Single-nucleotide polymorphisms link gout with health-related lifestyle factors in Korean cohorts.

Gout-a very painful inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints-is influenced by several factors. We identified the association of single- nucleotide polymorphisms (SNPs) that link gout with health-related lifestyle factors using genomic data from the Korean Genome and Epidemiology Study. We conducted a genome-wide association study (GWAS) on 18,927 samples of 438 Korean patients with gout and 18,489 controls for the discovery stage. For the replication stage, another batch containing samples of 326 patients with gout and 2,737 controls were analyzed. Lastly, a meta-analysis was performed using these two cohorts. We analyzed the effects of health-related lifestyle factors, including eating habits, physical activity, drinking behavior, and smoking behavior, on gout. After identifying the association between GWAS-derived SNPs and health-related lifestyle factors, we confirmed the interaction between the polygenic risk score (PRS) and health-related lifestyle factors. We identified 15 SNPs related to gout, among which rs1481012 of ABCG2 located on chromosome 4 has been newly discovered (P = 2.46e-11). On examining the interaction between SNPs and health-related lifestyles, rs3109823-located in ABCG2-was found to be associated with smoking status. In addition, rs11936395-located in SLC2A9-was significantly associated with the average momentum of exercise per session, whereas rs11066325 located in PTPN11, showed a significant association with the number of exercise sessions per week, smoking status, drinking status, and amount of soju drink per session. rs9421589-located in FAM35A-was significantly associated with the duration of smoking. In addition, we verified that the association between PRS and duration of smoking affects gout. Thus, in this study, we identified novel SNPs that link gout with health-related lifestyle factors in the Korean population.

Associations between the Genetic Heritability of Dyslipidemia and Dietary Patterns in Korean Adults Based on Sex Differences.

Dyslipidemia can be defined as an abnormality in serum lipid levels that is substantially linked to genetic variations and lifestyle factors, such as diet patterns, and has distinct sex-specific characteristics. We aimed to elucidate the genetic impact of dyslipidemia according to sex and explore the associations between genetic variants and dietary patterns in large-scale population-based cohorts. After performing genome-wide association studies (GWASs) in male, female, and entire cohorts, significant single nucleotide polymorphisms (SNPs) were identified in the three groups, and genetic risk scores (GRSs) were calculated by summing the risk alleles from the selected SNPs. After adjusting for confounding variables, the risk of dyslipidemia was 2.013-fold and 2.535-fold higher in the 3rd quartile GRS group in the male and female cohorts, respectively, than in the 1st quartile GRS group. While instant noodle and soft drink intake were significantly associated with GRS related to hyperlipidemia in male cohorts, coffee consumption was substantially related to GRS related to hyperlipidemia in female cohorts. Considering the influence of genetic factors and dietary patterns, the findings of this study suggest the potential for implementing sex-specific strategic interventions to avoid dyslipidemia.

Food Restriction Augmented Alpha1-Adrenergic Mediated Contraction in Mesenteric Arteries.

Food restriction (FR) enhances sensitivity to cardiopulmonary reflexes and α1-adrenoreceptors in females in the presence of hypotension. However, the effect of FR on cardiopulmonary and vascular function in males is not well-understood. This study examines the effects of FR on cardiopulmonary, isolated arterial function, and potential underlying mechanisms. Male Sprague-Dawley (SD) rats were randomly divided into 3 groups and monitored for 5 weeks: (1) control (n = 30), (2) 20% food reduction (FR20, n = 30), and (3) 40% food reduction (FR40, n = 30). Non-invasive blood pressure was measured twice a week. Pulmonary arterial pressure (PAP) was measured using isolated/perfused lungs. The isolated vascular reactivity was assessed using double-wire myographs. FR rats exhibited a lower mean arterial pressure and heart rate; however, only the FR40 group exhibited statistically significant differences. We observed that FR enhanced sensitivity (EC50) to vasoconstriction induced by the α1-adrenoreceptor phenylephrine (PhE) but not to serotonin, U46619, or high K+ in the mesenteric arteries. PhE-mediated vasoconstriction in the mesenteric arteries was eliminated in the presence of the eNOS inhibitor (L-NAME). In addition, incubation with NOX2/4 inhibitors (apocynin, GKT137831, and VAS2870) and the reactive oxygen species (ROS) scavenger inhibitor (Tiron) eliminated the differences in PhE-mediated vasoconstriction, but the cyclooxygenase inhibitor (indomethacin) in the mesenteric arteries did not. Augmentation of α1-adrenergic-mediated contraction via the inhibition of the eNOS-NO pathway increased the activation of ROS through NOX2/4 in response to FR. Reduced eNOS-NO signaling may be a pathophysiological counterbalance to prevent hypovolemic shock in response to FR.

