Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with IC₅₀ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect I(Na), I(Ks) or I(K1), but decreased I(hERG) in a dose-dependent manner (IC₅₀: 6.53 µM). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to 3 µM, but it at 10 µM induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.
Action Potentials ; Animals ; Antineoplastic Agents ; Aurora Kinases ; Cardiotoxicity ; Cell Division ; Cell Line ; Humans ; In Vitro Techniques ; Ion Channels ; Muscle Cells ; Myocardial Contraction ; Myocytes, Cardiac ; Phosphotransferases ; Rats ; Relaxation

BACKGROUND: New complications associated with sugammadex have been increased since its widespread use. We report a case of an 80-year-old male who experienced profound bradycardia and sustained hypotension after administration of sugammadex. CASE: Following administration of 200 mg sugammadex after laparoscopic cholecystectomy, sudden bradycardia (29 beats/min) developed for 10 seconds and his train-of-four (TOF) ratio remained at 0.2 for 5 min. An additional 200 mg sugammadex was administered and profound bradycardia (21–30 beats/min) and hypotension (60/40 mmHg) developed. Atropine at 0.5 mg was administered, but the effect lasted only 30 s. Profound bradycardia occurred four more times at 30 s intervals, and ephedrine and phenylephrine were injected intermittently to increase the patient's heart rate and blood pressure. The TOF ratio became 0.9 about 10 min after administration of additional sugammadex. CONCLUSIONS: Awareness must be heightened regarding the possibility of sugammadexinduced bradycardia and hypotension, and more attention should be paid to patients with slow recovery times following muscle relaxation, despite the use of sugammadex.
Aged, 80 and over ; Atropine ; Blood Pressure ; Bradycardia ; Cholecystectomy, Laparoscopic ; Ephedrine ; Heart Rate ; Humans ; Hypotension ; Male ; Muscle Relaxation ; Neuromuscular Blockade ; Phenylephrine ; Postoperative Complications

This article reviewed the current knowledge on time-course manifestation of diabetic urethral dysfunction (DUD), and explored an early intervention target to prevent the contribution of DUD to the progression of diabetes-induced impairment of the lower urinary tract (LUT). In the literature search through PubMed, key words used included “diabetes mellitus,” “diabetic urethral dysfunction,” and “diabetic urethropathy.” Polyuria and hyperglycemia induced by diabetes mellitus (DM) can cause the time-dependent changes in functional and morphological manifestations of DUD. In the early stage, it promotes urethral dysfunction characterized by increased urethral pressure during micturition. However, the detrusor muscle of the bladder tries to compensate for inducing complete voiding by increasing the duration and amplitude of bladder contractions. As the disease progresses, it can induce an impairment of coordinated micturition due to dyssynergic activity of external urethra sphincter, leading to detrusor-sphincter dyssynergia. The impairment of relaxation mechanisms of urethral smooth muscles (USMs) may additionally be attributable to decreased responsiveness to nitric oxide, as well as increased USM responsiveness to α1-adrenergic receptor stimulation. In the late stage, diabetic neuropathy may play an important role in inducing LUT dysfunction, showing that the decompensation of the bladder and urethra, which can cause the decrease of voiding efficiency and the reduced thickness of the urothelium and the atrophy of striated muscle bundles, possibly leading to the vicious cycle of the LUT dysfunction. Further studies to increase our understandings of the functional and molecular mechanisms of DUD are warranted to explore potential targets for therapeutic intervention of DM-induced LUT dysfunction.
Ataxia ; Atrophy ; Diabetes Mellitus ; Diabetic Neuropathies ; Early Intervention (Education) ; Hyperglycemia ; Lower Urinary Tract Symptoms ; Muscle, Smooth ; Muscle, Striated ; Nitric Oxide ; Polyuria ; Relaxation ; Urethra ; Urinary Bladder ; Urinary Tract ; Urination ; Urothelium

Arthritis of hip joints deteriorates the quality of life in ankylosing spondylitis (AS) patients. Secondary to the articular inflammatory process, the shortened hip-girdle muscles contribute to the decreased joint mobility which may lead to the functional impairment. As the limitation of range of motion (ROM) usually progress slowly, clinicians regard it as a chronic condition and prescribe long-term therapy. However, by short-term intensive multimodal treatment, a 20-year-old man diagnosed as AS with severely limited hip joint ROM who relied on crutches doubled the joint angle and could walk independently only within 2 weeks. The combination included intra-articular steroid injection, electrical twitch obtaining intramuscular stimulation, extracorporeal shock wave therapy, heat, manual therapy, and stretching exercises. The management focused on the relaxation of hip-girdle muscles as well as the direct control of intra-articular inflammation. Hereby, we emphasize the effectiveness of intensive multimodal treatment in improving the function even within a short period.
Arthritis ; Combined Modality Therapy ; Crutches ; Exercise ; Hip Joint ; Hip ; Hot Temperature ; Humans ; Inflammation ; Joints ; Muscle Relaxation ; Muscles ; Musculoskeletal Manipulations ; Quality of Life ; Range of Motion, Articular ; Relaxation ; Shock ; Spondylitis, Ankylosing ; Young Adult

