Maximal Relaxation Research Articles

Pharmacological evaluation of a new nanoformulation in the erectile tissue of rabbits and humans

The failure of achieving a penile erection for satisfactory sexual intercourse is known as erectile dysfunction (ED). The primary mediator for penile erection is nitric oxide (NO). ED is often associated with endothelial/nitrergic dysfunction characterized by a reduction of the bioavailability of NO. Phosphodiesterase-5 inhibitors (PDE-5Is) clinical efficacy in the treatment of ED depends on the integrity of the NO-sGC-PKG pathway. In the present study, we probed the effect of sodium nitroprusside incorporated into mesoporous silica nanoparticles (MPSi-NP), which traps cyanide and slowly releases NO. MPSi-NP induced a maximal relaxation of 92.8 ± 5.2% in rabbit corpora cavernosa (RbCC), blunted by a soluble guanylate cyclase (sGC) inhibitor and blockers of calcium-dependent potassium channels. MPSi-NP abolished spontaneous contractions of human corpora cavernosa (HCC) strips. In addition, MPSi-NP induced maximal relaxation of phenylephrine precontracted HCC by 118.6 ± 3.6%, and in comparison, tadalafil induced a maximal relaxation of HCC by 98.3 ± 1.2%. Similarly, the sGC inhibitor blocked the MPSi-NP relaxation. MPSi-NP potentiated the relaxation induced by tadalafil. MPSi-NP increased cGMP levels in HCC strips by 2.6-fold and increased by 3.5-fold the phosphorylation level of the VASP protein, which is a downstream target to PKG. MPSi-NP effectively relaxes RbCC and HCC by activating the sGC-PKG pathway and potentiates the tadalafil response. MPSi-NP could be helpful in conditions where nitric oxide availability is decreased. A topical gel formulation of MPSi-NP could be used as a rescue therapy to treat true non-responders of PDE5Is drugs.

Investigating the Difference Between Thoracic Kyphosis and its Mobility in Community-Dwelling Older Men and Women

Introduction: The amount of thoracic kyphosis and its mobility may be affected by gender in older adults. This study investigates gender differences in thoracic kyphosis and thoracic spine mobility in healthy older adults. Materials and Methods: In this cross-sectional study, 36 participants among which 21 were female and 15 were male with an age range of 65-80 years participated. The amount of thoracic spine kyphosis was measured in a relaxed standing position and the position of maximum correction of thoracic kyphosis using a flexible ruler between the spinous processes of T12 and C7. The difference between the thoracic kyphosis of the relaxed state and the condition of the maximum correction is used to determine the degree of thoracic spine mobility. Finally, men and women were compared in terms of thoracic kyphosis and thoracic spine mobility. The student t-test was employed to compare kyphosis and spinal mobility between men and women, and the paired student t-test was used to compare kyphosis angle in a relaxed posture and maximum kyphosis correction status. Meanwhile, the Pearson test was utilized to evaluate the relationship between variables. Results: Although there was no statistically significant difference in the mean thoracic kyphosis of relaxation (P=0.13) and maximal correction (P=0.18) status of healthy old men and women, there was a significant positive relationship between the rate of kyphosis angle and the amount of mobility of thoracic kyphosis (P=0.003; r=0.48). Conclusion: There is no difference in the degree of kyphosis and thoracic spine mobility in older men and women. In addition, people with more thoracic kyphosis had more spinal mobility.

Abstract 32: Vγ6 + γδ T cells protect against angiotensin II-induced hypertension and vascular injury in male mice