Sex-related differences in single nucleotide polymorphisms associated with dyslipidemia in a Korean population.

BACKGROUND: The prevalence of dyslipidemia has increased steadily in Korea, and the incidence of dyslipidemia differs by sex. In this study, we identified single nucleotide polymorphisms (SNPs) related to dyslipidemia in Korean cohorts through genome-wide association study (GWAS) analysis. METHODS: Genotyping was conducted to determine the genotypes of 72,298 participants and investigate genotypes for 7,079,946 SNPs. Sex, age, and BMI were set as covariates for GWAS, and significant SNPs were identified in the discovery and replication stages using logistic regression. RESULTS: GWAS of the entire cohort revealed a total of five significant SNPs: rs117026536 (LPL), rs651821 (APOA5), rs9804646 (APOA5), rs9926440 (CETP), and rs429358 (APOE). GWAS of the male subjects revealed a total of four significant SNPs. While rs9804646 (APOA5) and rs429358 (APOE) were significant for all the subjects, rs662799 (APOA5) and rs56156922 (CETP) were significant only for the male subjects. GWAS of the female subjects revealed two significant SNPs, rs651821 (APOA5) and rs9804646 (APOA5), both of which were significant in all the subjects. CONCLUSION: This is the first study to identify sex-related differences in genetic polymorphisms in Korean populations with dyslipidemia. Further studies considering environmental variables will be needed to elucidate these sex-related genetic differences in dyslipidemia.

Smartphone-based home workout program for shift-work nurses working during the COVID-19 pandemic.

This study aimed to develop a smartphone-based home workout program for shift-work nurses to increase their levels of exercise and examine its effects on health (sleep disturbance, fatigue, musculoskeletal problems, and resilience) and nursing performance. For this quasiexperimental study with a nonequivalent control group, 54 shift-work nurses were recruited from two general wards at a hospital in Korea and assigned to the intervention and control groups. Nurses in the intervention group were encouraged to exercise regularly using the home workout application for 18 weeks. For the first 12 weeks, text-message counseling and environmental improvement were carried out; only environmental improvement was implemented in the remaining 12-18 weeks. The control group did not receive any intervention. After excluding dropouts, the data of the final 25 participants in the intervention group and 24 participants in the control group were analyzed. Compared with the control group, the intervention group showed statistically significant improvements in physical and psychological health. Hospital organizations could adopt a smartphone-based home workout program to overcome obstacles to exercise, which could lead to positive health outcomes for shift-work nurses.

Oxygen-dependent regulation of ion channels: acute responses, post-translational modification, and response to chronic hypoxia.

Oxygen is a vital element for the survival of cells in multicellular aerobic organisms such as mammals. Lack of O2 availability caused by environmental or pathological conditions leads to hypoxia. Active oxygen distribution systems (pulmonary and circulatory) and their neural control mechanisms ensure that cells and tissues remain oxygenated. However, O2-carrying blood cells as well as immune and various parenchymal cells experience wide variations in partial pressure of oxygen (PO2) in vivo. Hence, the reactive modulation of the functions of the oxygen distribution systems and their ability to sense PO2 are critical. Elucidating the physiological responses of cells to variations in PO2 and determining the PO2-sensing mechanisms at the biomolecular level have attracted considerable research interest in the field of physiology. Herein, we review the current knowledge regarding ion channel-dependent oxygen sensing and associated signalling pathways in mammals. First, we present the recent findings on O2-sensing ion channels in representative chemoreceptor cells as well as in other types of cells such as immune cells. Furthermore, we highlight the transcriptional regulation of ion channels under chronic hypoxia and its physiological implications and summarize the findings of studies on the post-translational modification of ion channels under hypoxic or ischemic conditions.

Downregulation of Soluble Guanylate Cyclase and Protein Kinase G With Upregulated ROCK2 in the Pulmonary Artery Leads to Thromboxane A2 Sensitization in Monocrotaline-Induced Pulmonary Hypertensive Rats.

