Vasodilatory effect of pentoxifylline in isolated equine digital veins

The direct vasodilatory action of pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) and its signalling pathway was evaluated in equine digital veins. Cumulative concentration-response curves to pentoxifylline (1 nM to 300 μM) were recorded in phenylephrine-precontracted equine digital vein rings under different experimental conditions. Relaxation to pentoxifylline was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (a non-xanthine adenosine receptor antagonist; 3 μM). Nitric oxide synthase (NOS), soluble guanylate cyclase and cyclooxygenase (COX) inhibitors (Nω-nitro-L-arginine methyl ester (100 μM), ODQ (30 μM) and indomethacin (10 μM), respectively) significantly reduced the maximum relaxation induced by pentoxifylline. Moreover, pentoxifylline-induced relaxation was strongly reduced by Rp-8-Br-PET-cyclic guanosine monophosphate-S (a protein kinase G inhibitor; 3 μM), but remained unaffected by H-89 (a protein kinase A inhibitor; 2 μM). Pentoxifylline-induced relaxation was associated with a 3.4-fold increase in tissue cGMP content. To investigate whether pentoxifylline can affect cAMP- and cGMP-mediated relaxations, curves to forskolin, to sodium nitroprusside (SNP) and 8-bromo-cGMP were also recorded in endothelium-denuded equine digital vein rings pretreated with pentoxifylline (10 and 100 μM). Pentoxifylline only potentiated the SNP-mediated relaxation at the highest concentration (100 μM). Thus, pentoxifylline relaxed equine digital veins via endothelium-dependent and endothelium-independent components. The effect was mediated through both the NOS and COX pathways and could also result from inhibition of cGMP specific-phosphodiesterase activity at the highest concentrations used

Antibodies against the second extracellular loop of β1-adrenergic receptors induce endothelial dysfunction in conductance and resistance arteries of the Wistar rat

Autoantibodies against β1-adrenoceptors (β1-ARs) have been detected in the serum of patients with various cardiac diseases; however, the pathological impact of these autoantibodies (β1-AABs) has only been evaluated in cardiac tissue. The purpose of the present study was to evaluate whether β1-AABs have deleterious effects on vascular reactivity in rats. An enzyme-linked immunosorbent assay was used to detect β1-AABs in sera from immunized rats over a period of 1–3 months using the peptidic sequence of the second extracellular loop of human β1-AR. Functional studies were performed in thoracic aortic (TA) and small mesenteric artery (SMA) rings from immunized rats. Following pre-contraction with phenylephrine (0.3 μM and 3 μM for the TA and SMA respectively), cumulative concentration–response curves (CCRCs) to various β-AR agonists (isoproterenol, dobutamine, salbutamol, SR 58611A), acetylcholine, A23187, and sodium nitroprusside (SNP) were then plotted. The relaxations induced by dobutamine, SR 58611A, and acetylcholine were significantly impaired, but salbutamol-induced relaxations were not affected, in both vessels from immunized rats. A significant impairment of isoproterenol-induced relaxation was only observed in SMA. CCRCs to SNP were not modified in either of the vessels. A23187-induced relaxation was impaired in immunized rats. Following pretreatment with l-arginine, vasorelaxation to acetylcholine and SR 58611A was restored in immunized rats. This study demonstrates that immunization against the second extracellular loop of β1-ARs has a deleterious impact on vasorelaxations in the TA and SMA of rats, involving alterations in endothelium-dependent NO signaling pathways

Autoantibodies against cardiac β(1)-adrenoceptor do not affect the low-affinity state β(1)-adrenoceptor-mediated inotropy in rat cardiomyocytes

Circulating autoantibodies directed against the 2nd extracellular loop (EL-2) of β(1)-adrenoceptors (β(1)-AABs) have been detected in the serum of patients with various cardiovascular pathologies. β(1)-AABs induce agonistic, positive inotropic effects via β(1)-adrenoceptors (β(1)ARs). In the mammalian heart, β(1)-AR can exist in 2 distinct activated configurations (the so-called high- and low-affinity states). The aim of the present study was to investigate whether the action of β(1)-AAB is dependent on the affinity state of β(1)AR in isolated ventricular cardiomyocytes of adult Wistar rats. Immunoglobulin G (IgG) containing β(1)-AAB obtained from animals immunized with a peptide corresponding to the EL-2 of human β(1)-AR, caused a dose-dependent increase in cell shortening. Isoproterenol-induced inotropy was significantly reduced in cardiomyocytes that had been preincubated with IgG containing β(1)-AAB and in cardiomyocytes isolated from immunized rats. The negative effects of preincubation with IgG containing β(1)-AAB on the response to isoproterenol was inhibited in the presence of bisoprolol. CGP 12177A and pindolol-induced inotropy was not affected by IgG preincubation or immunization. No detectable inotropic effect of cell shortening was obtained with IgG containing β(1)-AAB in the presence of propranolol and 3-isobutyl-1-methylxanthine. The present study demonstrates that β(1)-AABs have no agonist/antagonist-like effects upon low-affinity state β(1)-ARs. This result indicates that β(1)-AABs recognize and stabilize the high-affinity state, but are unable to stabilize and (or) induce the low-affinity state receptor

