were administered. In the second group, endothelin-1 (ET1) was administered (200 pmol/kg) alone, in the presence of an endothelin receptor antagonist bosentan, (100 mg/kg) and PGE1 [40 microg/kg, orally] with submucosal injection. In the third group, NS398 and indomethacin were applied in the presence of bosentan. In the fourth group, NS398 were applied in the presence of N (G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg, s.c).

RESULTS

Indomethacin caused gastric mucosal injury. The effect of NS398 on gastric mucosa did not differ considerably from that of the control group. Submucosal injection of ET1 caused a gastric damage, which could not be prevented by intragastric administration of bosentan, while pretreatment with PGE1 prevented ET1-induced ulcer. Pretreatment with bosentan did not attenuate indomethacin-induced gastric mucosal damage but it increased NS398-induced damage by 1.5 fold. Pretreatment with L-NAME increased NS398-induced gastric mucosal damage as bosentan did.

CONCLUSIONS

These results suggest that neither endothelin-induced nor indomethacin-induced ulcer is completely receptor dependent. Cyclooxygenase-2 inhibitors caused ulcer in the presence of bosentan. Protective effects of gastric mucosal injury of COX2 inhibitors may be via endothelin receptor related nitric oxide release.

Ischemic preconditioning (IP) is a powerful cardioprotective cellular mechanism that has been related to the "warm-up phenomenon" or "walk-through" angina, and has been documented through the use of sequential exercise tests (ETs). It is known that several drugs, for example, cromokalim, pinacidil, adenosine, and nicorandil, can interfere with the cellular pathways of IP. The purpose of this article is to report the effect of the anti-ischemic agent trimetazidine (TMZ) on IP in symptomatic coronary artery disease (CAD) patients.We conducted a prospective study evaluating IP by the analysis of ischemic parameters in 2 sequential ETs. In phase I, without TMZ, patients underwent ET1 and ET2 with a 30-minute interval between them. In phase II, after 1 week of TMZ 35 mg twice daily, all patients underwent 2 consecutive ETs (ET3 and ET4). IP was considered present when the time to 1.0-mm segment ST on electrocardiogram deviation (T-1.0 mm) and rate pressure product (RPP) were greater in the second of 2 tests. The improvement in T-1.0 mm and RPP were compared in the 2 phases: without TMZ and after 1-week TMZ to assess the action of such drug in myocardial protective mechanisms. ETs were analyzed by 2 independent cardiologists.From 135 CAD patients screened, 96 met inclusion criteria and 62 completed the study protocol. Forty patients manifested IP by demonstrating an improvement in T-1.0 mm in ET2 compared with ET1, without the use of any drugs (phase I). In phase II, after 1-week TMZ, 26 patients (65%) did not show any incremental result in ischemic parameters in ET4 compared with ET3. Furthermore, of these patients, 8 (20%) had IP blockage.In this study, TMZ did not add any benefit to IP in patients with stable symptomatic CAD.