Protective effect of low-intensity treadmill exercise against acetylcholine-calcium chloride-induced atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia, and it corresponds highly with exercise intensity. Here, we induced AF in mice using acetylcholine (ACh)-CaCl2 for 7 days and aimed to determine the appropriate exercise intensity (no, low, moderate, high) to protect against AF by running the mice at different intensities for 4 weeks before the AF induction by ACh-CaCl2. We examined the AF-induced atrial remodeling using electrocardiogram, patch-clamp, and immunohistochemistry. After the AF induction, heart rate, % increase of heart rate, and heart weight/body weight ratio were significantly higher in all the four AF groups than in the normal control; highest in the high-ex AF and lowest in the low-ex (lower than the no-ex AF), which indicates that low-ex treated the AF. Consistent with these changes, G protein-gated inwardly rectifying K+ currents, which were induced by ACh, increased in an exercise intensity-dependent manner and were lower in the low-ex AF than the no-ex AF. The peak level of Ca2+ current (at 0 mV) increased also in an exercise intensity-dependent manner and the inactivation time constants were shorter in all AF groups except for the low-ex AF group, in which the time constant was similar to that of the control. Finally, action potential duration was shorter in all the four AF groups than in the normal control; shortest in the high-ex AF and longest in the low-ex AF. Taken together, we conclude that low-intensity exercise protects the heart from AF, whereas high-intensity exercise might exacerbate AF.

Caveolar remodeling is a critical mechanotransduction mechanism of the stretch-induced L-type Ca2+ channel activation in vascular myocytes.

Activation of L-type voltage-dependent Ca2+ channels (VDCCL) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCCL activation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCCL in rat mesenteric arterial smooth muscle cells. The VDCCL currents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique. Hypotonic (~230 mOsm) swelling-induced membrane stretch reversibly increased the VDCCL currents. Electron microscope and confocal imaging analysis revealed that both hypotonic swelling and cholesterol depletion by methyl-ß-cychlodextrin (MßCD) similarly disrupted the caveolae structure and translocated caveolin-1 (Cav-1) from membrane to cytosolic space. Accordingly, MßCD also increased VDCCL currents. Moreover, subsequent hypotonic swelling after MßCD treatment failed to increase the VDCCL currents further. Western blotting experiments revealed that hypotonic swelling phosphorylated Cav-1 and JNK. Inhibitors of tyrosine kinases (genistein) and JNK (SP00125) prevented the swelling-induced facilitation of VDCCL currents. Knockdown of Cav-1 by small interfering RNA blocked both the VDCCL current facilitation by stretch and the related phosphorylation of JNK. Taken together, the results suggest that membrane stretch is transduced to the facilitation of VDCCL currents via caveolar structure-dependent tyrosine phosphorylation of Cav-1 and subsequent activation of JNK in rat mesenteric arterial myocytes.

Association Between Alcohol Consumption and Academic Achievement: a Cross-sectional Study.

AIM: Alcohol consumption among adolescents is a serious public health problem in South Korea. Our study examined the relationship between alcohol consumption and academic achievement in Korean adolescents. In 2011, 75,643 students from seventh to twelfth grade participated in the Seventh Korea Youth Risk Behaviour Web-based Survey (KYRBWS-VII). METHOD: We performed multivariate logistic regression analysis to examine the associations between alcohol consumption, frequency of severe alcohol intoxication, and academic achievement for both girls and boys. RESULTS: Compared to non-drinkers, the odds of achieving average or higher academic performance significantly decreased for both boys and girls with increasing number of days per month with reported alcohol consumption (p≤0.008). Further, odds of achieving average or higher academic performance significantly decreased with increasing amounts of alcohol consumed compared to non-drinkers (p≤0.026). Additionally, the odds of achieving average or higher academic performance according to the frequency of severe alcohol intoxication were only significantly decreased for 1-2 days per month of severe intoxication (p<0.001). CONCLUSION: Both boys and girls with increased alcohol consumption and frequency of severe alcohol intoxication had below average academic achievement in Korea. To improve academic achievement, we recommend interventions that reduce alcohol consumption among adolescents.

Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation.

Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca(2+)-activated K(+) channels and inward rectifier K(+) channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.

Blockade of voltage-gated K⁺ currents in rat mesenteric arterial smooth muscle cells by MK801.

MK801 (dizocilpine), a phencyclidine (PCP) derivative, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). Another PCP derivative, ketamine, was reported to block voltage-gated K(+) (Kv) channels, which was independent of NMDAr function. Kv currents are major regulators of the membrane potential (Em) and excitability of muscles and neurons. Here, we investigated the effect of MK801 on the Kv channels and Em in rat mesenteric arterial smooth muscle cells (RMASMCs). We used the whole-cell patch clamp technique to analyze the effect of MK801 enantiomers on Kv channels and Em. (+)MK801 inhibited Kv channels in a concentration-dependent manner (IC50 of 89.1 ± 13.1 µM, Hill coefficient of 1.05 ± 0.08). The inhibition was voltage- and state- independent. (+)MK801 didn't influence steady-state activation and inactivation of Kv channels. (+)MK801 treatment depolarized Em in a concentration-dependent manner and concomitantly decreased membrane conductance. (-)MK801 also similarly inhibited the Kv channels (IC50 of 134.0 ± 17.5 µM, Hill coefficient of 0.87 ± 0.09). These results indicate that MK801 directly inhibits the Kv channel in a state-independent manner in RMASMCs. This MK801-mediated inhibition of Kv channels should be considered when assessing the various pharmacological effects produced by MK801, such as schizophrenia, neuroprotection, and hypertension.

The relationships between lifestyle factors and hypertension in community-dwelling Korean adults.

[Purpose] This study was performed to determine whether certain lifestyle factors are associated with hypertension in community-dwelling Korean adults. [Subjects and Methods] The subjects were 586 males and 1,135 females > 20 years old who had visited a public health promotion center in Seoul, Republic of Korea to take a survey related to lifestyle factors. Hypertension status was defined according to the criteria of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VII report. [Results] The relationships between lifestyle factors and hypertension status were assessed using multivariate logistic regression analysis after adjusting for age and gender. Only mental stress and economic status significantly predicted hypertension status. [Conclusion] We conclude that sleep duration, education level, frequency of drinking and smoking status were not associated with hypertension status. However, economic status and mental stress were significantly associated with hypertension in community-dwelling Korean adults, regardless of age or gender.

Receptor-specific contributions of caveolae, PKC, and Src tyrosine kinase to serotonergic and adrenergic regulation of Kv channels and vasoconstriction.

AIMS: Caveolae are invaginated, Ω-shaped membrane structures. They are now recognized as portals for signal transduction of multiple chemical and mechanical stimuli. Notably, the contribution of caveolae has been reported to be receptor-specific. However, details of how they differentially contribute to receptor signaling remain unclear. MAIN METHODS: Using isometric tension measurements, patch-clamping, and western blotting, we examined the contribution of caveolae and their related signaling pathways to serotonergic (5-HT2A receptor-mediated) and adrenergic (α1-adrenoceptor-mediated) signaling in rat mesenteric arteries. KEY FINDINGS: Disruption of caveolae by methyl-ß-cyclodextrin effectively blocked vasoconstriction mediated by the 5-HT2A receptor (5-HT2AR), but not by the α1-adrenoceptor. Caveolar disruption selectively impaired 5-HT2AR-mediated voltage-dependent K+ channel (Kv) inhibition, but not α1-adrenoceptor-mediated Kv inhibition. In contrast, both serotonergic and α1-adrenergic effects on vasoconstriction, as well as Kv currents, were similarly blocked by the Src tyrosine kinase inhibitor PP2. However, inhibition of protein kinase C (PKC) by either GO6976 or chelerythrine selectively attenuated the effects mediated by the α1-adrenoceptor, but not by 5-HT2AR. Disruption of caveolae decreased 5-HT2AR-mediated Src phosphorylation, but not α1-adrenoceptor-mediated Src phosphorylation. Finally, the PKC inhibitor GO6976 blocked Src phosphorylation by the α1-adrenoceptor, but not by 5-HT2AR. SIGNIFICANCE: 5-HT2AR-mediated Kv inhibition and vasoconstriction are dependent on caveolar integrity and Src tyrosine kinase, but not on PKC. In contrast, α1-adrenoceptor-mediated Kv inhibition and vasoconstriction are not dependent on caveolar integrity, but rather on PKC and Src tyrosine kinase. Caveolae-independent PKC is upstream of Src activation for α1-adrenoceptor-mediated Kv inhibition and vasoconstriction.