Background: γδ T cells mediate angiotensin II (AngII)-induced blood pressure (BP) elevation, vascular injury and activated T cell infiltration in mesenteric vessels with adherent perivascular adipose tissue (MV/PVAT). γδ T cells expressing specific T cell receptor (TCR) variable (V) chain γ develop in several waves in the thymus and migrate to diverse tissues. We hypothesized that γδ T cells expressing specific Vγ subtypes in perivascular tissue are implicated in AngII detrimental hypertensive effects. Methods: C57BL/6J male mice were infused or not with AngII (490 ng/kg/min, SC) for 14 days. Vγ1 and Vγ2 (Vγ1/2) + , Vγ4 + , Vγ5 + , Vγ6 + , and Vγ7 + γδ T cell frequencies and T cell phenotypes were determined by flow cytometry in the spleen, descending thoracic aorta (DTAo)/PVAT, and MV/PVAT (n=7-13). Other sets of AngII-infused mice were injected with control or anti-Vγ6 (n=7-12) or Vγ4 antibodies (n=5-8). BP was determined by telemetry, mesenteric artery (MA) function and remodeling by pressurized myography, and T cell phenotypes by flow cytometry. Results: In DTAo/PVAT and MV/PVAT, respectively, 43±5% and 51%±6% of γδ T cells were Vγ6 + , and 17±2% and 23±4% Vγ4 + , whereas in the spleen, 36±2% of the γδ T cells were Vγ1/2 + , 32±1% Vγ4 + and 24±1% Vγ6 + . AngII increased the frequency of Vγ6 + γδ T cells in the spleen (0.8±0.1 vs 0.5±0.0% of CD3, P <0.001) and DTAo/PVAT (5.9±0.8 vs 3.6±0.5% of CD3, P <0.05), and tended to increase their frequency in MV/PVAT. The majority of Vγ6 + γδ T cells were activated (CD69 + ) in DTAo/PVAT (75±5%) and MV/PVAT (84±2%). Vγ6 + γδ T cell depletion caused a steeper BP elevation ( P <0.05) and worsened MA endothelial dysfunction (maximal acetylcholine relaxation response: 28±3 vs 55±8%, P <0.05) in mice infused with AngII. This was associated with increased CD69 + non-Vγ6 + γδ T cells in DTAo/PVAT (3.0±0.7 vs 0.8±0.4% of CD3, P <0.01) and MV/PVAT (15.2±2.6 vs 4.9±1.0% of CD3, P <0.01). Depletion of Vγ4 + γδ T cells in perivascular tissues, did not alter the AngII detrimental effects. Conclusions: Vγ6 + γδ T cells are the most abundant γδ T cell Vγ subtype in perivascular tissues. AngII increased Vγ6 + γδ T cells in the spleen and perivascular tissue. Vγ6 + γδ T cell depletion in AngII-infused mice induced a steeper BP elevation, worsened MA endothelial dysfunction, and activated non-Vγ6 + γδ T cells. Vg6 + γδ T cells may play a protective role in AngII-induced hypertension and vascular injury.

Abstract P153: The Role of Lipoprotein Lipase Activation in Vascular Aging

Lipoprotein metabolism plays a role in cardiovascular diseases and becomes impaired with aging. Angiopoietin-like proteins (ANGPTLs) regulate lipoprotein lipase (LPL) and endothelial lipase (EL), key hydrolases in triglyceride catabolism. We hypothesized that ANGPTL3 and ANGPTL4 would be elevated in aging and that the response to LPL activation would be impaired in mesenteric resistance arteries (MRAs) from old rats. To assess this, MRAs were isolated from 3 and 16-month-old male and female Fischer344 rats and mounted on wire myographs. Concentration-response curves (CRC) to phenylephrine (PE, 10nM-100μM), Ca 2+ channel agonist Bay-K8644 (10nM-30nM), and acetylcholine (ACh, 0.1nM-100uM) were performed with or without LPL activator, NO-1886 (10uM and 50uM). Protein expression was assessed by Western blot. We show for the first time that circulating ANGPTL3 (young: 1.5±0.8 vs old: 5±0.7) and ANGPTL4 (young: 1.7±0.3 vs old: 2.5±0.5) are increased in aging. In MRAs from young rats, NO-1886 attenuated PE-induced contraction in males (Emax; vehicle: 106±3 vs NO-1886 10uM: 86 ± 5* vs NO-1886 50uM: 69±8*, p<0.05) and females (Emax; vehicle: 104±4 vs NO-1886 10uM: 91±5* vs NO-1886 50uM: 75±8*, p<0.05). While 16-month-old males presented a similar reduction in contraction (Emax; vehicle: 105±6 vs NO-1886 10uM: 88±11* vs NO-1886 50uM: 73±17*, p<0.05), in females only 50uM showed a significant anti-contractile effect in a sex-dependent manner (Emax; vehicle: 100±7 vs NO-1886 10uM: 95±7 vs NO-1886 50uM: 83±22*, p<0.05). CRC to bay-K8644 showed decreased contraction after NO-1886 incubation (Emax; vehicle: 16±8 vs NO-1886 50uM: 5±3) indicating that L-type Ca 2+ channel Ca 2+ influx isn’t involved in NO-1886’s anti-contractile effect. NO-1886 incubation did not change the maximal ACh response in young rat MRAs, but a rightward shift in the curve was seen in both sexes. As expected, MRAs from old males (Emax; young: 97±2 vs old: 86±7) and females (Emax; young: 95±2 vs old: 92±6) had decreased maximal relaxation to ACh, compared to young rats. Interestingly, in old rats NO-1886 induced further impaired relaxation to ACh in males (Emax; vehicle: 86±7 vs NO-1886 10uM: 78±14) and females (Emax; vehicle: 92±6 vs NO-1886 10uM: 77±22). Together, this data suggests (1) ANGPTL3 and ANGPTL4 are increased in old rats, (2) LPL/EL activity diminished with age in females, but not males, and (3) while NO-1886 exerts an anti-contractile effect, it can also induce endothelial dysfunction.

