Vasomodulator Mechanisms in Rat Carotid Artery and in Vessels from an Experimental Model of Heart Failure

The purpose of the work presented here was to investigate: i) in the rat isolated common carotid artery the population of postjunctional alpha-adrenoceptors, subtypes of alpha1-adrenoceptors and their interaction with nitric oxide, ii) in the rabbit isolated saphenous vein the subtypes of alpha1-adrenoceptors, iii) in the rabbit coronary ligation model of heart failure endothelium-dependent and -independent relaxations, contraction to NA and effect of cocaine treatment on large blood vessels. The major findings are briefly summarised below: Rat carotid artery 1 The dominance of alpha1-adrenoceptors is shown by the high sensitivity of NA or PE to prazosin and the ineffectiveness of rauwolscine except in non-selective concentrations. UK-14304 produced contraction and it is theoretically possible that UK-14304 exerts its actions through combined alpha1 and alpha2 activation, but the effectiveness of prazosin and the ineffectiveness of rauwolscine except in non-selective concentrations, shows that even this effect is mediated through alpha1-adrenoceptors. Thus we suggest that the population of postjunctional alpha-adrenoceptors mediating contraction of smooth muscle in the rat carotid artery is predominantly alpha1. 2 Rat carotid artery showed moderate sensitivity to alpha1A-selective antagonists and low sensitivity to CEC. The pA2 values correlated best with the published affinities of these compounds for the expressed alpha1d-adrenoceptor clone and poorly with those at either the expressed alpha1b- or alpha1a-adrenoceptor clones. This suggests negative evidence that contractions of the rat common carotid artery are mediated by non-alpha1A non-alpha1B-adrenoceptors. The data is consistent with a functional alpha1-adrenoceptor such as was reported in rat aorta. 3 In the rat isolated carotid artery, UK-14304 induced relaxation of NA-induced tone (but not thromboxane-induced tone) which was independent of alpha2-adrenoceptors, functional endothelium, production of NO and cyclo-oxygenase products. There was no specific evidence from our study that alpha2-adrenoceptors can mediate the release of EDRF in rat carotid artery. We suggest that UK-14304 acted as a partial agonist at alpha1-adrenoceptors in this artery. 4 Inhibition of NO synthesis by L-NAME results in significant vasoconstriction. Also, L-NAME prevented the relaxation of rat carotid artery by acetylcholine. Thus we suggest that both basal and stimulated release of nitric oxide can regulate vascular tone in this artery. 5 Mechanical disruption of the vascular endothelium (to an extent which prevented vasodilation by acetylcholine) reduced, but did not abolish the ability of L-NAME to produce contraction. This suggests an extra-endothelial site for nitric oxide synthesis in rat common carotid artery. 6 The effect of UK-14304 was significantly enhanced in the presence of L-NAME. Inhibition of nitric oxide synthase with L-NAME potentiates responses to PE and UK-14304 but not to NA. Mechanical disruption of the vascular endothelium mimicked the effect of L-NAME on contractile responses to UK-14304 and PE consistent with L-NAME inhibiting endothelium-derived nitric oxide synthase. There was one unexplained difference between L-NAME and denuding endothelium. Although L-NAME did not increase sensitivity to NA, mechanical disruption increases potency of NA. Overall the results suggest that constitutive NO activity has substantial inhibitory influence on vasoconstrictor responses to PE and UK-14304 but not to NA. 7 Since L-NAME greatly potentiates responses to UK-14304, a series of experiments were conducted to see whether other stimuli that produces submaximal contraction would have a similar synergistic effect. Submaximal contraction with KCl increased responses significantly, but inducing tone with PE, U-46619 and 5HT had no effect on responses to UK-14304. The presence of All increased responses though less than KCl. Overall the greatest influence found was blockade of nitric oxide synthase. (Abstract shortened by ProQuest.)