Blockade of K+ and Ca2+ channels by azole antifungal agents in neonatal rat ventricular myocytes.

Some azole antifungal agents induce long QT syndrome and arrhythmias. Although composite functions of ion channels in cardiomyocytes contribute to the shaping of action potentials, information on the effects of azole antifungal agents on ion currents, except human-ether-a-go-go-related gene (HERG) K+ currents, is largely lacking. Using the whole cell patch-clamp technique, we investigated the effects of four azole agents (miconazole, ketoconazole, fluconazole, and itraconazole) on inward rectifying K+ currents (IKir), voltage-gated L-type Ca2+ currents (ICaL), and delayed rectifier K+ currents (IKdr) in rat neonate ventricular myocytes. Strikingly, miconazole and ketoconazole strongly inhibited IKir, IKdr, and ICaL at clinically relevant concentrations. The IC50 values of miconazole for IKdr, IKir, and ICaL inhibition were 2.5, 10.4, and 3.0 µM, respectively. The IC50 values of ketoconazole for IKdr, IKir and ICaL inhibition were 3.2, 20.8, and 3.5 µM, respectively. Fluconazole and itraconazole had relatively little effect on ion currents. These findings indicate that miconazole and ketoconazole are multiple ion channel inhibitors in cardiomyocytes. We suggest that it is necessary to consider this inhibition of ion channels by azole agents when assessing cardiovascular side effects.

Differential expression profiles of miRNA in the serum of sarcopenic rats.

As the geriatric population and life expectancy increase, the interest in preventing geriatric diseases, such as sarcopenia, is increasing. However, the causes of sarcopenia are unclear, and current diagnostic methods for sarcopenia are unreliable. We hypothesized that the changes in the expression of certain miRNAs may be associated with the pathophysiology of sarcopenia. Herein, we analyzed the miRNA expression profiles in the blood of young (3-months-old) healthy rats, old sarcopenic (17-months-old) rats, and age-matched (17-months-old) control rats. The changes in miRNA expression levels were analyzed using Bowtie 2 software. A total of 523 miRNAs were detected in the rat serum. Using scatter plots and clustering heatmap data, we found 130 miRNAs that were differentially expressed in sarcopenic rats (>2-fold change) compared to the expression in young healthy and age-matched control rats. With a threshold of >5-fold change, we identified 14 upregulated miRNAs, including rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-133c, rno-miR-208a-3p, and rno-miR434-5p among others in the serum of sarcopenic rats. A protein network map based on these 14 miRNAs identified the genes involved in skeletal muscle differentiation, among which Notch1, Egr2, and Myocd represented major nodes. The data obtained in this study are potentially useful for the early diagnosis of sarcopenia and for the identification of novel therapeutic targets for the treatment and/or prevention of sarcopenia.

Prevalence of obesity in korean adolescents and its relationship with the weekly frequency of the physical education classes.