Inelastic relaxation in tin oxide thin films with an amorphous structure

Inelastic relaxation in amorphous tin oxide thin films obtained by ion-beam sputtering in an argon atmosphere were studied. The films retain an amorphous structure after annealing at temperatures below 623 K for 30 min and crystallization begins after annealing at 673 K with the formation of two phases, where the SnO2 phase predominates over the SnO phase. Annealing at 723 K for 30 min leads to a partial transition of the SnO crystalline phase to the SnO2 phase.The temperature dependence of internal friction revealed maxima at 585 K and 603 K, identified as β - relaxation maxima, as well as at 690 K, identified as α - relaxation maximum. It is assumed that the β - relaxation maxima at 585 K and 603 K are associated with local hopps of oxygen atoms within the defect structure of SnO2 and with local hopps of tin atoms within the defect structure of SnO, respectively. The exponential increase in internal friction up to a temperature of 690 K in the α - relaxation region is associated with the diffusion of nonequilibrium vacancy-like defects of the amorphous structure below the glass transition temperature and equilibrium ones above the glass transition temperature. Estimates of the migration energy and formation energy of vacancy-like defects in amorphous tin oxide were made.

Electron-ion relaxation times in 1–100 eV warm dense aluminum and gold

We calculated the electron-ion energy relaxation times in warm dense aluminum and gold. Our calculations span a wide temperature range from a thousand to a million kelvins for both dense aluminum and gold. To determine the temporal evolution of electron and ion temperatures, we employed the two-temperature model with the SESAME equation-of-state tables, and well-known electron-ion coupling factors. Our calculations indicate that the relaxation times for warm dense aluminum were within 5 ps, whereas they were within 20 ps for warm dense gold. The maximum relaxation times were observed at initial electron temperatures of approximately 30,000 K for both aluminum and gold. Our calculated relaxation times using the SESAME database agree very well with the existing theories both in the cold-solid and hot-plasma limits. Furthermore, we found that the melting times calculated using the Lindemann criterion were in good agreement with the melting times for gold from measurements in recent literature.

Non-similar analysis of two-phase hybrid nano-fluid flow with Cattaneo-Christov heat flux model: a computational study

The purpose of this research elaborates the behaviour of the two-phase hybrid nano-fluid flow of viscous fluid through the stretching sheet. Impacts of heat transfer, for MHD two-dimensional steady flow over stretching surface with Cattaneo-Christov (CC) model are discussed. Bio-convective, thermal radiation and convective conditions are considered. Porous surface and velocity slip effects are also considered. Darcy-Forchheimer relation characterizes porous medium. The governing equations are solved through MATLAB. Plots of temperature and velocity fields are discussed via various estimations of emerging variables. Results findings shows the velocity profile decreases in case of both simple and hybrid nano-fluids for higher estimations of magnetic parameter and local inertia coefficient parameter. Fluid temperature reduces for maximum thermal relaxation parameter and possess higher values against radiation parameter. Microorganism profile reduces bio-convection Lewis number but increases for the magnetic parameter. Prominent results from this study include determining the effective parameters to enhance heat transfer efficiency and defining the circumstances in which the nano-fluid performs better than traditional fluids. These discoveries offer significant perspectives on the utilization of Cattaneo-Christov model with hybrid nano-fluid flow in comprehensive thermal management systems and establish a basis for subsequent practical and theoretical investigations within the domain.

Spinel ferrites having conductive grains, resistive interfacial boundaries and relaxation mechanism for possible supercapacitor applications

Linear increase in crystallite size (16–24 nm) of MnxZn1−xFe2O4 nanostructures and mixed behavior of lattice constant (8.429–8.462 Å) is reported. The system exhibits considerable promise for microwave applications due to its elevated dielectric constants and minimal dispersion losses from 20 Hz to 20 MHz. With x = 0.75, sample is good for energy storage devices like supercapacitors due to large specific surface area (53 m2/g) and dielectric constant. These samples exhibit maximum relaxation times ranging from 1.97 × 10−7 s to 2.43 × 10−4 s, with corresponding relaxation energy values spanning from 159.22 meV to 341 meV for x = 0 and x = 1 samples. The Cole-Cole plots reveal that grains exhibit conductive behavior at lower frequencies, while grain boundaries contribute significantly to the resistive behavior. Additionally, we have introduced Bode diagrams and equivalent electronic circuit models for the first time, offering valuable insights into the electrical behavior of the nanomaterial samples.

