Contraction In Response Research Articles

Effects of In Vivo / In Vitro Melatonin Application on the Duodenum in Rats with Experimental Hyperthyroidism

The aim of this study was to investigate the effects of melatonin on the intestinal motility of hyperthyroidism rats. Therefore, we determined in vivo and in vitro effects of melatonin on duodenal tissue in experimental hyperthyroid rats. 34 Wistar-Albino male rats were fed with physiological conditions, and then euthanized by cervical dislocation. The experimental animals, Group 1: Control group (n=5), Group 1B: Melatonin group in vitro (n=5), Group 1C: Melatonin group in vivo (n=6), Group 2: 2A: Hypertension group (n=6), 2B: Group 2: Hyperthyroidi sm in vitro melatonin group (n=6), 2C: Hyperthyroidism in vivo melatonin group (n=6). Acetylcholine (ACh, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M), potassium chloride (KCl, 20, 40, 60, 80, 100 mM) at the end of the incubation period different doses were given to the bathing environment. In in vitro melatonin groups, the determined submaximal doses (ACh 10-4 M, KCl 60 mM) and melatonin at different doses (Mel 10-10, 10-9, 10-8, 10-7, 10-6, 10-5 and 10-4 M) were applied. It was determined that the contraction responses of the isolated duodenal tissues induced by KCl and ACh increased significantly (p

Eccentric contraction response of stimulated skeletal muscle fascicle at the various strain rates and stimulation timing

Eccentric contraction response of stimulated skeletal muscle fascicle at the various strain rates and stimulation timing

Effect of Vitamin K2 on Blood Rheology and Vascular Responses in Diabetic Rats

Background/aim: Diabetes is manifested by endothelial dysfunction and an imbalance between vasoconstriction and vasodilation. The aim of our study is to examine the effect of vitK2 application on vascular and rheological parameters in a rat diabetes model. Materials and methods: A total of 60 male Wistar Albino rats were used to examine vascular responses and hemorheological parameters. A total of 6 groups were: control (C), control+vehicle (Cv), control+vitK2 administered (C + K2), diabetes (D), diabetes+vehicle (Dv), and diabetes+vitK2 (D + K2) group. After the animals were sacrificed, blood and vascular samples were taken and the contraction and relaxation responses of the aorta and erythrocyte deformability and aggregation were examined. Results: When KCl dose-response curves are evaluated; Increased vasoconstriction response was found in the Dv group compared to the Cv group. The increase in vasoconstriction observed in the Dv group decreased with the application of vit K2. D+vitK2 group thoracic aorta contraction responses returned to Cv group levels. In response to increasing cumulative doses of Phe, a significant increase in vasoconstriction response was observed in the Dv group compared to the Cv group. VitK2 application reduced the Phe-mediated contractile response, which was increased in the Dv group, and returned the contraction response to Cv conditions except for two intermediate Phe doses. In the Dv + K2 group, a significant decrease was observed in the aggregation index, which was tended to increase. Conclusion: Considering the cardiovascular complications frequently observed in diabetes, it can be suggested that vitK2 therapy may yield positive outcomes in diabetes.

Role of Phenylethanolamine-N-methyltransferase on Nicotine-Induced Vasodilation in Rat Cerebral Arteries.

The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on β2-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak β2-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the β2-adrenoceptors to induce neurogenic vasodilation. Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats. Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and Nω-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a β1-adrenoceptor antagonist) combined with ICI-118,551 (a β2-adrenoceptor antagonist). These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.