The purpose of this study was to investigate differences in the prevalence of obesity among Korean adolescents and to determine the relationship of obesity prevalence with weekly frequency of physical education (PE) classes. In 2009, 72,399 students from grades 7 to 12 participated in the fifth Korea Youth Risk Behavior Web-based Survey (KYRBWS-V) project. Body mass index (BMI) and the frequency of PE classes attended were assessed by the KYRBWS- V. BMI was computed to classify the participants as underweight, normal weight, overweight, and obese. The association between the frequency of PE classes and BMI were examined using one-way ANOVA and logistic regression analysis. The differences in the weekly frequency of PE classes and the BMI values among both the boys and girls were significant (p < 0.001). A post-hoc test showed that underweight boys and girls attended the PE classes more frequently (p < 0.001), and overweight girls attended these classes less frequently (p < 0.01) than the other groups did; moreover, obese boys and girls, compared to boys and girls in the other groups, attended less number of PE classes per week while at school (p < 0.05). Besides, the odds ratio (95% confidence interval, CI) for normal-weight vs. underweight boys attending 1 PE class, 2 PE classes, and ≥ 3 PE classes per week were 1.168 (1.011-1.349, p = 0.035), 1.621 (1.450-1.812, p < 0.001), and 3.023 (2.704-3.381, p < 0.001), respectively, compared with those for boys who did not attend PE classes. The OR (95% CI) of normal-weight vs. obese boys attending ≥ 3 PE classes attended across normal vs. obese boys was 0.862 (0.762-0.974, p = 0.017), compared with those of boys who did not attend PE classes. The OR (95% CI) for normal-weight vs. underweight girls who attended 2 PE classes and ≥ 3 PE classes per week were 1.235 (1.131-1.349, p < 0.001) and 2.238 (2.048-2.446, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) of for normal-weight vs. overweight girls who attended ≥ 3 PE classes per week were 0.886 (0.787- 0.997, p = 0.045) and 0.772 (0.679-0.878, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) for normal-weight vs. obese girls who attended 2 PE classes and ≥ 3 PE classes per week were 0.788 (0.675-0.919, p = 0.002) and 0.709 (0.599-0.838, p < 0.001), respectively, compared with those of girls who did not attend the PE class. Increase in the frequency of PE classes should be considered in any attempt for curbing weight-related problems in Korean adolescents. Key pointsIncrease in the frequency of PE classes is a factor that should be considered to improve weight status.

Diet control to achieve euglycaemia induces tau hyperphosphorylation via AMPK activation in the hippocampus of diabetic rats.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles. Insulin resistance and hyperglycaemia have been proposed as risk factors for AD development. As the maintenance of optimal blood glucose level is an important indicator of diabetes mellitus (DM) treatment, diet control is essential. AMPK is a crucial sensor of cellular bioenergetics for controlling anabolic and catabolic metabolism. Since AMPK is a direct regulator of tau phosphorylation, we hypothesized that strict diet control to achieve euglycaemia affects tau protein phosphorylation through increased AMPK activity in the hippocampus of DM rats. To test this hypothesis, we generated insulin-deficient DM rats by subtotal pancreatectomy and the animals were categorized into the diet-restriction (R) group and ad libitum (AL) feeding group. We found that tau phosphorylation was significantly higher in the R group than that in the sham-control (C) or AL group. AMPK activity in the R group was significantly higher than that in the C or AL group, as expected. Furthermore, the R group showed more critical tau pathology in the hippocampus than the other groups. These results suggest that diet control to achieve euglycaemia in an insulin-deficient DM condition may be harmful because of the greater possibility of AD development through increased tau phosphorylation by AMPK activation in the hippocampus.

Heterogeneity in liver histopathology is associated with GSK-3ß activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets.

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague- Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorierestricted (18R group), and 11 were both calorie- and proteinrestricted with the low-protein diet (6R group). Overnightfasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3ß inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3ß activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3ß activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3ß activity and mitochondrial function in insulin-deficient state. [BMB Reports 2020; 53(2): 100-105].

Bone-Loading Physical Activity and Alcohol Intake but not BMI Affect Areal Bone Mineral Density in Young College-Aged Korean Women: A Cross-Sectional Study.