Thromboxane A2 (TXA2) promotes various physiological responses including pulmonary artery (PA) contraction, and pathophysiological implications have been suggested in cardiovascular diseases including pulmonary hypertension. Here, we investigated the role of TXA2 receptor (TP)-mediated signaling in the pathophysiology of pulmonary arterial hypertension (PAH). The sensitivity of PA to the contractile agonist could be set by relaxing signals such as the nitric oxide (NO), soluble guanylate cyclase (sGC), and cGMP-dependent kinase (PKG) pathways. Changes in the TP agonist (U46619)-induced PA contraction and its modulation by NO/cGMP signaling were analyzed in a monocrotaline-induced PAH rat model (PAH-MCT). In the myograph study, PA from PAH-MCT showed higher responsiveness to U46619, that is decreased EC50. Immunoblot analysis revealed a lower expression of eNOS, sGC, and PKG, while there was a higher expression of RhoA-dependent kinase 2 (ROCK2) in the PA from PAH-MCT than in the control. In PAH-MCT, the higher sensitivity to U46619 was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog, but not by the NO donor, sodium nitroprusside (SNP 30 µM). In contrast, in the control PA, inhibition of sGC by its inhibitor (1H- [1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), 10 µM) lowered the threshold of U46619-induced contraction. In the presence of ODQ, SNP treatment had no effect whereas the addition of 8-Br-cGMP lowered the sensitivity to U46619. The inhibition of ROCK by Y-27632 attenuated the sensitivity to U46619 in both control and PAH-MCT. The study suggests that the attenuation of NO/cGMP signaling and the upregulation of ROCK2 increase the sensitivity to TXA2 in the PAH animal, which might have pathophysiological implications in patients with PAH.

Higher expression of KCNK10 (TREK-2) K+ channels and their functional upregulation by lipopolysaccharide treatment in mouse peritoneal B1a cells.

Innate-like CD5+ B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca2+ influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca2+ concentration of B cells was decreased by high-K+-induced depolarization (ΔRKCl (%)), suggesting the basal Ca2+ influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔRKCl (%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca2+ influx by the stimulation of Toll-like receptor 4 in B1a cells.

Teaching cardiac excitation-contraction coupling using a mathematical computer simulation model of human ventricular myocytes.

To understand the excitation-contraction (E-C) coupling of cardiomyocytes, including the electrophysiological mechanism of their characteristically long action potential duration, is one of the major learning goals in medical physiology. However, the integrative interpretation of the responses occurring during the contraction-relaxation cycle is challenging due to the dynamic interaction of underlying factors. Starting in 2017, we adopted the mathematical computer simulation model of human ventricular myocyte (Cardiac E-C_Sim), hypothesizing that this educational technology may facilitate students' learning of cardiac physiology. Here, we describe the overall process for the educational application of Cardiac E-C_Sim in the human physiology practicum of Seoul National University College of Medicine. We also report the results from questionnaires covering detailed assessment of the practicum class. The analysis of results and feedback opinions enabled us to understand how the students had approached the problem-solving process. As a whole, the students could better accomplish the learning goals using Cardiac E-C_Sim, followed by constructive discussions on the complex and dynamic mechanisms of cardiac E-C coupling. We suggest that the combined approach of lecture-based teaching and computer simulations guided by a manual containing clinical context would be broadly applicable in physiology education.

Anti-Inflammatory Effects of Alnus Sibirica Extract on In Vitro and In Vivo Models.

Alnus sibirica extracts (ASex) have long been used in Oriental medicine to treat various conditions. To provide a scientific basis for this application and the underlying mechanism, we investigated the anti-inflammatory effects of ASex in vitro and in vivo. The in vitro model was established using human dermal fibroblasts (HDFs) treated with inflammatory stimulants (lipopolysaccharide, tumor necrosis factor-alpha, interferon-gamma). Lactate dehydrogenase and reverse transcription-polymerase chain reaction showed that ASex inhibited the increased expression of acute-phase inflammatory cytokines. The in vivo model was established by inducing skin inflammation in NC/Nga mice via the repeated application of house dust mite (HDM) ointment to the ears and back of the mice for eight weeks. HDM application increased the severity of skin lesions, eosinophil/mast cell infiltration, and serum immunoglobulin E levels, which were all significantly decreased by ASex treatment, demonstrating the same degree of protection as hydrocortisone. Overall, ASex showed excellent anti-inflammatory effects both in vitro and in vivo, suggesting its potential as an excellent candidate drug to reduce skin inflammation.