Effects of Myocardial Infarction-induced Heart Failure on Diaphragm Arteriolar Vasorelaxation

INTRODUCTION: Diaphragm atrophy and contractile dysfunction are prevalent in heart failure (HF), diminishing physical capacity and quality of life. The delivery of blood flow and oxygen necessary to support the metabolic demand of contractions is largely governed by the resistance vasculature (i.e., arterioles) with the endothelium playing a central role in arteriolar vasorelaxation. Adequate perfusion and blood flow distribution, and thus resistance vessel vasodilation, is a major determinate of diaphragm contractile function. While the mechanistic bases of HF-induced diaphragm dysfunction continue to be elucidated, the impact of HF on diaphragm vasomotor control has not been investigated. METHODS: Adult (6 mo) Sprague-Dawley rats (n=7) were divided into two groups: 1) Healthy Control (HC; n=4) and 2) MI-induced heart failure (HF; n=3). First-order arterioles (1A) from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O and allowed to equilibrate for 60 min to develop spontaneous tone. Thereafter, endothelium-dependent and -independent vasorelaxation responses to cumulative doses of acetylcholine (ACh; 10−9 to 10−4M) and sodium nitroprusside (SNP; 10−9 to 10−4M) were determined. RESULTS: There were no differences in spontaneous development (%) or maximal diameter (μm) between HC (20 ± 4%; 178 ± 11 μm) and HF (18 ± 2%; 184 ± 29 μm) diaphragm 1As ( P > 0.05). Maximal ACh-mediated relaxation (%) was significantly reduced in HF rats compared to HC rats (52 ± 2 versus 68 ± 5%; P < 0.05). Maximal endothelial-independent vasorelaxation with SNP, was not different between HC and HF rats (71 ± 3 versus 73 ± 1%; P > 0.05). CONCLUSION: The preliminary data herein demonstrate that HF impaired endothelial function and vasomotor function in the medial costal diaphragm resistance vasculature. This suggests that, in HF, there may be a redistribution of blood flow to less effcient regions of the diaphragm (e.g., ventral costal) to sustain contractile function and compensate for the diminished medial costal vasomotor function demonstrated herein. Studies including a larger sample size are warranted to investigate the impact of HF on regional blood flow distribution and resistance vessel function in the diaphragm. Such investigations would yield novel mechanistic insights into HF-induced diaphragm dysfunction. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Strain Relaxation Characterization on Lithium‐ion Batteries at Different States of Charge and Charging Rates

The strain on the cell casing can serve as an indicator of the internal state of the cell. Monitoring strain during the charging and discharging processes aids in determining optimal charging and discharging operations, thereby maximizing the lifespan and performance of the battery. Herein, strain dynamic curves are obtained for lithium‐ion batteries at low, medium, and high charge and discharge rates by affixing strain gauges to individual cells. The investigation delves into parameters such as strain relaxation time, maximum strain, and residual strain at various charge rates and states of charge. The experimental findings reveal distinctive patterns, indicating that the strain curve during high‐rate charging resembles a second‐order function, exhibiting more pronounced fluctuations as the rate increases. This stands in stark contrast to the strain exponential decay observed during conventional medium and low‐rate charging. Notably, the strain residual resulting from high‐rate charging proves to be several times higher than that observed in low‐rate charging, hinting at potential differences in the dynamic distribution of lithium ions within batteries during high‐rate versus medium‐low‐rate charging modes.

Multiscale simulations of viscoelastic fluids in complex geometries using a finitely extensible nonlinear elastic transient network model

This paper presents a novel implementation of a numerical scheme for predicting complex flows of viscoelastic fluids using a finitely extensible nonlinear elastic (FENE) transient network model. This model extends the FENE model by incorporating chain interactions and accounting for the way in which the maximum chain length, drag, and relaxation time are influenced by entanglement and disentanglement processes. Three different initial networks are considered (disentanglement, entanglement, and aleatory), and the influence of variables such as the kinetic rate constants, elasticity, and chain length on the microstate concentration, stresses, and drag force is investigated. It is shown that although the concentrations of the microstates are independent of the Weissenberg number and the maximum extension length, the stresses and hence the drag are influenced by them.