BACKGROUND: Nicardipine, a calcium channel blocker, is used to treat hypertension in pregnancy or preterm labor. The current study was conducted to investigate the relaxant effects of nicardipine on the isolated uterine smooth muscle of the pregnant rat.METHODS: We obtained uterine smooth muscle strips from pregnant female SD rats. After uterine contraction with oxytocin 10 mU/ml, we added nicardipine (10⁻¹² to 10⁻⁸ M) accumulatively every 20 min. We recorded active tension and frequency of contraction, and calculated EC₅ (effective concentration of 5% reduction), EC₂₅, EC₅₀, EC₇₅, and EC₉₅ of active tension and frequency of contraction using a probit model.RESULTS: Nicardipine (10⁻¹² to 10⁻⁸ M) decreased active tension and frequency of contraction in a concentration-dependent manner. The EC₅₀ and EC₉₅ of nicardipine in the inhibition of active tension of the uterine smooth muscle were 2.41 × 10⁻¹⁰ M and 3.06 × 10⁻⁷ M, respectively. The EC₅₀ and EC₉₅ of nicardipine in the inhibition of frequency of contraction of the uterine smooth muscle were 9.04 × 10⁻¹¹ and 4.18 × 10⁻⁷ M, respectively.CONCLUSIONS: Nicardipine relaxed and decreased the frequency of contraction of the uterine smooth muscle in a concentration-dependent pattern. It might be possible to adjust the clinical dosage of nicardipine in the obstetric field based on our results, but further clinical studies are needed to confirm them.
Animals ; Calcium Channels ; Female ; Humans ; Hypertension ; Muscle, Smooth ; Nicardipine ; Obstetric Labor, Premature ; Oxytocin ; Pregnancy ; Rats ; Relaxation ; Uterine Contraction ; Uterus

PURPOSE: This study compared the effects of Static stretching and Mulligan's Two-leg rotation about the Hamstring flexibility, Hip range of motion, and pain.METHODS: The subjects were allocated randomly into two groups: Static stretching group (n=13) and Mulligan's two leg rotation group (n=14). The study was designed with stretching protocols for four minutes and thirty seconds per day five times a week for three weeks in total. Measurements, including the Sit and reach test, Active/Passive Straight leg raise, and Visual analogue scale, were conducted before and after the intervention. The data were analyzed using a paired t-test and independent t-test.RESULTS: The flexibility of the two leg rotation group was higher than the static stretching group after the intervention. The post-sit and reach test value of the two leg rotation group was significantly higher than the pre-sit and reach test value of the static stretching group. In addition, the variance of the sit and reach test of the two leg rotation group was significantly higher than that of the static stretching group.CONCLUSION: These results showed that two leg rotation techniques have a positive effect on the changes in the sit and reach test and active straight leg raise test. Two leg rotation techniques can be recommended as a self-stretching and easier way to stabilize the lumbopelvic rhythm, reduce the stiffness of the muscle and relieve pain. This is effective in preventing muscle damage, enabling muscle relaxation and reducing the risk of injury to the spine during daily lives and in sports activities.
Hip ; Humans ; Leg ; Muscle Relaxation ; Muscle Stretching Exercises ; Pliability ; Range of Motion, Articular ; Spine ; Sports ; Young Adult

Lotus( Nelumbo nucifera) is a traditional medicinal plant,and nowadays it is regarded both as medicine and food. It is widespread across China and rich in natural resources. Almost every part of N. nucifera could be used for medical or edible purpose,including seeds( Lianzi),black ripe fruits( Shilianzi),seed coats( Lianyi),green embryos of mature seed( Lianzixin),flowers( Lianhua),stamens( Lianxu),receptacles( Lianfang),leaves( Heye),leaf or flower stalks( Hegeng),leaf bases( Heyedi),rhizomes( Ou) and rhizome nodes( Oujie). Therefore,this plant is praised as a commercial crop with great economic values. Isoquinoline type alkaloids are the main chemical components of lotus. Smooth muscles usually exist in the digestive tract,respiratory tract and vascular,urinary,reproductive and other human systems. Dysfunction of smooth muscle contraction will induce many diseases including hypertension,asthma and gastrointestinal disorder,etc.,and most of current therapeutic strategies rely on relaxation of smooth muscle by drugs.Previous studies have shown that alkaloids of lotus have strong relaxation activity on smooth muscle. The present paper reviews phytochemistry and smooth muscle relaxation activity of 59 isoquinoline alkaloids from N. nucifera through accessing CNKI,PubMed and multiple databases for biomedical sciences.
Alkaloids/pharmacology* ; China ; Humans ; Isoquinolines/pharmacology* ; Muscle Relaxation ; Muscle, Smooth/drug effects* ; Nelumbo/chemistry* ; Phytochemicals/pharmacology* ; Plant Extracts