Decreased inward rectifier and voltage-gated K+ currents of the right septal coronary artery smooth muscle cells in pulmonary arterial hypertensive rats.

In vascular smooth muscle, K+ channels, such as voltage-gated K+ channels (Kv), inward-rectifier K+ channels (Kir), and big-conductance Ca2+-activated K+ channels (BKCa), establish a hyperpolarized membrane potential and counterbalance the depolarizing vasoactive stimuli. Additionally, Kir mediates endothelium-dependent hyperpolarization and the active hyperemia response in various vessels, including the coronary artery. Pulmonary arterial hypertension (PAH) induces right ventricular hypertrophy (RVH), thereby elevating the risk of ischemia and right heart failure. Here, using the whole-cell patch-clamp technique, we compared Kv and Kir current densities (IKv and IKir) in the left (LCSMCs), right (RCSMCs), and septal branches of coronary smooth muscle cells (SCSMCs) from control and monocrotaline (MCT)-induced PAH rats exhibiting RVH. In control rats, (1) IKv was larger in RCSMCs than that in SCSMCs and LCSMCs, (2) IKv inactivation occurred at more negative voltages in SCSMCs than those in RCSMCs and LCSMCs, (3) IKir was smaller in SCSMCs than that in RCSMCs and LCSMCs, and (4) IBKCa did not differ between branches. Moreover, in PAH rats, IKir and IKv decreased in SCSMCs, but not in RCSMCs or LCSMCs, and IBKCa did not change in any of the branches. These results demonstrated that SCSMC-specific decreases in IKv and IKir occur in an MCT-induced PAH model, thereby offering insights into the potential pathophysiological implications of coronary blood flow regulation in right heart disease. Furthermore, the relatively smaller IKir in SCSMCs suggested a less effective vasodilatory response in the septal region to the moderate increase in extracellular K+ concentration under increased activity of the myocardium.

Increased inward rectifier K+ current of coronary artery smooth muscle cells in spontaneously hypertensive rats; partial compensation of the attenuated endothelium-dependent relaxation via Ca2+ -activated K+ channels.

Endothelium-dependent vasorelaxation is partly mediated by small-conductance (SK3) and intermediate-conductance Ca2+ -activated K+ channels (SK4) in the endothelium that results in endothelium-dependent hyperpolarization (EDH). Apart from the electrical propagation through myoendothelial gap junctions, the K+ released from the endothelium facilitates EDH by increasing inward rectifier K+ channel (Kir) conductance in smooth muscle cells. The EDH-dependent relaxation of coronary artery (CA) and Kir current in smooth muscle cells (CASMCs) of hypertensive animals are poorly understood despite the critical role of coronary flow in the hypertrophic heart. In spontaneously hypertensive (SHR) and control (WKY) rats, we found attenuation of the CA relaxation by activators of SK3 and SK4 (NS309 and 1-EBIO) in SHR. In isolated CASMCs, whole-cell patch-clamp study revealed larger IKir in SHR than WKY, whereas the myocytes of skeletal and cerebral arteries showed smaller IKir in SHR than WKY. While the treatment with IKir inhibitor (0.1 mmol/L Ba2+ ) alone did not affect the WKY-CA, the SHR-CA showed significant contractile response, suggesting relaxing influence of the higher IKir in the CASMCs of SHR. Furthermore, the attenuation of NS309-induced relaxation of CA by the combined treatment with 0.1 mmol/L Ba2+ was more prominent in SHR than WKY. Our study firstly shows a distinct increase of IKir in the CASMCs of SHR, which could partly compensate for the attenuated relaxation via endothelial SK3 and SK4.

The novel high-frequency variant of TRPV3 p.A628T in East Asians showing faster sensitization in response to chemical agonists.