Ability of Adjusting Grip Strength From Childhood to Adulthood

Purpose: This cross-sectional study aimed to investigate the ability to adjust grip strength by comparing the characteristics of force generation and relaxation from childhood to adulthood. Method: This study included 225 participants aged 6, 11, 17, and 19–23 years (adults) who performed isometric hand-grip force as follows: maximum, half generation, and half relaxation. The force was recorded, and relative values and errors were calculated for half tasks. Results: The maximum task values increased with age, but there was no significant age difference between 17-year-olds and adults. The difference between sexes was significant; males were stronger than females in both 17-year-olds and adults. Both sexes in all age groups had greater errors in half relaxation than in half generation tasks. Females had negatively greater constant error than males in half tasks. The errors of 6-year-olds were greater than the other age groups in half tasks. Conclusion: There is a developmental trend for producing maximal strength that is similar across sexes until adolescence when males are stronger and females plateau. The ability of force relaxation was more difficult to accurately control than force generation for all age groups and was adult-like by middle childhood.

Preferential vasodilator effects of levosimendan in resistance pulmonary arteries in a rodent pulmonary embolism model

Background: We compared the vasoactive effects of levosimendan on isolated conduit pulmonary arteries (CPA) and resistance pulmonary arteries (RPA) versus mesenteric arteries, and we assessed the pulmonary artery (PA) vascular function and the PA vasoactive effects of levosimendan in a rodent pulmonary embolism (PE) model.Methods: One group of male Wistar rats (200-300 g) was killed by decapitation to obtain pulmonary and mesenteric rings. Another group was assigned to a massive PE or saline solution infusion. After euthanasia, mesenteric arteries and CPA (1-2 mm) and RPA (≤0.5 mm) were dissected and cut into 2-3 mm wide rings, recording contractile tension. We obtained the concentration-response curves of cumulative doses of levosimendan on pre-contracted arterial rings from decapitated and sham/embolized animals. A set of RPA rings was exposed to acute hypoxia. The effect of PE on the pulmonary vasoactive function was assessed by dose-response curves of acetylcholine (ACh) and endothelin-1 (ET-1) of PA rings from sham/embolized animals.Results: Levosimendan relaxant potency of RPA was similar to that of mesenteric arteries and higher than CPA, while mesenteric rings showed the maximal relaxant effect, followed by RPA and CPA, respectively. PE did not affect the vasoactive response of PA rings either to ACh or to ET-1, and the relaxant effects of CPA and RPA to levosimendan were also preserved. Acute hypoxia reduced (p<0.05) but did not avoid the RPA relaxant effect of levosimendan.Conclusions: Levosimendan is a more specific vasodilator of RPA with a similar relaxant potency as mesenteric arteries, which is preserved after PE but significantly reduced during hypoxia.

Naodesheng decoction regulating vascular function via G-protein-coupled receptors: network analysis and experimental investigations.

Introduction: Ischemic stroke (IS) is a detrimental neurological disease with limited treatment options. Recanalization of blocked blood vessels and restoring blood supply to ischemic brain tissue are crucial for post-stroke rehabilitation. The decoction Naodesheng (NDS) composed of five Chinese botanical drugs, including Panax notoginseng (Burk.) F. H. Chen, Ligusticum chuanxiong Hort., Carthamus tinctorius L., Pueraria lobata (Willd.) Ohwi, and Crataegus pinnatifida Bge., is a blood-activating and stasis-removing herbal medicine commonly used for the clinical treatment of cerebrovascular diseases in China. However, the material basis of NDS on the effects of blood circulation improvement and vascular tone regulation remains unclear. Methods: A database comprising 777 chemical metabolites of NDS was constructed. Then, the interactions between various herbal metabolites of NDS and five vascular tone modulation G-protein-coupled receptors (GPCRs), including 5-HT1AR, 5-HT1BR, β2-AR, AT1R, and ETBR, were assessed by molecular docking. Using network analysis and vasomotor experiment of the cerebral basilar artery, the potential material basis underlying the vascular regulatory effects of NDS was further explored. Results: The Naodesheng Effective Component Group (NECG) was found to induce relaxation of rat basilar artery rings precontracted using Endothelin-1 (ET-1) and KCl in vitro in a dose-dependent manner. Several metabolites of NDS, including C. tinctorius, C. pinnatifida, and P. notoginseng, were found to be the main plant resources of metabolites with high docking scores. Furthermore, several metabolites in NDS, including formononetin-7-glucoside, hydroxybenzoyl-coumaric anhydride, methoxymecambridine, puerarol, and pyrethrin II, were found to target multiple vascular GPCRs. Metabolites with moderate-to-high binding energy were verified to have good rat basilar artery-relaxing effects, and the maximum artery relaxation effects of all three metabolites, namely, isorhamnetin, kaempferol, and daidzein, were found to exceed 90%. Moreover, metabolites of NDS were found to exert a synergistic effect by interacting with vascular GPCR targets, and these metabolites may contribute to the cerebrovascular regulatory function of NDS. Discussion: The study reports that various metabolites of NDS contribute to its vascular tone regulating effects and demonstrates the multi-component and multi-target characteristics of NDS. Among them, metabolites with moderate-to-high binding scores in NDS may play an important role in regulating vascular function.