BACKGROUND/AIMS: Efficient transport through the esophago-gastric junction (EGJ) requires synchronized circular and longitudinal muscle contraction of the esophagus including relaxation of the lower esophageal sphincter (LES). However, there is a scarcity of technology for measuring esophagus movements in the longitudinal (axial) direction. The aim of this study is to develop new analytical tools for dynamic evaluation of the length change and axial movement of the human LES based on the functional luminal imaging probe (FLIP) technology and to present normal signatures for the selected parameters. METHODS: Six healthy volunteers without hiatal hernia were included. Data were analyzed from stepwise LES distensions at 20, 30, and 40 mL bag volumes. The bag pressure and the diameter change were used for motion analysis in the LES. The cyclic bag pressure frequency was used to distinguish dynamic changes of the LES induced by respiration and secondary peristalsis. RESULTS: Cyclic fluctuations of the LES were evoked by respiration and isovolumetric distension, with phasic changes of bag pressure, diameter, length, and axial movement of the LES narrow zone. Compared to the respiration-induced LES fluctuations, peristaltic contractions increased the contraction pressure amplitude (P < 0.001), shortening (P < 0.001), axial movement (P < 0.001), and diameter change (P < 0.01) of the narrow zone. The length of the narrow zone shortened as function of the pressure increase. CONCLUSIONS: FLIP can be used for evaluation of dynamic length changes and axial movement of the human LES. The method may shed light on abnormal longitudinal muscle activity in esophageal disorders.
Esophageal Sphincter, Lower ; Esophagus ; Healthy Volunteers ; Hernia, Hiatal ; Humans ; Methods ; Muscle Contraction ; Peristalsis ; Phenobarbital ; Relaxation ; Respiration

Tidal volume by sevoflurane in small amounts is stable due to the increase in the breathing rate. But alveolus ventilation decreases due to sevoflurane as the degree of sedation increases; this ultimately causes PaCO2 to rise. The occurrence of suppression of breath increases the risk of severe hypoxia and hypercapnia in deeply sedated patients with disabilities. Sevoflurane inhalation anesthesia has a number of risks and may have unexpected problems with hemodynamic changes depending on the underlying state of the body. This study was conducted to examine the stability of internal acid-base system caused by respiratory depression occurring when patients with disabilities are induced by sevoflurane.Anesthetic induction was carried out by placing a mask on top of the patient's face and through voluntary breathing with 4 vol% of sevoflurane, 4 L/min of nitrous oxide, and 4 L/min of oxygen. After the patient's loss of consciousness and muscle relaxation, IV line was inserted by an expert and intravenous blood gas was analyzed by extracting blood from vein.In a deeply sedated state, the average amount of pH of the entire patients was measured as 7.36 ± 0.06. The average amount of PvCO₂ of the entire patients was measured as 48.8 ± 8.50 mmHg. The average amount of HCO₃₋ of the entire patients was measured as 27.2 ± 3.0 mmol/L.In conclusion, in dental treatment of patients with disabilities, the internal acid base response to inhalation sedation using sevoflurane is relatively stable.
Anesthesia, General ; Anesthesia, Inhalation ; Anoxia ; Blood Gas Analysis ; Hemodynamics ; Humans ; Hydrogen-Ion Concentration ; Hypercapnia ; Inhalation ; Masks ; Muscle Relaxation ; Nitrous Oxide ; Oxygen ; Respiration ; Respiratory Insufficiency ; Tidal Volume ; Unconsciousness ; Veins ; Ventilation

OBJECTIVETo investigate whether the methanol extract of Berberis amurensis Rupr. (BAR) augments penile erection using in vitro and in vivo experiments.

METHODSThe ex vivo study used corpus cavernosum strips prepared from adult male New Zealand White rabbits. In in vivo studies for intracavernous pressure (ICP), blood pressure, mean arterial pressure (MAP), and increase of peak ICP were continuously monitored during electrical stimulation of Sprague-Dawley rats.

RESULTSPreconstricted with phenylephrine (PE) in isolated endotheliumintact rabbit corus cavernosum, BAR relaxed penile smooth muscle in a dose-dependent manner, which was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one, a soluble guanylyl cclase inhibitor. BAR significantly relaxed penile smooth muscles dose-dependently in ex vivo, and this was inhibited by pretreatment with L-NAME H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one. BAR-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA, P<0.01), a nonselective K channel blocker, 4-aminopyridine (4-AP, P<0.01), a voltage-dependent K channel blocker, and charybdotoxin (P<0.01), a large and intermediate conductance Ca sensitive-K channel blocker, respectively. BAR induced an increase in peak ICP, ICP/MAP ratio and area under the curve dose dependently.

CONCLUSIONBAR augments penile erection via the nitric oxide/cyclic guanosine monophosphate system and Ca sensitive-K (BK and IK) channels in the corpus cavernosum.

Animals ; Area Under Curve ; Berberis ; chemistry ; Blood Pressure ; drug effects ; Cyclic GMP ; metabolism ; Epoprostenol ; pharmacology ; In Vitro Techniques ; Indomethacin ; pharmacology ; Male ; Models, Biological ; Muscle Relaxation ; drug effects ; Muscle, Smooth ; drug effects ; physiology ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; metabolism ; Penile Erection ; drug effects ; Phenylephrine ; pharmacology ; Plant Extracts ; pharmacology ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; metabolism ; Pressure ; Rabbits