TRPV3, a member of the thermosensitive Ca2+-permeable TRPV channel subfamily expressed in skin and sensory nerves, is also activated by chemical agonists such as 2-aminoethyl diphenylborinate (2-APB). Repetitive stimuli induce sensitization of TRPV3 activation, characterized by the cumulative increase in current amplitude and linearization of current-voltage relation (I/V curve). Through genomic analysis of various populations, we found non-rare TRPV3 mutation (p.A628T) in East Asian people with an allele frequency of 0.249 while 0.007 in Caucasian. Slope conductance of unitary channel was not different between WT and p.A628T. Whole-cell patch clamp study of wildtype TRPV3 (WT) and p.A628T overexpressed in HEK293T cells showed similar sensitization by the repetitive increase in temperature from 23 to 37 °C, while slightly higher sensitization to 43 °C in p.A628T. In contrast, the repetitive application of 2-APB (10 µM) or carvacrol (100 µM) induced faster sensitization in p.A628T than WT. However, 1 µM farnesyl pyrophosphate, an intrinsic lipid metabolite agonist, induced similar level of slow activations in WT and p.A628T. In Fura-2 microspectrofluorimetry, the 2-APB pulses induced a faster increase of [Ca2+]c in p.A628T than WT. In terms of ionic selectivity of channels, WT and p.A628T showed similar Ca2+ permeability (PCa/PNa) calculated from the reversal potential of I/V curves. Taken together, p.A628T shows faster sensitization to chemical agonists that are reflected as higher [Ca2+]c signaling. Based on the intriguing pharmacological sensitivity, the physiological implications of p.A628T in the East Asian population require further investigation.

Differential effects of saturated and unsaturated fatty acids on vascular reactivity in isolated mesenteric and femoral arteries of rats.

Free fatty acid (FFA) intake regulates blood pressure and vascular reactivity but its direct effect on contractility of systemic arteries is not well understood. We investigated the effects of saturated fatty acid (SFA, palmitic acid), polyunsaturated fatty acid (PUFA, linoleic acid), and monounsaturated fatty acid (MUFA, oleic acid) on the contractility of isolated mesenteric (MA) and deep femoral arteries (DFA) of Sprague-Dawley rats. Isolated MA and DFA were mounted on a dual wire myograph and phenylephrine (PhE, 1-10 µM) concentration-dependent contraction was obtained with or without FFAs. Incubation with 100 µM of palmitic acid significantly increased PhE-induced contraction in both arteries. In MA, treatment with 100 µM of linoleic acid decreased 1 µM PhE-induced contraction while increasing the response to higher PhE concentrations. In DFA, linoleic acid slightly decreased PhE-induced contraction while 200 µM oleic acid significantly decreased it. In MA, oleic acid reduced contraction at low PhE concentration (1 and 2 µM) while increasing it at 10 µM PhE. Perplexingly, depolarization by 40 mM KCl-induced contraction of MA was commonly enhanced by the three fatty acids. The 40 mM KCl-contraction of DFA was also augmented by linoleic and oleic acids while not affected by palmitic acid. SFA persistently increased alpha-adrenergic contraction of systemic arteries whereas PUFA and MUFA attenuated PhE-induced contraction of skeletal arteries. PUFA and MUFA concentration-dependent dual effects on MA suggest differential mechanisms depending on the types of arteries. Further studies are needed to elucidate underlying mechanisms of the various effects of FFA on systemic arteries.

Fast relaxation and desensitization of angiotensin II contraction in the pulmonary artery via AT1R and Akt-mediated phosphorylation of muscular eNOS.

