Effect Of Penehyclidine Hydrochloride Research Articles

Effects of penehyclidine hydrochloride on myocardial ischaemia-reperfusion injury in rats by inhibiting TLR4/MyD88/NF-κB pathway via miR-199a-3p

This study was to probe the role of penehyclidine hydrochloride (PHC) mediating the impact of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signalling pathway on myocardial ischaemia-reperfusion injury (MI/RI) in rats through miR-199a-3p. The rat MI/RI model was established through ligating left anterior descending (LAD) coronary artery. PHC was injected preoperatively into the model rats, and injected with miR-199a-3p lentiviral vector or TLR4 antagonist (TAK-242). Next, cardiac function of rats was examined by echocardiography, and rat serum indicators, oxidative stress levels and inflammatory factors were detected. HE staining was applied to detect pathological tissue structure, TUNEL staining to detect apoptosis rate, qRCR and western blot to detect miR-199a-3p and TLR4/MyD88/NF-κB expressions in rat myocardial tissues. Dual luciferase reporter experiment was conducted to confirm the relationship between miR-199a-3p and TLR4. In conclusion, PHC suppresses TLR4/MyD88/NF-κB signalling pathway through miR-199a-3p, thereby improving MI/RI in rats.

Analysis of Respiratory Mechanisms in Chronic Obstructive Pulmonary Disease Patients Under the Effects of Penehyclidine Hydrochloride Combined with Continuous Positive Airway Pressure Ventilation

Objective: Our aim was to evaluate the respiratory mechanical effects of penehyclidine hydrochloride combined with intraoperative pulmonary continuous positive airway pressure (CPAP) ventilation on pulmonary function and postoperative pulmonary complications in patients with chronic obstructive pulmonary disease (COPD) during one-lung ventilation. Methods: Eighty patients with COPD who underwent thoracoscopic surgery under general anesthesia were selected and their conditions were validated using chest X-rays. They were then divided into 4 groups in the light of the random number table (n = 20), the regular group (group-C), the penehyclidine hydrochloride group (Group-P), CPAP ventilation group (Group A) and combination group (PA group). All patients underwent mechanical ventilation after double lumen bronchial intubation, inhaled oxygen concentration 100%, oxygen flow 2 L/min, VT 6~8 ml/kg, RR 10~14 times/min, single lung ventilation (OLV) RR 12~16 times/min, maintaining PETCO2 40~45 mmHg. Before the endotracheal intubation, the P group and the PA group were intravenously infused with penehyclidine hydrochloride 0.01 mg/kg. After the start of the incision, each group was changed to OLV. During the OLV of groups A and PA, the lungs of the operation side were CPAP. The pressure is 2 cm H2O. The respiratory mechanics parameters (Ppeak, Pplat , Raw, Cdyn) were monitored immediately before the incision (T1), OLV 60 min (T2), and OLV 120 min (T3). The blood gas analysis of the radial artery was collected at T2, and the OI, RI was calculated. VD/VT , Aa DO2; venous blood was collected at 120 minutes (OL) of OLV, serum concentrations IL-10, TNF-α, IL-6 were detected by EELISA; pulmonary complications occurred within 72 hours after operation. Results: Compared with group C, the serum concentrations TNF-α, IL-6, IL-10, Ppeak, Pplat , Raw, RI, VD/VT, A-aDO2 and pulmonary complications were lower in group P and PA. Cdyn and OI increased (P < 0.05). The serum concentrations IL-10, TNF-α, IL-6 in group A decreased, the incidence of RI, VD/VT, A-aDO2 and pulmonary complications decreased, and OI increased (P < 0.05); compared with group-P or group-A, the concentration of serum IL-10, TNF-α, IL-6 in the PA group, RI, VD/VT, A-aDO2 and pulmonary complications decreased, and OI increased (P < 0.05). Conclusion: Compared with the single application, penehyclidine hydrochloride combined with CPAP ventilation can improve lung function, inhibit inflammation and reduce lung injury in patients with COPD during thoracoscopic surgery, and help to improve prognosis.