Iterative convex relaxation of unbalanced power distribution system integrated multi-energy systems

This study describes a multi-period, multi-energy operation of a three-phase unbalanced Electric Distribution System (EDS) that coordinates with a District Heating System (DHS) and a Natural Gas (NG) distribution system. The electrical subsystem problem is formulated as a bi-level programming problem, with levels 1 and 2 solving the subsystem’s linearized and relaxed nonlinear versions, respectively. Second-Order Cone Programming (SOCP) and polyhedral relaxations are availed to circumvent the non-convexities involved in the subsystems. The SOCP relaxation for an unbalanced power distribution network is inexact; also, the subsystems applying polyhedral relaxation may not generate a meaningful solution as the relaxations are not tight. Therefore, a solution recovery algorithm is developed for each subsystem to recover a feasible solution from their relaxed counterparts. The successive bound tightening algorithm employing a solution recovery procedure is proposed for each subsystem, improving solution quality and strengthening the relaxations with the desired computational efficiency. The proposed solution strategy to optimize the Multi-Energy System (MES) operation cost is verified on the three-phase IEEE-13 and IEEE-123 bus systems, each coordinating with a 30-node DHS and a 6-bus NG network. The results analyses demonstrate that the proposed solution strategy efficiently achieves an optimal solution, reducing maximum relaxation error below 0.1% for each subsystem. The proposed strategy delivered a 14.58% reduction in real power losses and a 12.73% decrease in phase voltage unbalance rate for the EDS in MES. Furthermore, a 1.96% decrease in operational cost demonstrates the techno-economic benefits of the proposed strategy.

(250) NLRP3 Inflammasome Might Contribute to Erectile Dysfunction Induced by Chronic Unpredictable Stress in Male Mice

Abstract Introduction Introduction: The association of stress with erectile dysfunction (ED) is well known, however, it is not clear whether psychological stressors affect the vasculature and the erectile tissue in a manner that could contribute to a vasculogenic erectile dysfunction. Besides hormonal changes, cellular damage induced by stress could lead to the activation of the NLRP3, to increase production of cytokines associated with ED. In this study, we aimed to evaluate the reactivity of the corpus cavernosum and pudendal artery of male mice undergoing chronic unpredictable stress (CUS). Objective Objective: We hypothesize that CUS leads to mitochondrial damage and activates the NLRP3 inflammasome leading to impaired reactivity of the pudendal artery and corpus cavernosum which might cause erectile dysfunction. Methods Methods: Male C57Bl/6 mice were submitted to 28 days of chronic unpredictable stress (CUS). The pudendal artery and corpus cavernosum were removed and mounted in a myograph to evaluate reactivity. Tissues were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2 and concentration-response curves to acetylcholine (ACh; 1 nM – 30 uM) and phenylephrine (PE; 1 nM – 30 uM) were obtained. Using non-linear regression, we obtained the maximal response (Emax) and potency (pEC50) of ACh and PE. Expression of NLRP3, pro-caspase1 and caspase1 were measured in arteries by Western blot. Data are expressed as mean ± S.E.M. P<0.05 was considered statistically different. Results Results: CUS led to a significant decrease in the maximal relaxation induced by acetylcholine in the pudendal artery (Non-CUS: 96 ± 3% vs CUS: 84 ± 7%, n=6 and 7, respectively) and in the corpus cavernosum (Non-CUS: 88 ± 4% vs CUS: 75 ± 4%, n=7 each group) as well as an impaired contraction to PE in the corpus cavernosum (non-CUS: 1.72 ± 0.17% vs CUS: 1.07 ± 0.15%, n= 7 each group). In arteries, there were no differences in the expression of NLRP3, however, the ratio of caspase1/pro-caspase-1 was increased in CUS, suggesting that CUS increases the NLRP3 inflammasome pathway. Taken together, our data suggest that CUS led to an activation of the NLRP3 inflammasome pathway, and impaired the relaxation of the pudendal artery and corpus cavernosum by a mechanism that might be associated with decreased nitric oxide bioavailability (endothelium-dependent relaxation), whereas impaired contraction might be associated with desensitization of alpha-adrenergic receptors in response to stress. Conclusions Conclusion: Our findings demonstrate that stress impairs the reactivity of the corpus cavernosum and pudendal artery likely associated with the activation of NLRP3 inflammasome, which might play a role in the development of erectile dysfunction in stressed males. Disclosure No.