On characteristics of K0 value and shear behaviour of loess using triaxial test

Compared with conventional soils, such as sand and clay, little knowledge on the coefficient of lateral earth pressure at-rest (K0) has been established for loess in the current literature. This paper presents an experimental investigation on K0 of compacted loess and the associated impacts on undrained shear behaviour. By adopting a K0 consolidation module in the triaxial system, the K0 stress state for loess samples was achieved through a unique feedback control. During the K0 consolidation, the deviatoric stress (q) increases progressively with the premise that the volumetric strain (εv) of the sample equals to the axial strain (εa). The results show that the K0 value of compacted loess is in a range of 0.28 to 0.53, which is dependent on the packing density and the clay content. A distinguishable decrease of K0 was found in the course of K0 consolidation for the loosely compacted loess sample, whereas a similar trend was not observed in the dense sample. In the undrained shear stage, all loess specimens revealed contractive response in the stress path (q-p’) diagram, which can be quantified by a modified collapsibility index (Ic). The index is consistently higher for the K0 consolidated loess samples than for the isotropic ones. The experimental results indicate a strong impact of the initial stress state on the shear behaviour of compacted loess.

The relaxation effect of endocannabinoid anandamide on isolated rat bladder and vas deferens tissues and possible mechanisms.

The endocannabinoid system plays important roles in various systems, including the genitourinary system; however, its mechanism of action is not fully understood. This study aimed to investigate the direct relaxant effects of anandamide and its possible mechanisms in isolated rat bladder and vas deferens tissues. Twenty-one adult male Wistar albino rats were used. Bladder and vas deferens (prostatic and epididymal portions) tissues were mounted in 10 mL of organ baths. Relaxation responses to anandamide were recorded at 3 and 10 μM concentrations. After the rest period, the procedures were repeated in the presence of cannabinoid (CB) and vanilloid receptor antagonists, various potassium channel blockers, cyclo-oxygenase, and nitric oxide synthase inhibitors. In different tissues to investigate the Ca2+-channel antagonistic effect of anandamide, concentration-response curves to CaCl2 were obtained in the absence and presence of anandamide. Anandamide caused a significant relaxation response in the bladder and epididymal vas deferens tissues, but not in the prostatic portion. The effect of anandamide was antagonized in the presence of the CB1 antagonist AM251 or the non-selective potassium channel blocker tetraethylammonium in bladder tissue. In the epididymal vas deferens, anandamide significantly inhibited the calcium contraction responses, especially at high concentrations. The CB2 antagonist AM630 reversed this inhibition. The results show that anandamide has a direct relaxant effect on the isolated rat bladder and epididymal vas deferens. Anandamide triggers different mechanisms in different types of tissues, and further studies are needed to elucidate the mechanism of action of anandamide.

An investigation into the wound-healing mechanism in gill injuries of varying severity in the freshwater mussel Solenaia oleivora (Heude, 1877)

The Solenaia oleivora is an important freshwater economically farmed shellfish, and the traditional hooking method often causes different degrees of gill damage to the S. oleivora. Therefore, in this study, we investigated the mechanism of wound-healing in gill injuries in the freshwater mussel S. oleivora by simulating varying degrees of gill injury. It was found that the rates of oxygen consumption, ammonia excretion, and feeding did not change significantly in the mild-injury group at 2 and 12 h post-injury, while the rates were significantly lower in the severe-injury group compared with the control group, likely due to impairment of the respiratory metabolism. The rates of oxygen consumption, feeding, and ammonia excretion increased significantly in the mild-injury group at 24, 48, 72 h, compared with the control, as well as in the severe-injury group at 72 h post-injury, possibly due to increased energy requirements for tissue repair. Histological and transcriptomic analyses of tissues showed that in the mild-injury group at 2 and 12 h, blood cells migrated toward the wound, plugging it and triggering an inflammatory response associated with upregulation of TNF signaling, immune-related genes, and genes associated with the actin cytoskeleton, suggesting wound contraction and phagocytosis of blood cells. At 24 h post-injury, genes and pathways associated with antioxidant enzymes, chaperonins, autophagy, lysosomes, biochemical pathways, and energy metabolism were activated, suggesting a transition from an inflammatory response to an epithelialization process. At 48 h post-injury, Toll and Imd signaling were downregulated, together with upregulation of genes associated with the extracellular matrix, such as collagen, integrins, and glycoproteins, promoting epithelialization of the wound. After 72 h, proline and arginine metabolism were increased, as well as expression of mitochondrial genes. The severe-injury group showed reduced amino acid metabolism and activation of primary immunodeficiencies after 2 and 12 h, suggesting disturbances in metabolism and immunity, while after 2, 12, 24, and 48 h, genes related to the actin cytoskeleton, lipid metabolism, glycolysis, glycosyltransferases, chaperonins, guanylate-binding proteins, and NOD-like receptors were upregulated to promote wound contraction and inflammatory responses. At 72 h after injury, interleukin-4 and thymosin β-4 were activated and the NF-κB signaling pathway was inhibited to reduce inflammation, while epithelialization of the wounds was visible on tissue sections, possibly facilitated by the upregulation of ribosomal proteins, ATP. This study provides new insights into the mechanism of gill wound-healing in S oleivora.

