Irisin relaxes rat thoracic aorta: MEK1/2 signaling pathway, KV channels, SKCa channels, and BKCa channels are involved in irisin-induced vasodilation

In this study, it was aimed to investigate the effects of irisin on vascular smooth muscle contractility in rat thoracic aorta, and the hypothesis that mitogen-activated protein kinase kinase (MEK1/2) signalling pathway, voltage-gated potassium (KV) channels, small-conductance calcium-activated potassium (SKCa) channels, and large-conductance calcium-activated potassium (BKCa) channels may have roles in these effects. Isometric contraction-relaxation responses of isolated thoracic aorta rings were measured with an organ bath model. The steady contraction was induced with 10-5 M phenylephrine (PHE), and then the concentration-dependent responses of irisin (10-9-10-6 M) were examined. Irisin exerted the vasorelaxant effects at concentrations of 10-8, 10-7, and 10-6 M compared to the control group (p<0.001). Besides, MEK1/2 inhibitor U0126, KV channel blocker XE-991, SKCa channel blocker apamin, and BKCa channel blocker tetraethylammonium (TEA) incubations significantly inhibited the irisin-induced relaxation responses. In conclusion, the first physiological findings were obtained regarding the functional relaxing effects of irisin in rat thoracic aorta. The findings demonstrated that irisin induces relaxation responses in endothelium-intact aortic rings in a concentration-dependent manner. Furthermore, this study is the first to report that irisin-induced relaxation responses are related to the activity of the MEK1/2 pathway, KV channels, and calcium-activated K+ (SKCa and BKCa) channels.

Validation of Fenoterol to Study β2-Adrenoceptor Function in the Rat Urinary Bladder

Fenoterol is a β₂-adrenoceptor (AR)-selective agonist that is commonly used to investigate relaxation responses mediated by β₂-AR in smooth muscle preparations. Some data have questioned this because fenoterol had low potency in the rat urinary bladder when a muscarinic agonist was used as a pre-contraction agent and because some investigators proposed that fenoterol may act in part via β₃-AR. We designed the present study to investigate whether fenoterol is a proper pharmacological tool to study β₂-AR-mediated relaxation responses in the rat urinary bladder. Firstly, we have compared the effect of pre-contraction agents on fenoterol potency and found that fenoterol potency was about 1.5 log units greater against KCl than carbachol (pEC₅₀ 7.19 ± 0.66 and 5.62 ± 1.09 of KCl and of carbachol, respectively). To test the selectivity of fenoterol, we have determined the effects of the β₂-AR antagonist ICI 118,551 and the β₃-AR antagonist L 748,337 on relaxation responses to fenoterol. While 300 nM L 748,337 had little effect on the potency of fenoterol (pEC₅₀ 6.56 ± 0.25 and 6.33 ± 0.61 in the absence and presence of L 748,337, respectively), the relaxation curve for fenoterol was right-shifted in the presence 300 nM ICI 118,551 (pEC₅₀ 5.03 ± 0.18). Thus, we conclude that fenoterol is a proper pharmacological tool to assess β₂-AR-mediated responses in the rat urinary bladder and most likely in other smooth-muscle preparations containing multiple subtypes of the β-AR.

Calcitonin gene related peptide, adrenomedullin and adrenomedullin2 function in uterine artery during human pregnancy

Rationale Calcitonin gene-related peptide (CGRP) and its family members adrenomedullin (ADM) and adrenomedullin2 (ADM2) also known as Intermedin support vascular adaptions in rat pregnancy. Objective To assess the relaxation response of uterine artery (UA) for CGRP, ADM, and ADM2 in non-pregnant and pregnant women and identify the involved mechanisms. Findings 1) Segments of UA from non-pregnant women that were pre-contracted with U46619 (1μM) in-vitro are insensitive to the hypotensive effects of CGRP, ADM and ADM2, 2) CGRP, ADM, and ADM2 (0.1nM – 100nM) dose-dependently relax UA segments from pregnant women with efficacy for CGRP&gt;ADM=ADM2 , 3) The relaxation responses to CGRP, ADM and ADM2 are differentially affected by the inhibitors of nitric oxide (NO) synthase (L-NAME), adenylyl cyclase (SQ22536), apamin and charybdotoxin, 4) UA smooth muscle cells (UASMC) express mRNA for calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)1 and RAMP2 but not RAMP3, 5) Receptor heterodimer comprised of CRLR/RAMP1 and CRLR/RAMP2 but not CRLR/RAMP3 is present in UA, 6) soluble fms-like tyrosine kinase (sFLT-1) and TNF-α treatment decrease the expression of RAMP1mRNA (p&lt; 0.05) in UASMC and, 7) sFLT-1 treatment impairs the association of CRLR with all the three peptides while TNF-α inhibits the interaction of CGRP but not ADM or ADM2 with CRLR in UASMC (p&lt; 0.05). Conclusions Relaxation sensitivity of UA for CGRP, ADM and ADM2 is increased during pregnancy via peptide specific involvement of NO system and endothelium derived hyperpolarizing factors, and vascular disruptors such as sFLT-1 and TNFα adversely impact their receptor system in UASMC.

Recording quality does not influence relaxation responses to lullabies; sampling criteria do, as they should (Reply to "Sampling criteria and recording quality influence relaxation responses to lullabies")

This is a short reply to "Sampling criteria and recording quality influence relaxation responses to lullabies".