The purpose of this cross-sectional study was to determine the differences in areal bone mineral density (aBMD) based on alcohol consumption behaviors, bone-loading history as assessed by a bone-specific physical activity questionnaire (BPAQ), and the body mass index (BMI). College-aged female students (N = 112) were recruited from the universities in Seoul and Gyeonggi province, South Korea. The aBMD of the lumbar spine and non-dominant side of the proximal femur (total hip, TH; femoral neck, FN; femoral trochanter, FT) were measured using dual energy X-ray absorptiometry (DXA). Alcohol consumption was determined by the frequency and amount of alcohol intake during the past 12 months using a self-reported questionnaire. The X-scan plus II was used to measure height (cm), body mass (kg), fat-free mass (FFM, kg), and % body fat. Drinking two or more times alcohol per week was associated with greater aBMD of the TH (p = 0.04-0.002) and FN (p = 0.043) compared to a lower frequency of alcohol consumption and 2-4 times per month, respectively. Based on the drinking amount per occasion, there were no significant group differences (p > 0.05) in aBMD at any of the sites. The highest group of total BPAQ had greater aBMD of the TH, FN, and FT versus the lowest (p = 0.023-0.009) and mid of total BPAQ groups (p = 0.004-0.009). Additionally, the highest group had greater aBMD of the lumbar spine compared to the mid group (p = 0.001). No significant group differences in aBMD at any of the sites were noted based on the BMI (p > 0.05). Young college-aged women with greater bone-loading physical activity showed greater aBMD at the TH, FN, FT, and lumbar spine, while a moderate alcohol intake was associated with greater aBMD of the TH and FN. These findings have clinical implications for young women who may not participate in high-impact physical activity and are binge drinkers.

Transcranial Direct Current Stimulation of motor cortex enhances running performance.

Transcranial direct current stimulation (tDCS) is a technique used to modulate neuronal excitability through non-invasive brain stimulation that can enhance exercise performance. We hypothesize that tDCS would improve submaximal running time to exhaustion (TTE) and delay the increase in the rating of perceived exertion (RPE) over time. We also hypothesize that tDCS would not lead to difference in cardiorespiratory responses. We employed a randomized, single-blinded, and counterbalanced design in which 10 trained men participated. After receiving either 20 min of 1.98 mA anodal tDCS applied over the primary motor cortex (M1) or sham-operated control on separate days, participants completed a constant-load test involving running at a speed equivalent to 80% of their own maximum oxygen consumption (VO2max). During this constant-load test, RPE, heart rate (HR), VO2, pulmonary ventilation (VE), respiratory exchange ratio (RER), and ventilatory threshold (VT) were continuously monitored. TTE was recorded at the end of the test. TTEs were significantly longer in the tDCS than in the sham conditions (21.18 ± 7.13 min; 18.44 ± 6.32 min; p = 0.011). For TTE, no significant differences were found in RPE between conditions at isotime. In addition, no significant differences in HR, VO2, VE, RER, and VT were found during TTE between the two stimulation conditions at any time point. These results indicate that the application of tDCS does not induce a change of the exercise performance-related index; however, it can affect the increase of the exercise duration due to the stimuli in the M1 area.

Hydrogen peroxide constricts rat arteries by activating Na+-permeable and Ca2+-permeable cation channels.

Oxidative stress is associated with many cardiovascular diseases, such as hypertension and arteriosclerosis. Oxidative stress reportedly activates the L-type voltage-gated calcium channel (VDCCL) and elevates [Ca2+]i in many cells. However, how oxidative stress activates VDCCL under clinical setting and the consequence for arteries are unclear. Here, we examined the hypothesis that hydrogen peroxide (H2O2) regulates membrane potential (Em) by altering Na+ influx through cation channels, which consequently activates VDCCL to induce vasoconstriction in rat mesenteric arteries. To measure the tone of the endothelium-denuded arteries, a conventional isometric organ chamber was used. Membrane currents and Em were recorded by the patch-clamp technique. [Ca2+]i and [Na+]i were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that H2O2 (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of H2O2 on isometric contraction. H2O2 increased [Ca2+]i as well as [Na+]i, and depolarised Em. Gd3+ (1 µM) blocked all these H2O2-induced effects including Em depolarisation and increases in [Ca2+]i and [Na+]i. Although both nifedipine (30 nM) and low Na+ bath solution completely prevented the H2O2-induced increase in [Na+], they only partly inhibited the H2O2-induced effects on [Ca2+]i and Em. Taken together, the results suggested that H2O2 constricts rat arteries by causing Em depolarisation and VDCCL activation through activating Gd3+-and nifedipine-sensitive, Na+-permeable channels as well as Gd3+-sensitive Ca2+-permeable cation channels. We suggest that unidentified Na+-permeable cation channels as well as Ca2+-permeable cation channels may function as important mediators for oxidative stress-induced vascular dysfunction.