Understanding the radial contraction and axial mechanical responses of carbon nanotube yarns under axial tensile loading

Carbon nanotube yarns (CNTYs) are hierarchical fibers with outstanding mechanical and electrical properties, with promising applications in the composite industry and as smart materials. In situ scanning electron microscopy observations are performed herein on individual dry-spun CNTYs during axial tensile testing in order to study their radial contraction response and structural changes. The CNTYs exhibited significant diameter reduction and untwisting due to the rearrangement of their fibrils during axial loading. In situ measurements of CNTY diameter reduction led to an exponential decrease of the radial contraction ratio with axial strain, with average values ranging between 5.43 and 1.08. The major failure mechanism was identified as fibril pull-out triggered by fibril slipping. The simultaneous stress and electrical resistance decay of CNTYs under axial tensile relaxation tests fit to a Wiechert's viscoelastic model using a Prony series. The rate of exponential decrease of the electrical resistance over time, however, is slower than that of the stress relaxation, indicating that additional charge carrier relaxation phenomena are present. Using the measured structural and material data input, a nonlinear analytical model based on classical theory of staple yarns is able to reproduce the mechanical response of the yarn. The model suggests that the most prominent parameters affecting the axial mechanical response of the CNTY are the radial contraction ratio, the slip factor, fibril radius, and fibril length.

Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.

To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS). Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot. The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05). These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.

MiR-221-5p regulates blood–brain barrier dysfunction through the angiopoietin-1/-2/Tie-2 signaling axis after subarachnoid hemorrhage

ABSTRACT Aim To explore the potential role of microRNA miR-221-5p on the angiopoietin-1 (Ang-1)/Ang-2/Tie-2 signaling axis after subarachnoid hemorrhage (SAH) in a rat model. Methods Aspects of the rat’s behavior were measured using the Kaoutzanis scoring system to test neurological responses. This included feeding behavior, body contraction, motor, and eye-opening responses. Brain sections were studied using transmission electron microscopy and Evans blue extravasation. Levels of Ang-1, Ang-2, and Tie-2 were determined by Western blot, while miR-221-5p was quantified using stem-loop real-time quantitative PCR (RT-qPCR). Results The SAH group responded worse to the neurological response test than the sham-operated group. The intercellular space was widened in the SAH group, but not in the sham-operated group. Evans blue dye leaked significantly more into brain tissue cells of the SAH group. Stem-loop qRT-PCR showed elevated miR-221-5p levels. Additionally, Ang-1 and Tie-2 were reduced but Ang-2 expression was increased after SAH. This led to a significant reduction of the Ang-1/Ang-2 ratio in the brain tissue, which was associated with the destruction of the blood-brain barrier. Conclusion The data indicate that miR-221-5p might regulate blood-brain barrier dysfunction through the Ang-1/Ang-2/Tie-2 signaling axis, suggesting that it should be further investigated as a potential novel biomarker.