Angiotensin II (AngII) triggers a transient contraction of pulmonary arteries (PAs) followed by protracted desensitization. Based on the unconventional eNOS expression in PA smooth muscle cells (PASMCs), we hypothesized that activation of smooth muscle eNOS by AngII might be responsible for fast relaxation and tachyphylaxis. Using dual-wire myograph, mechanically endothelium-denuded rat PA [E(-)PA] showed AngII concentration-dependent transient contractions (ΔTAngII, 95% decay within 1 min), which were abolished by losartan (AT1R antagonist). Neither PD123319 (AT2R antagonist) nor A779 (MasR antagonist) affected ΔTAngII. When the vessels were pretreated with L-NAME (NOS inhibitor), ODQ (guanylate cyclase inhibitor), or KT5823 (PKG inhibitor), ΔTAngII of E(-)PA became larger and sustained, whereas nNOS or iNOS inhibitors had no such effect. Immunoblotting of human PASMCs (hPASMCs) also showed eNOS expression, and AngII treatment induced activating phosphorylations of Ser1177 in eNOS and of Ser473 in Akt (Ser/Thr protein kinase B), an upstream signal of eNOS phosphorylation. In addition, L-NAME co-treatment promoted AngII-induced Ser19 phosphorylation of myosin light chain. In hPASMCs, AngII abolished plasma membrane expression of AT1R, and recovery by washout took more than 1 h. Consistent with the data from hPASMCs, the second application of AngII to E(-)PA did not induce contraction, and significant recovery of ΔTAngII required prolonged washout (> 2 h) in the myography study. L-NAME treatment before the second application facilitated recovery of ΔTAngII. Muscular eNOS plays an auto-inhibitory role in ΔTAngII of PAs. The molecular changes investigated in hPASMCs revealed eNOS phosphorylation and internalization of AT1R by AngII. We propose that the rat PA smooth muscle eNOS-induced lusitropy and slow recovery of AT1R from tachyphylaxis might counterbalance the excessive contractile response to AngII, contributing to the distinctive low-pressure pulmonary circulation.

Endurance exercise training restores atrophy-induced decreases of myogenic response and ionic currents in rat skeletal muscle artery.

Atrophic limbs exhibit decreased blood flow and histological changes in the arteries perfusing muscles. However, the effect of atrophy on vascular smooth muscle function is poorly understood. Here, we investigated the effect of unilateral sciatic denervation on the myogenic response (MR) and the ionic currents in deep femoral artery (DFA) smooth muscles from Sprague-Dawley rats. Because denervated rats were capable of treadmill exercise (20 m/min, 30 min, 3 times/wk), the impact of exercise training on these effects was also assessed. Skeletal arteries were harvested 3 or 5 wk after surgery. Then skeletal arteries or myocytes were subjected to video analysis of pressurized artery, myography, whole-cell patch clamp, and real-time quantitative PCR to determine the effect of hindlimb paralysis in the presence/absence of exercise training on MR, contractility, ionic currents, and channel transcription, respectively. In sedentary rats, atrophy was associated with loss of MR in the DFA at 5 wk. The contralateral DFA had a normal MR. At 5 wk after surgery, DFA myocytes from the atrophic limbs exhibited depressed L-type Ca2+ currents, GTPγS-induced transient receptor potential cation channel (TRPC)-like currents, 80 mM KCl-induced vasoconstriction, TRPC6 mRNA, and voltage-gated K+ and inwardly rectifying K+ currents. Exercise training abrogated the differences in all of these functions between atrophic side and contralateral side DFA myocytes. These results suggest that a probable increase in hemodynamic stimuli in skeletal artery smooth muscle plays an important role in maintaining MR and ionic currents in skeletal artery smooth muscle. This may also explain the observed benefits of exercise in patients with limb paralysis. NEW & NOTEWORTHY Myogenic responses (MRs) in rat skeletal arteries feeding the unilateral atrophic hindlimb were impaired. In addition, the L-type Ca2+ channel current, the TRPC6-like current, and TRPC6 mRNA levels in the corresponding myocytes decreased. Voltage-gated K+ channel currents and inwardly rectifying K+ channel currents were also attenuated in atrophic side myocytes. Exercise training effectively abrogated electrophysiological dysfunction of atrophic side myocytes and prevented loss of the MR.

Parental Occupational Status and Suicidal Ideation in Adolescent: Cross-Sectional Secondary Data Analysis.

PURPOSE: This study aimed to identify the effect of parental occupational status on adolescents' suicidal ideation from a representative sample of the Korean population. DESIGN AND METHODS: A cross-sectional analysis was performed. Participants were 3201 adolescents aged 12-18 years from the Korean National Health and Nutrition Examination Survey. RESULTS: Adolescents experiencing suicidal ideation were found to be more likely to be female, have a history of smoking or alcohol use, a shorter sleep duration, greater perception of stress, and greater experience of depression when compared to those who did not report suicidal ideation. There was a statistically significant difference in perception of stress, experience of depression, and experience of suicidal ideation according to parental occupational status. Adolescents' suicidal ideation was associated with parents' employment status, work status, work schedule patterns, and working hours per week. CONCLUSIONS: Parental occupational status was associated with adolescents' suicidal ideation, but fathers' and mothers' occupational status affected children's suicidal ideation in different ways. Adolescents' suicidal ideation seems to have been affected by economic difficulty and stress, resulting from the father's occupational status, amount of time spent interacting with the mother, and the mother's employment status. Policies are needed to improve the quality of employment to reduce the financial difficulties and stresses of the father. A strategy for work-family compatibility is needed so that the mother can have enough time with her children while she has a job. PRACTICE IMPLICATIONS: It is necessary to consider parents' occupational status when assessing adolescents' suicidal ideation and providing interventions.