Triterpenes and Steroids from Euphorbia denticulata Lam. with Anti-Herpes Symplex Virus Activity

In this research, dried acetone: chloroform extract of aerial parts of E. denticulata as one of the endemic plants to Iran, afforded a number of triterpenes and steroids including: betulin, 24-methylene-cycloart-3-ol, cycloart-23Z-ene-3 beta,25-diol, cycloart-23E-ene-3 beta,25-diol, ergosta-8,24-dien-3-ol (obtusifoliol) and beta-sitosterol which were reported for the first time from this plant. The structure of these compounds was elucidated by NMR and mass spectroscopic methods. The MTS assay was used to determine the toxicity and antiviral activity of betulin and (3 beta,23E)-cycloarta-23-ene-3,25-diol. Betulin showed anti-HSV-1 activity with EC50 value of 84.37 +/- 0.02 mu g/mL, and toxicity on normal vero cells with CC50 value of 660.718 +/- 0.072 mu g/mL. (3 beta,23E)-Cycloarta-23-ene-3,25-diol showed antiviral effect with EC50 value of 86.63 +/- 0.03 mu g/mL, and toxicity with CC50 value of 1089.21 +/- 0.25 mu g/mL. The results revealed that these two compounds have the antiviral activity far below the CC50 value with selectivity index (CC50/EC50) values of 7.83, and 12.57, respectively

Voluntary Exercise Prevents Lead-Induced Elevation of Oxidative Stress and Inflammation Markers in Male Rat Blood

Regular mild exercise enhances antioxidant and anti-inflammatory systems of the body. The present study investigates voluntary exercise effects on lead toxicity as a known oxidative stressor. Male Sprague-Dawley rats were randomly divided into 2 groups. Sedentary control: the animals were housed 7 weeks in the regular cages. Exercise group: the animals were housed 7 weeks in the running wheel equipped cages, that is, the animal model of voluntary exercise. During the 7th week, all animals were administered lead acetate. Blood samples were collected at the end of the 6th week and 7th week (before and after lead administrations). Glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and tumor necrosis factor (TNF-) were measured in the samples. Our results showed that lead administration reduced blood SOD, GPx and CAT and increased TNF-; in the controls, but in the exercise group, changes were not statistically significant. MDA in both groups increased after lead injections but it was significantly lower in exercise group compared to the sedentary animals. We concluded that voluntary exercise may be considered as a preventive tool against lead-induced oxidative stress and inflammation

Combination of Vildagliptin and Ischemic Postconditioning in Diabetic Hearts as a Working Strategy to Reduce Myocardial Reperfusion Injury by Restoring Mitochondrial Function and Autophagic Activity

Purpose: Diabetic hearts are resistant to cardioprotection by ischemic-postconditioning (IPostC). Protection of diabetic hearts and finding related interfering mechanisms would have clinical benefits. This study investigated the combination effects of vildagliptin (Vilda) and IPostC on cardioprotection and the levels of autophagy and mitochondrial function following myocardial ischemia/reperfusion (I/R) injury in type-II diabetic rats. Methods: Diabetes was established by high fat diet/low dose of streptozotocin and lasted for 12 weeks. The diabetic rats received Vilda (6 mg/kg/day, orally) for one month before I/R. Myocardial regional ischemia was induced through the ligation of left coronary artery, and IPostC was applied immediately at the onset of reperfusion. The infarct size was assessed by a computerised planimetry and left ventricles samples were harvested for cardiac mitochondrial function studies (ROS production, membrane potential and staining) and western blotting was used for determination of autophagy markers. Results: None of Vilda or IPostC but combination of them could significantly reduce the infarct size of diabetic hearts, comparing to control (P<0.001). IPostC could not significantly affect p62 expression level in diabetic hearts, but pre-treatment with Vilda alone (p<0.05) and in combination with IPostC (p<0.01) more significantly decreased p62 expression in comparison with corresponding control group. The expression of LC3B-II and LC3BII/LC3BI as well as mitochondrial ROS production were decreased significantly in treatment groups (p<0.001). Mitochondrial membrane depolarization was significantly higher and mitochondrial density was lower in untreated diabetic I/R hearts than treated groups (p<0.001). IPostC in combination with vildagliptin prevented the mitochondrial membrane depolarization and increased the mitochondrial content more potent than IPostC alone in diabetic hearts. Conclusion: Combination of vildagliptin and IPostC in diabetic hearts was a well-working strategy to reduce myocardial I/R damages by restoring mitochondrial membrane potential and ROS production and modulating the autophagic activity in I/R hearts