P114 Role of NLRX1 Agonist NX-13 in Reducing Visceral Hypersensitivity in Preclinical Gastrointestinal Inflammation

Abstract Background NLRX1 activation reduces inflammation by decreasing oxidative stress and altering cellular metabolism within multiple cell types implicated in ulcerative colitis (UC). Colitis animal models demonstrated reduced disease severity and a phase 1b clinical trial showed signs of rapid symptom and endoscopic improvement in patients with active UC.1, 2 Abdominal pain driven by visceral hypersensitivity may persist in patients even after inflammation has resolved, negatively affecting their quality of life.3, 4 Therapeutic agents which address inflammation, epithelial healing, and visceral hypersensitivity concurrently may provide greater symptomatic relief and improved quality of life as many patients, even in remission, still complain of abdominal pain. We here describe the effects of oral NX-13 in a rat model of visceral hypersensitivity. Methods Rats (n=8) were dosed daily for a period of 3 days with NX-13 or vehicle. Under anesthesia, electrodes were positioned to monitor oblique abdominal muscle contraction and a colonic balloon catheter was inserted intra-anally. Visceral pain was assessed at baseline and 3 h post lipopolysaccharide injection (1 mg/kg subcutaneous) through measuring of visceromotor response (VMR) via electromyogram (EMG) recording and visual assessment of abdominal withdrawal reflex (AWR). Data are represented as median (IQR) and statistical significance determined by non-parametric Mann-Whitney U test. Results Compared to the vehicle control, oral NX-13 delayed the onset of muscle contraction in response to colonic distension in LPS-treated rats. Further, NX-13 treated rats experienced reduced contraction intensity and reduced sustained abdominal muscle contraction period compared to the vehicle control. Specifically, NX-13 decreased the number of AWR during colonic expansion compared to the control group (p=0.01, Fig1A). Moreover, NX-13 desensitized the VMR response by numerically increasing the minimum volume of the colonic distension balloon required to induce significant VMR. The mean minimum volume of water injected required to induce significant VMR increased 23%, from 650 μL in the vehicle group to 800 μL in the NX-13 treated rats (p=0.16, Fig1B). Lastly, NX-13 visually reduced the maximum abdominal EMG amplitude during colonic distention (p=0.19, Fig1C). Conclusion Adequate management of persistent pain in IBD patients with or without active bowel inflammation remains an unmet need in the treatment of IBD. The potential for NX-13 to specifically reduce visceral hypersensitivity and abdominal pain will be evaluated further in the ongoing phase 2 human NEXUS trial in patients with UC. 1Leber et al. J Immunol 203(12) 2Peyrin-Biroulet et al. JCC (17)Supp 3Abreu et al. JCC (14)Supp 4Wils et al. J Clin Med 11(15)

Osmoregulatory physiology of the angel wing bivalve Cyrtopleura costata (Pholadidae), an estuarine intertidal burrowing mollusc

ABSTRACT Cyrtopleura costata is a pholadid bivalve that inhabits tidal flats inside burrows c. 40 cm deep, and its visceral mass outgrows its shell significantly. Thus, unlike other bivalves, it cannot isolate its soft tissues from the external environment through complete valve closure. One can thus hypothesize that this bivalve would be inevitably more exposed and susceptible to the tidal changes in salinity. No information regarding its osmoregulatory physiology has been found in the literature. We thus investigated how its fluids would respond to seawater dilution and seawater concentration, and how its tissues would be able to keep their moisture content. Individuals of C. costata were acclimated to 30‰ and then independently exposed stepwise (1 h for each 5‰ change) to 25, 20, 15 and 10‰ or to 35, 40, 45 and 50‰. Isolated tissue slices obtained from control animals (30‰) of siphon, mantle and muscle were exposed in vitro to salines corresponding to salinities of 10, 30 and 50‰. Cyrtopleura costata responded as a typical euryhaline osmoconformer between 25 and 40‰, with haemolymph and mantle cavity water being isosmotic to the external medium. However, some ‘buffering’ of haemolymph osmolality was displayed in the most extreme salinities, 10–20‰ and 45–50‰. This could result from muscle contraction and other cellular responses, reducing ‘apparent permeability’ and diffusive fluxes; the muscle was the tissue with the highest capacity to maintain constant hydration despite significant osmotic challenge. Both in vivo and in vitro experiments indicated a higher tolerance of salinity increases than decreases. Thus, if global and local changes in climate and precipitation rates result in more frequent seawater dilution in its habitat, the area occupied by its realized niche may be reduced.