Biphasic augmentation of alpha-adrenergic contraction by plumbagin in rat systemic arteries.

Plumbagin, a hydroxy 1,4-naphthoquinone compound from plant metabolites, exhibits anticancer, antibacterial, and antifungal activities via modulating various signaling molecules. However, its effects on vascular functions are rarely studied except in pulmonary and coronary arteries where NADPH oxidase (NOX) inhibition was suggested as a mechanism. Here we investigate the effects of plumbagin on the contractility of skeletal artery (deep femoral artery, DFA), mesenteric artery (MA) and renal artery (RA) in rats. Although plumbagin alone had no effect on the isometric tone of DFA, 1 µM phenylephrine (PhE)-induced partial contraction was largely augmented by plumbagin (ΔTPlum, 125% of 80 mM KCl-induced contraction at 1 µM). With relatively higher concentrations (>5 µM), plumbagin induced a transient contraction followed by tonic relaxation of DFA. Similar biphasic augmentation of the PhE-induced contraction was observed in MA and RA. VAS2870 and GKT137831, specific NOX4 inhibitors, neither mimicked nor inhibited ΔTPlum in DFA. Also, pretreatment with tiron or catalase did not affect ΔTPlum of DFA. Under the inhibition of PhE-contraction with L-type Ca2+ channel blocker (nifedipine, 1 µM), plumbagin still induced tonic contraction, suggesting Ca2+-sensitization mechanism of smooth muscle. Although ΔTPlum was consistently observed under pretreatment with Rho A-kinase inhibitor (Y27632, 1 µM), a PKC inhibitor (GF 109203X, 10 µM) largely suppressed ΔTPlum. Taken together, it is suggested that plumbagin facilitates the PKC activation in the presence of vasoactive agonists in skeletal arteries. The biphasic contractile effects on the systemic arteries should be considered in the pharmacological studies of plumbagin and 1,4-naphthoquinones.

Maxi-K channel (BKCa) activity veils the myogenic tone of mesenteric artery in rats.

Arterioles and small arteries change their tone in response to transmural pressure changes, called myogenic tone (MT). In comparison to the branches of cerebral arteries (CA) showing prominent MT, the third branches of mesenteric arteries (MA) with similar diameters show weaker MT Here, we aimed to analyze the electrophysiological differences responsible for the weaker MT in MA (MTMA) than MT in CA (MTCA). We measured ionic current using patch clamp in isolated MA smooth muscle cells (MASMCs) and CA smooth muscle cells (CASMCs) of rats. MT was analyzed using video analysis of pressurized small arteries. Quantitative-PCR (q-PCR) and immunofluorescence confocal microscopy were used to compare the mRNA and protein expression level of big-conductance Ca2+-activated K+ channel (BKCa) subunits (Slo1α and Sloß1). Whole-cell patch clamp study revealed higher density of voltage-operated Ca2+ channel current (ICaV) in the MASMCs than in CASMCs. Although voltage-gated K+ channel current (IKv) was also higher in MASMCs, treatment with Kv inhibitor (4-aminopyridine) did not affect MTMA Interestingly, BKCa current density and the frequency of spontaneous transient outward currents (STOCs) were consistently higher in MASMCs than in CASMCs. Inside-out patch clamp showed that the Ca2+-sensitivity of BKCa is higher in MASMCs than in CASMCs. Iberiotoxin, a selective BKCa inhibitor, augmented MTMA by a larger extent than MTCA Although q-PCR analysis did not reveal a significant difference of mRNAs for Slo1α and Sloß1, immunofluorescence image suggested higher expression of Slo1α in MASMCs than in CASMCs. Despite the large ICaV density, the high activities of BKCa including the more frequent STOCs in MASMCs veils the potentially strong MTMA.