Mechanism of Acitretin-Induced Relaxations in Isolated Rat Thoracic Aorta Preparations

Acitretin is a member of vitamin A-derived retinoids and its effect on vascular smooth muscle had not been studied yet. The aim of this study is to investigate the effect of acitretin, a retinoid, on vascular smooth muscle contractility. Thoracic aorta preparations obtained from 34 male Sprague-Dawley rats (355 ± 15 g) were studied in isolated organ baths containing Krebs-Henseleit solution. The relaxation responses were obtained with acitretin (10-12‒10-4 M) in endothelium-preserved and endothelium-denuded aorta preparations precontracted with submaximal concentration of phenylephrine. The roles of retinoic acid receptor (RAR), nitric oxide, adenylyl and guanylyl cyclase enzymes, and potassium channels in these relaxation responses were investigated. Acitretin produced concentration-dependent relaxations, which were independent of its solvent dimethylsulfoxide, in endothelium-denuded phenylephrine-precontracted thoracic aorta preparations. While incubation with the RAR antagonist (AGN193109, 10-5 M) had no effect on these relaxations; nitric oxide synthase inhibitor (L-NAME, 10-4 M), adenylyl cyclase inhibitor (SQ2253, 10-5 M), guanylyl cyclase inhibitor (ODQ, 10-6 M), and potassium channel blocker (tetraethylammonium-TEA, 10-2 M) significantly eliminated the relaxation responses induced by acitretin. Acitretin induces relaxation in rat isolated thoracic aorta preparations without endothelium, which may be mediated by nitric oxide, cyclic adenosine monophosphate and cyclic guanosine monophosphate-dependent kinases and potassium channels.

Sampling criteria and recording quality influence relaxation responses to lullabies

The original paper’s sampling criteria involved selecting lullabies that adults rated as most likely to soothe a baby and non-lullabies rated as least likely to do so. Our analysis shows that lullabies in the stimulus set had systematically higher recording quality than non-lullabies, and those differences in recording quality were substantially greater than the paper’s primary pre-registered analysis comparing infant heart rate when listening to lullabies vs. non-lullabies (original effect size: d=0.23). Accordingly, the authors’ conclusion that infants relax more in response to unfamiliar foreign lullabies than to non-lullabies may be an artefact of their sampling methods.

Ameliorative Effects of Quercetin in Cyclophosphamide-Induced Vascular Toxicity in Rats

Cyclophosphamide (CYP) causes vascular toxicity and endothelial damage. In this study aimed the determination of the protective effects of Quercetin (Q) in the CYP-induced vascular toxicity in rats. The rats were randomly divided into the following five groups: Control, CYP, Q50+CYP, Q100+CYP and Q100. The control group was given intragastric (i.g.) corn oil for seven days. The CYP group received i.g. corn oil for seven days and a single dose (200 mg/kg) of CYP via intraperitoneal (i.p.) injection on the seventh day. The rats in the three Q-treated groups received Q for seven days. On the seventh day after the Q treatment, the Q50+CYP, and Q100+CYP groups were injected to single dose (200 mg/kg, i.p.) of CYP. The CYP-treatment both worsen the Phenylephrine (PE)-induced contractions and acetylcholine (ACh)-induced relaxation responses in isolated thoracic aorta of rats, and the application of Q corrected these responses. The malondialdehyde (MDA) levels were significantly higher in the CYP-treated groups. The both dose of Q decreased the MDA level. Superoxide dismutase (SOD) and glutathione (GSH) activities were significantly decreased in the CYP group, whereas the high dose of Q increased SOD and GSH activities. Q treatment attenuated CYP-induced pathologies, and endothelial damage. According to results, Q has protective effects against CYP-induced vascular toxicity in rats.

Overview

An overview is provided of multiple book themes. A critical one is explaining how and where conscious states of seeing, hearing, feeling, and knowing arise in our minds, why they are needed to choose effective actions, yet how unconscious states also critically influence behavior. Other themes include learning, expectation, attention, imagination, and creativity; differences between illusion and reality, and between conscious seeing and recognizing, as embodied within surface-shroud resonances and feature-category resonances, respectively; roles of visual boundaries and surfaces in understanding visual art, movies, and TV; different legacies of Helmholtz and Kanizsa towards understanding vision; how stable opaque percepts and bistable transparent percepts are explained by the same laws; how solving the stability-plasticity dilemma enables brains to learn quickly without catastrophically forgetting previously learned but still useful knowledge; how we correct errors, explore novel experiences, and develop individual selves and cumulative cultural accomplishments; how expected vs. unexpected events are regulated by interacting top-down and bottom-up processes, leading to either adaptive resonances that support fast and stable new learning, or hypothesis testing whereby to learn about novel experiences; how variations of the same cooperative and competitive processes shape intelligence in species, cellular tissues, economic markets, and political systems; how short-term memory, medium-term memory, and long-term memory regulate adaptation to changing environments on different time scales; how processes whereby we learn what events are causal also support irrational, superstitious, obsessional, self-punitive, and antisocial behaviors; how relaxation responses arise; and how future acoustic contexts can disambiguate conscious percepts of past auditory and speech sequences that are occluded by noise or multiple speakers.

Relaxation capacity of cartilage is a critical factor in rate- and integrity-dependent fracture

Articular cartilage heals poorly but experiences mechanically induced damage across a broad range of loading rates and matrix integrity. Because loading rates and matrix integrity affect cartilage mechanical responses due to poroviscoelastic relaxation mechanisms, their effects on cartilage failure are important for assessing and preventing failure. This paper investigated rate- and integrity-dependent crack nucleation in cartilage from pre- to post-relaxation timescales. Rate-dependent crack nucleation and relaxation responses were obtained as a function of matrix integrity through microindentation. Total work for crack nucleation increased with decreased matrix integrity, and with decreased loading rates. Critical energy release rate of intact cartilage was estimated as 2.39 ± 1.39 to 2.48 ± 1.26 kJ m−2 in a pre-relaxation timescale. These findings showed that crack nucleation is delayed when cartilage can accommodate localized loading through poroviscoelastic relaxation mechanisms before fracture at a given loading rate and integrity state.