Amplified P2X3 pathway activity in muscle afferent dorsal root ganglion neurons and exercise pressor reflex regulation in hindlimb ischaemia-reperfusion.

Hindlimb ischaemia-reperfusion (IR) is among the most prominent pathophysiological conditions observed in peripheral artery disease (PAD). An exaggerated arterial blood pressure (BP) response during exercise is associated with an elevated risk of cardiovascular events in individuals with PAD. However, the precise mechanisms leading to this exaggerated BP response are poorly elucidated. The P2X3 signalling pathway, which plays a key role in modifying the exercise pressor reflex (EPR), is the focus of the present study. We determined the regulatory role of P2X3 on the EPR in a rat model of hindlimb IR. In vivo and in vitro approaches were used to determine the expression and functions of P2X3 in muscle afferent nerves and EPR in IR rats. We found that in IR rats there was (1) upregulation of P2X3 protein expression in the L4-6 dorsal root ganglia (DRG); (2) amplified P2X currents in isolated isolectin B4 (IB4)-positive muscle DRG neurons; and (3) amplification of the P2X-mediated BP response. We further verified that both A-317491 and siRNA knockdown of P2X3 significantly decreased the activity of P2X currents in isolated muscle DRG neurons. Moreover, inhibition of muscle afferents' P2X3 receptor using A-317491 was observed to alleviate the exaggerated BP response induced by static muscle contraction and P2X-induced BP response by α,β-methylene ATP injection. P2X3 signalling pathway activity is amplified in muscle afferent DRG neurons in regulating the EPR following hindlimb IR.

Evaluation of Flow Liquefaction Susceptibility in Non-Plastic Silty Soils Using the Seismic Cone

The state parameter allows the evaluation of the in situ state of soils, which can be particularly useful in tailings impoundments where flow liquefaction is the most common failure model. Positive state parameter values characterize a contractive response during shearing and, for non-plastic soils, can indicate flow liquefaction susceptibility. This paper presents a methodology to classify and estimate the state parameter (Ψ) for non-plastic silty soils based on seismic cone penetration measurements. The method expands on a previous methodology developed for sands that use the ratio of the small strain shear modulus and the cone tip resistance G0/qt for classification and Ψ assessment. For non-plastic silty soils, drainage conditions during cone penetration must be accounted for and are used to allow soil classification and correct the cone tip resistance. An empirical formulation is proposed to correct qt for partial drainage measurements and predict Ψ for non-plastic silty soils. Mining tailings results of in situ and laboratory tests were used to validate the proposed methodology producing promising responses. The Ψ value estimated through the proposed methodology are in the range of those obtained from laboratory tests, indicating an adequate prediction of behavior for non-plastic silty soils.

Effects of a Sustained, Isometric Forearm Flexion Task to Failure on Torque and Neuromuscular Responses at 3 Elbow Joint Angles