Adiponectin secretion by perivascular adipose tissue supports impaired vasodilation in a mouse model of accelerated vascular smooth muscle cell and adipose tissue aging

ObjectivePerivascular adipose tissue (PVAT) function during aging has not been investigated in detail so far and its effect on vasodilation remains to be fully elucidated. The aim of this study was to investigate endothelium-dependent vasodilation of thoracic aorta in a mouse model of accelerated, selective vascular smooth muscle and PVAT aging, induced by SM22α-Cre-driven genetic deletion of the endonuclease ERCC1 (SMC-KO mice) versus healthy littermates (LM). We hypothesized that PVAT enhances vasodilation in LM, possibly through adiponectin secretion, which might be compromised in SMC-KO animals. MethodsThoracic aorta was isolated from SMC-KO animals and LM and segments with and without PVAT were mounted in wire myography setups. The endothelium-dependent vasodilation was assessed via acetylcholine dose-response curves and pathway contribution was studied. Moreover, adiponectin secretion was measured after stimulating the aortic segments with PVAT with acetylcholine. ResultsAdiponectin, secreted by PVAT, led to increased NO-contribution to endothelium-dependent vasodilation in healthy LM, although this did not increase maximum relaxation due to loss of EDH. Endothelium-dependent vasodilation was decreased in SMC-KO animals due to reduced NO-contribution and complete EDH loss. Despite strong lipodystrophy the PVAT partially compensated for lost vasodilation in SMC-KO. LM PVAT contained acetylcholinesterase that attenuated acetylcholine responses. This was lost in SMC-KO. ConclusionsPVAT-derived adiponectin is able to partially compensate for age-related decline in NO-mediated vasodilation, even during strong lipodystrophy, in conditions of absence of compensating EDH. In aorta with healthy PVAT acetylcholinesterase modulates vascular tone, but this is lost during aging, further compensating for decreased acetylcholine responsiveness. Thus, preservation of adiponectin levels, through relatively increased production in lipodystrophic PVAT, and reduction of cholinesterase might be regulatory mechanisms of the PVAT to preserve cholinergic vasodilation during aging.

Magnetic anisotropy and slow relaxation of magnetisation in double salts containing four- and six-coordinate cobalt(II) complex ions.

Four novel Co(II) coordination compounds 1-4 of the general formula [Co(Ln)2][Co(NCY)4]·mCH3CN (where Ln are tridentate ligands L1 = 2,6-bis(1-hexyl-1H-benzimidazol-2-yl)pyridine for 1 and 2; L2 = 2,6-bis(1-octyl-1H-benzimidazol-2-yl)pyridine for 3; L3 = 2,6-bis(1-dodecyl-1H-benzimidazol-2-yl)pyridine for 4, Y = O for 1, 3, and 4 and Y = S for 2; m = 0 for 1 and 3, m = 0.5 for 2 and m = 2 for 4) were prepared and characterised. The molecular structures of all four compounds consist of the hexacoordinate complex cation [Co(Ln)2]2+ and tetracoordinate complex anion [Co(NCY)4]2-, with distorted octahedral and tetrahedral symmetry of coordination polyhedra, respectively. The electronic structures of all compounds feature an orbitally non-degenerate ground state well-separated from the lowest excited state, which allows the analysis of the magnetic anisotropy by the spin Hamiltonian model. ZFS parameters, derived from both CASSCF-NEVPT2 calculations and magnetic data analysis, indicate that tetrahedral anions [Co(NCY)4]2- exhibit small axial parameters |D| spanning the range of 2.2 to 7.7 cm-1, while octahedral cations [Co(Ln)2]2+ display significantly larger |D| parameters in the range of 37 to 95 cm-1. For 1-3, the Fourier-transform infrared magnetic spectroscopy (FIRMS) revealed a reasonable transmission with a magnetic absorption around the expected value for the ZFS accompanied by features allowing to identify phonon frequencies and simulate spin-phonon couplings. Dynamic magnetic investigations unveiled the field-induced slow relaxation of magnetisation, with maximal relaxation times (τ) of 92(2) μs for 2 at 2 K and BDC = 0.3 T. The temperature evolution of τ was analysed using a combination of Orbach, direct and Raman relaxations (Ueff = 8(1) K (5.6 cm-1)) or Orbach, direct and spin-phonon induced relaxations (Ueff = 10.3(9) K (7.2 cm-1)). The rest of the complexes, namely 1, 3, and 4 show field-induced slow relaxation of magnetisation with τ smaller than 16 μs.