Energy Response and Longitudinal Shower Profiles Measured in CMS HCAL and Comparison With Geant4

The response of the CMS combined electromagnetic and hadron calorimeter to beams of pions with momenta in the range 5-300 GeV/c has been measured in the H2 test beam at CERN. The raw response with the electromagnetic compartment calibrated to electrons and the hadron compartment calibrated to 300 GeV pions may be represented by sigma = (1.2) sqrt{E} oplus (0.095) E. The fraction of energy visible in the calorimeter ranges from 0.72 at 5 GeV to 0.95 at 300 GeV, indicating a substantial nonlinearity. The intrinsic electron to hadron ratios are fit as a function of energy and found to be in the range 1.3-2.7 for the electromagnetic compartment and 1.4-1.8 for the hadronic compartment. The fits are used to correct the non-linearity of the e pi response to 5% over the entire measured range resulting in a substantially improved resolution at low energy. Longitudinal shower profile have been measured in detail and compared to Geant4 models, LHEP-3.7 and QGSP-2.8. At energies below 30 GeV, the data, LHEP and QGSP are in agreement. Above 30 GeV, LHEP gives a more accurate simulation of the longitudinal shower profile

Synchronization and Timing in CMS HCAL

The synchronization and timing of the hadron calorimeter (HCAL) for the Compact Muon Solenoid has been extensively studied with test beams at CERN during the period 2003-4, including runs with 40 MHz structured beam. The relative phases of the signals from different calorimeter segments are timed to 1 ns accuracy using a laser and equalized using programmable delay settings in the front-end electronics. The beam was used to verify the timing and to map out the entire range of pulse shapes over the 25 ns interval between beam crossings. These data were used to make detailed measurements of energy-dependent time slewing effects and to tune the electronics for optimal performance

Design, Performance and Calibration of the CMS Forward Calorimeter Wedges

We report on the test beam results and calibration methods using charged particles of the CMS Forward Calorimeter (HF). The HF calorimeter covers a large pseudorapidity region (3\l |\eta| \le 5), and is essential for large number of physics channels with missing transverse energy. It is also expected to play a prominent role in the measurement of forward tagging jets in weak boson fusion channels. The HF calorimeter is based on steel absorber with embedded fused-silica-core optical fibers where Cherenkov radiation forms the basis of signal generation. Thus, the detector is essentially sensitive only to the electromagnetic shower core and is highly non-compensating (e/h \approx 5). This feature is also manifest in narrow and relatively short showers compared to similar calorimeters based on ionization. The choice of fused-silica optical fibers as active material is dictated by its exceptional radiation hardness. The electromagnetic energy resolution is dominated by photoelectron statistics and can be expressed in the customary form as a/\sqrt{E} + b. The stochastic term a is 198% and the constant term b is 9%. The hadronic energy resolution is largely determined by the fluctuations in the neutral pion production in showers, and when it is expressed as in the electromagnetic case, a = 280% and b = 11%

Design, Performance, and Calibration of CMS Hadron Endcap Calorimeters

Detailed measurements have been made with the CMS hadron calorimeter endcaps (HE) in response to beams of muons, electrons, and pions. Readout of HE with custom electronics and hybrid photodiodes (HPDs) shows no change of performance compared to readout with commercial electronics and photomultipliers. When combined with lead-tungstenate crystals, an energy resolution of 8\% is achieved with 300 GeV/c pions. A laser calibration system is used to set the timing and monitor operation of the complete electronics chain. Data taken with radioactive sources in comparison with test beam pions provides an absolute initial calibration of HE to approximately 4\% to 5\%