Photoproduction of K+K− meson pairs on the proton

The exclusive reaction γp→pK+K− was studied in the photon energy range 3.0–3.8  GeV and momentum transfer range 0.6<−t<1.3  GeV2. Data were collected with the CLAS detector at the Thomas Jefferson National Accelerator Facility. In this kinematic range the integrated luminosity was approximately 20  pb−1. The reaction was isolated by detecting the K+ and the proton in CLAS, and reconstructing the K− via the missing-mass technique. Moments of the dikaon decay angular distributions were extracted from the experimental data. Besides the dominant contribution of the ϕ meson in the P wave, evidence for S−P interference was found. The differential production cross sections dσ/dt for individual waves in the mass range of the ϕ resonance were extracted and compared to predictions of a Regge-inspired model. This is the first time the t-dependent cross section of the S-wave contribution to the elastic K+K− photoproduction has been measured

The CLAS12 software framework and event reconstruction

We describe offline event reconstruction for the CEBAF Large Acceptance Spectrometer at 12 GeV (CLAS12), including an overview of the offline reconstruction framework and software tools, a description of the algorithms developed for the individual detector subsystems, and the overall approach for charged and neutral particle identification. We also present the scheme for data processing and the code management procedures

First Measurement of Deeply Virtual Compton Scattering on the Neutron with Detection of the Active Neutron

: Measuring deeply virtual Compton scattering (DVCS) on the neutron is one of the necessary steps to understand the structure of the nucleon in terms of generalized parton distributions (GPDs). Neutron targets play a complementary role to transversely polarized proton targets in the determination of the GPD E. This poorly known and poorly constrained GPD is essential to obtain the contribution of the quarks' angular momentum to the spin of the nucleon. DVCS on the neutron was measured for the first time selecting the exclusive final state by detecting the neutron, using the Jefferson Lab longitudinally polarized electron beam, with energies up to 10.6 GeV, and the CLAS12 detector. The extracted beam-spin asymmetries, combined with DVCS observables measured on the proton, allow a clean quark-flavor separation of the imaginary parts of the Compton form factors H and E

Photoproduction of the ς+ hyperon using linearly polarized photons with CLAS

Background: Measurements of the polarization observables ς,P,T,Ox,Oz for the reaction γ - p→KS0ς+ using a linearly polarized photon beam of energy 1.1 to 2.1 GeV are reported. Purpose: The measured data provide information on a channel that has not been studied extensively, but is required for a full coupled-channel analysis in the nucleon resonance region. Method: Observables have been simultaneously extracted using likelihood sampling with a Markov-Chain Monte Carlo process. Results: Angular distributions in bins of photon energy Eγ are produced for each polarization observable. T,Ox, and Oz are first time measurements of these observables in this reaction. The extraction of ς extends the energy range beyond a previous measurement. The measurement of P, the recoil polarization, is consistent with previous measurements. Conclusions: The measured data are shown to be significant enough to affect the estimation of the nucleon resonance parameters when fitted within a coupled-channels model

Beam Charge Asymmetries for Deeply Virtual Compton Scattering on the Proton at CLAS12

The parameterization of the nucleon structure through Generalized Parton Distributions (GPDs) shed a new light on the nucleon internal dynamics. For its direct interpretation, Deeply Virtual Compton Scattering (DVCS) is the golden channel for GPDs investigation. The DVCS process interferes with the Bethe-Heitler (BH) mechanism to constitute the leading order amplitude of the $eN \to eN\gamma$ process. The study of the $ep\gamma$ reaction with polarized positron and electron beams gives a complete set of unique observables to unravel the different contributions to the $ep \gamma$ cross section. This separates the different reaction amplitudes, providing a direct access to their real and imaginary parts which procures crucial constraints on the model dependences and associated systematic uncertainties on GPDs extraction. The real part of the BH-DVCS interference amplitude is particularly sensitive to the $D$-term which parameterizes the Gravitational Form Factors of the nucleon. The separation of the imaginary parts of the interference and DVCS amplitudes provides insights on possible higher-twist effects. We propose to measure the unpolarized and polarized Beam Charge Asymmetries (BCAs) of the $\vec{e}^{\pm}p \to e^{\pm}p \gamma$ process on an unpolarized hydrogen target with {\tt CLAS12}, using polarized positron and electron beams at 10.6~GeV. The azimuthal and $t$-dependences of the unpolarized and polarized BCAs will be measured over a large $(x_B,Q^2)$ phase space using a 100 day run with a luminosity of 0.66$\times 10^{35}$cm$^{-2}\cdot$s$^{-1}$.Comment: Proposal to the Jefferson Lab Program Advisory Committee (PAC51

First measurements of the double-polarization observables F, P, and H in ω photoproduction off transversely polarized protons in the N* resonance region

First measurements of double-polarization observables in ω photoproduction off the proton are presented using transverse target polarization and data from the CEBAF Large Acceptance Spectrometer (CLAS) FROST experiment at Jefferson Lab. The beam-target asymmetry F has been measured using circularly polarized, tagged photons in the energy range 1200–2700 MeV, and the beam-target asymmetries H and P have been measured using linearly polarized, tagged photons in the energy range 1200–2000 MeV. These measurements significantly increase the database on polarization observables. The results are included in two partial-wave analyses and reveal significant contributions from several nucleon (N∗) resonances. In particular, contributions from new N∗ resonances listed in the Review of Particle Properties are observed, which aid in reaching the goal of mapping out the nucleon resonance spectrum