Abstract Ortega, DG, Housh, TJ, Smith, RW, Arnett, JE, Neltner, TJ, Anders, JPV, Schmidt, RJ, and Johnson, GO. The effects of a sustained, isometric forearm flexion task to failure on torque and neuromuscular responses at 3 elbow joint angles. J Strength Cond Res 38(1): e25–e33, 2024—This study examined the effects of a sustained, isometric forearm flexion task anchored to torque to task failure on maximal voluntary isometric contraction (MVIC) and neuromuscular responses at 3 elbow joint angles. Eleven women (mean ± SD: age = 20.8 ± 2.7 years, height = 169.3 ± 7.4 cm, body mass = 67.7 ± 6.9 kg) performed two 3s forearm flexion MVICs at elbow joint angles (JAs) of 75°, 100°, and 125° before and after a sustained, isometric forearm flexion task to failure at a fatiguing joint angle of 100° anchored to a torque value that corresponded to a rating of perceived exertion of 8 (RPE = 8). The amplitude (AMP) and mean power frequency (MPF) of the electromyographic (EMG) and mechanomyographic (MMG) signals were recorded from the biceps brachii. Repeated-measures ANOVAs were used to compare mean differences for MVIC and neuromuscular parameters. Collapsed across JAs, MVIC (p &lt; 0.001) and EMG MPF (p = 0.006) pretest values were greater than posttest values. Collapsed across time, EMG MPF at JA75 was greater than JA100 (p &lt; 0.001) and JA125 (p &lt; 0.001), and JA100 was greater (p = 0.007) than JA125. For EMG AMP, there was a fatigue-induced decrease at JA75 (p = 0.003). For neuromuscular efficiency (NME = normalized torque/normalized EMG AMP), there were decreases from pretest to posttest at JA100 (p = 0.002) and JA125 (p = 0.008). There were no significant interactions or main effects for MMG AMP and MMG MPF. From these findings, it was hypothesized that the decline in MVICs at JA75, JA100, and JA125 was due to fatigue-induced metabolic perturbations that resulted in JA-specific neuromuscular responses. Thus, neuromuscular parameters may provide insight into the JA-specific mechanisms of fatigue.

Numerical sensitivity analysis for stress-strain simulation and flow liquefaction assessment of tailings storage facilities using the NorSand constitutive model

With the advent of critical state Soil Mechanics (CSSM), the void ratio began to be recognized as a key parameter, along with the stress state, which defines the mechanical behavior of soils and other particulate geomaterials by using the state parameter. The state parameter is the difference between the current and critical void ratio so that its definition requires the critical state line (CSL) identification. This work presents numerical calibration results, using the NorSand constitutive model, from three sets of triaxial compression tests selected from the literature. The SIGMA/W module of the Geostudio® System was adopted to perform the simulations of the triaxial compression tests, and the results showed adequate fit between real tests and numerical simulations. The parameters necessary for the modeling with NorSand model, defined from the numerical calibration, were used in a stress-strain evaluation of a hypothetical upstream tailings dam. These simulations allowed the evaluation of the differences in the tailings storage facility (TSF) responses in terms of both deformation behavior and flow liquefaction instability. Flow liquefaction instability is described in the literature as a complete loss in shear strength and the development of excessive strains due to the contractive response of tailings when subjected to low confining stress. The results suggest that the use of the NorSand model is, in general, a good option to reproduce the typical strain-softening behavior of such structures. Furthermore, it was clear the high sensitivity of the constitutive model parameters, drawing attention to the importance of best laboratory practices for carrying out triaxial tests to obtain reliable parameters for NorSand modeling.

Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries.

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N'-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K+)2), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K+)2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K+)2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K+)2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

Unique ocean circulation pathways reshape the Indian Ocean oxygen minimum zone with warming