Optimization of resting tension for wire myography in male rat pulmonary arteries.

Wire myography to test vasomotor functions of blood vessels ex-vivo are well-established for the systemic circulation, however, there is no consensus on protocols for pulmonary arteries. We created a standardized wire myography protocol for healthy rat PAs and validated this in a pulmonary hypertension (PH) model. Vessels stretched to higher initial tensions (5.0, 7.5 and 10.0 mN) exhibited a uniform response to phenylephrine, a larger dynamic range, and lower EC50 values. The endothelium-mediated relaxation showed that moderate tensions (7.5 and 10.0 mN) produced robust responses with higher maximum relaxation and lower EC50 values. For endothelium independent responses, the higher initial tension groups had lower and more consistent EC50 values than the lower initial tension groups. Pulmonary arteries from rats with PH were more responsive to vasoactive drugs when subjected to a higher initial tension. Notably, vessels in the PH group subjected to 15.0 mN exhibited high dynamic ranges in contractile and relaxation responses without tearing. Lastly, we observed attenuated cholinergic responses in these vessels-consistent with endothelial dysfunction in PH. Therefore, a moderate initial tension of 7.5-10.0 mN is optimal for healthy rat pulmonary arteries and a higher initial tension of 15.0 mN is optimal for pulmonary arteries from animals with PH.

286 Evaluation of Serotonin as a Vasorelaxant in Ovine Saphenous Artery and Vein

Abstract Herbivores that consume ergot alkaloids frequently suffer from vasoconstriction that can result in a myriad of symptoms that can range from necrosis of peripheral tissues to fetal intra-uterine growth restriction. As part of a larger study screening compounds that may mitigate the vasoconstrictive effects of ergot alkaloids, the objective of this experiment was to evaluate serotonin (5-HT) as vasorelaxant in the ovine saphenous artery and vein. Blood vessels were collected from a total mixed breed market rams (n = 16; approximate BW = 58 kg) at slaughter, cleaned of surrounding adipose and connective tissue, sliced into 2-mm cross-sections, and mounted in a multimyograph. Artery and vein cross-sections were equilibrated to 1 g tension in continuously gassed (95% O2/5% CO2) Krebs-Henseleit buffer (pH 7.4; 37.5 °C) for 90 min, precontracted with 0.0001 M phenylephrine for 15 min, exposed to concentrations of 5-HT that ranged from 1 x 10-9 to 1 x 10-4 M for a 5-min interval. Response data were normalized to the 0.0001 M phenylephrine response and were analyzed as a completely randomized design in SAS. The lateral saphenous vein (n = 5 lambs) relaxed to increasing concentrations of 5-HT (P < 0.05) with 65 to 75 % relaxation occurring at 1 x 10-7 M through 1 x 10-4 5-HT. Conversely, the lateral saphenous artery (n = 6 lambs) contracted in response to increasing concentrations of 5-HT (P < 0.05) resulting in a 255% increase from the phenylephrine response by the 1 x 10-4 M addition. In a subsequent experiment, saphenous veins from the remaining lambs (n = 5) were treated the same, but in place of increasing concentrations of 5-HT, saphenous veins were exposed to increasing concentrations of selective 5-HT receptor agonists to determine the receptor subtypes involved in the previously observed vasorelaxation. Agonists for receptors 5-HT2B (BW 723C86; α-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride), 5-HT4 (BIMU-8; 2,3-Dihydro-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride), and 5-HT7 (LP44; 4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide, monohydrochloride) were used. These 5-HT receptor subtypes were selected based on their association with vascular smooth muscle relaxation. While all three 5-HT receptor subtypes resulted in vasorelaxation (P < 0.05), the 5-HT2B agonist only stimulated a maximal relaxation of 32% compared with the agonists for 5-HT4 and 5-HT7 that resulted in maximal relaxation of 68% and 50%, respectively. The agonist for 5-HT4 produced the greatest relaxation in the ovine lateral saphenous vein and should be targeted in subsequent research. It is likely that the combined effect of binding multiple receptor subtypes contributes to the overall effect of 5-HT. The focus on development of ergot alkaloid mitigation strategies should consider the divergent responses of arteries and veins to serotonin in peripheral tissues.