Enhancement of 5-HT2A receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models.

MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HT2ARs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HT2AR signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HT2AR signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5-HT2AR-mediated response. Using isometric organ bath experiments with arterial rings and conventional whole-cell patch-clamp recording of Chinese hamster ovary (CHO) cells ectopically overexpressing Kv1.5, we examined the effect of ketamine and MK801 on 5-HT2AR-mediated vasocontraction and Kv1.5 channels. Both ketamine and MK801 potentiated 5-HT2AR-mediated vasocontraction. This potentiation of 5-HT2AR function occurred in a membrane potential-dependent manner, indicating the involvement of ion channel(s). Both ketamine and MK801 rapidly and directly inhibited Kv1.5 channels from the extracellular side independently of NMDArs. The potencies of MK801 in facilitating the 5-HT2AR-mediated response and blocking Kv1.5 were higher than those of ketamine. Our data demonstrated the direct inhibition of Kv1.5 channels by MK801/ketamine and indicated that this inhibition may potentiate the functions of 5-HT2ARs. We suggest that 5-HT2AR-Kv1.5 may serve as a receptor-effector module in response to 5-HT and is a promising target in the pathogenesis of MK801-/ketamine-induced disease states such as hypertension and schizophrenia.

Serotonin-induced ion channel modulations in mesenteric artery myocytes from normotensive and DOCA-salt hypertensive rats.

Although serotonin (5-hydroxytryptamine, 5-HT) has been found to be a potent vasoconstrictor, a pivotal role of 5-HT in the control of appetite and mood control by the modulation of neuronal synapse has also been proposed. Selective 5-HT reuptake inhibitors (SSRIs) are frequently used to suppress appetite and treat depressive disorder, and the target protein of SSRIs is the 5-HT transporter (5-HTT) in the neuronal synapse. However, SSRIs may increase the free 5-HT concentration in circulating blood because platelets and vascular smooth muscles express functional 5-HTT. In addition, enhanced vasoactive action of 5-HT and alterations in 5-HT receptor subtypes have been reported in some types of hypertension. Therefore, we can infer that the use of drugs such as SSRIs in some hypertensive patients is potentially risky. Altered functional expression of ion channels in vascular smooth muscle is suggested to be a mechanism for the enhanced vasoconstriction by vasoactive agonists, including 5-HT. In this brief review, we compared the electrophysiological properties of mesenteric artery myocytes and their modulation by 5-HT between sham-operated control and deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

Therapeutic effectiveness of instrument-assisted soft tissue mobilization for soft tissue injury: mechanisms and practical application.

This article reviews the mechanism and effects of instrument-assisted soft tissue mobilization (IASTM), along with guidelines for its practical application. IASTM refers to a technique that uses instruments to remove scar tissues from injured soft tissues and facilitate healing process through formation of new extracellular matrix proteins such as collagen. Recently, frequent use of this instrument has increased in the fields of sports rehabilitation and athlete training. Some experimental studies and case reports have reported that IASTM can significantly improve soft tissue function and range of motion following sports injury, while also reducing pain. Based on the previous studies, it is thought that IASTM can help shorten the rehabilitation period and time to return to sports among athletes and ordinary people who have suffered sports injuries. However, few experimental studies of the mechanisms and effects of IASTM have examined, while case reports have accounted for the majority of articles. In the future, the scientific basis of IASTM and its reliability should be provided through well-designed experimental studies on humans. Moreover, IASTM studies that have mostly focused on tendons need to broaden their scope toward other soft tissues such as muscles and ligaments.