Abstract. The global ocean is losing oxygen with warming. Observations and Earth system model projections, however, suggest that this global ocean deoxygenation does not equate to a simple and systematic expansion of tropical oxygen minimum zones (OMZs). Previous studies have focused on the Pacific Ocean; they showed that the outer OMZ deoxygenates and expands as oxygen supply by advective transport weakens, the OMZ core oxygenates and contracts due to a shift in the composition of the source waters supplied by slow mixing, and in between these two regimes oxygen is redistributed with little effect on OMZ volume. Here, we examine the OMZ response to warming in the Indian Ocean using an ensemble of Earth system model high-emissions scenario experiments from the Coupled Model Intercomparison Project Phase 6. We find a similar expansion–redistribution–contraction response but show that the unique ocean circulation pathways of the Indian Ocean lead to far more prominent OMZ contraction and redistribution regimes than in the Pacific Ocean. As a result, only the outermost volumes (oxygen&gt;180 µmol kg−1) expand. The Indian Ocean experiences a broad oxygenation in the southwest driven by a reduction in waters supplied by the Indonesian Throughflow in favor of high-oxygen waters supplied from the southern Indian Ocean gyre. Models also project a strong localized deoxygenation in the northern Arabian Sea due to the rapid warming and shoaling of marginal sea outflows (Red Sea and Persian Gulf) and increases in local stratification with warming. We extend the existing conceptual framework used to explain the Pacific OMZ response to interpret the response in the Indian Ocean.

The effects of inflammation and acidosis on placental blood vessels reactivity

IntroductionInflammation and acidosis are two stress stimuli that correspond to pathophysiological processes occurring in placental-mediated vascular disorders. We aimed to investigate the effects of these stimuli on placental chorionic blood vessels reactivity using the ex-vivo placental perfusion model. MethodsTerm placentas were obtained immediately after cesarean deliveries, and selected cotyledons were cannulated and dually perfused ex-vivo. Placentas were perfused with three different protocols: culture medium (M199-controls, n = 5), culture medium with lipopolysaccharide (inflammatory stimuli) (LPS,1 μg/ml, n = 7), and acidotic culture medium (M − 199, pH: 6.9–7, n = 6). Each perfusion experiment was maintained for 180 min. Fetal perfusion pressure was continuously measured. Measurements in response to angiotensin II (AT II) at the end of the perfusion were compared between the treatment groups, including amplitude of the contraction response, relaxation factor, time to maximal constriction and the area under the pressure curve (AUC). ResultsIn response to ATII there was a significant difference in the amplitude of the contraction and the AUC between the treatment groups, (p = 0.049, p = 0.015, respectively). As compared with control perfused cotyledon, the inflammatory stimuli significantly increased the vasoconstriction response to ATII in fetal placental blood vessels, as expressed by increased AUC - median (IQR): 555 (235–1184) vs. 133 (118–207), respectively, p = 0.017. The time to maximal constriction and the relaxation factor did not differ between the groups. DiscussionInflammatory stimuli but not acidosis impact fetal-placental vasculature in response to ATII, suggesting that inflammation can compromise vascular function.

Methodological challenges in using human umbilical artery as a model for in vitro studies.

What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries. Human umbilical artery (HUA) preparations are of particular importance for in vitro studies on isolated blood vessels because their sampling is not risky for the patient, and they can provide the closest possible impression of changes related to the uteroplacental circulation during pre-eclampsia. Using organ bath techniques, useful experimental protocols are provided for measuring some pathophysiological phenomena in the vascular responses of HUAs. Several vasoconstrictors (serotonin, prostaglandin F and phenylephrine) and vasodilators (acetylcholine and minoxidil) were seleted for determination of their vasoactivity in HUAs. The role of L-type voltage-operated calcium channels and different types of potassium channels (KATP , BKCa and KV ) were assessed, as was the impact of homocysteine. Serotonin was confirmed to be the most potent vasoconstrictor, while acetylcholine and phenylephrine caused variability in the relaxation and contraction response of HUA, respectively. The observed increase in serotonin-induced contraction and a decrease in minoxidil-induced relaxation in the presence of homocysteine suggested its procontractile effect on HUA preparations. Using selective blockers, it was determined that KATP and KV channels participate in the minoxidil-induced relaxation, while L-type voltage-dependent Ca2+ channels play an important role in the serotonin-induced contraction. The presented protocols reveal some of the methodological challenges related to HUA preparations and indicate potential outcomes in interpreting the vascular effects of the investigated substances, both in physiological conditions and in the homocysteine-induced pre-eclampsia model.