Effect of penehyclidine hydrochloride on hyperoxia-induced acute lung injury and the relationship with endoplasmic reticulum stress-dependent apoptosis in infantile rats

Objective To evaluate the effect of penehyclidine hydrochloride on hyperoxia-induced acute lung injury and the relationship with endoplasmic reticulum stress-dependent apoptosis in infantile rats. Methods Ninety-six clean-grade male infantile Sprague-Dawley rats, weighing 40-50 g, aged 14 days, were allocated into 4 groups (n=24 each) using a random number table method: control group (C group), penehyclidine hydrochloride group (P group), hyperoxia group (HO group) and hyperoxia plus penehyclidine hydrochloride group (HP group). Infantile rats were intravenously injected with penehyclidine hydrochloride (0.3 mg/kg) at the same time point every day for 3 consecutive days in P and HP groups.Infantile rats were injected with the equal volume of normal saline instead of penehyclidine hydrochloride in C and H groups.Acute lung injury was induced by inhaling oxygen at concentration greater than 90% for 72 h starting from 4th day after administration.Infantile rats were sacrificed at the end of inhaling, and lungs were removed for examination of the pathological changes and for determination of weight to dry weight ratio (W/D ratio), index of quantitative evaluation for alveolar damage (IQA), pneumonocyte apoptosis (using TUNEL), expression of glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein(CHOP) protein and mRNA in lung tissues (by Western blot or using reverse transcription-polymerase chain reaction). The mitochondrial injury score was assessed, and apoptotic index (AI) was determined. Results Compared with C group, the W/D ratio, IQA, AI and mitochondrial injury score were significantly increased, and the expression of GRP78 and CHOP protein and mRNA was up-regulated in HO and HP groups(P 0.05). Compared with HO group, the W/D ratio, IQA, AI and mitochondrial injury score were significantly decreased, the expression of GRP78 and CHOP protein and mRNA was down-regulated (P<0.05), and the pathological changes of lung tissues were significantly attenuated in HP group. Conclusion Penehyclidine hydrochloride can mitigate hyperoxia-induced acute lung injury, and the mechanism may be related to inhibiting endoplasmic reticulum stress-dependent apoptosis in infantile rats. Key words: Cholinergic antagonist; Acute lung injury; Hyperoxia; Endoplasmic reticulum stress; Apoptosis

Penehyclidine hydrochloride protects organs through the regulation of inflammatory mediators

Inflammatory reaction is the most common characteristic reactions of tissue or organ injury. Sepsis and ischemia/reperfusion injury in organs can cause the massive release of inflammatory factors, resulting in systemic inflammatory response syndrome or multiple organ dysfunction syndrome. Regulation of inflammatory factors is an important method to ameliorate organ and tissue injury. In the present study, we investigated the regulation of penehyclidine hydrochloride on inflammatory factors, as well as the safety and effectiveness of its protective effects on tissue and organ injury. Recent studies concerning the regulation of the inflammatory response by penehyclidine hydrochloride were summarized, especially the protective effects of penehyclidine hydrochloride on the lung, and the anti-inflammatory protective effect on other organs such as the heart, brain, kidneys and liver. It is necessary to further explore the mechanisms of penehyclidine hydrochloride in tissue and organ protection. Key words: Penehyclidine hydrochloride; Inflammation mediator; Organ protection

Effect of penehyclidine hydrochloride on expression of caveolin-1 during LPS-induced lung injury in rats

Objective To evaluate the effect of penehyclidine hydrochloride (PHC) on the expression of caveolin-1 (Cav-1) with lipopolysaccharide (LPS)-induced lung injury (LI)in rats. Methods Thirty SPF healthy male Sprague-Dawley rats, weighing 170-190 g, were divided into 3 groups (n=10 each) using a random number table method: control group (group C), LPS-induced LI group (group LI) and PHCD group.LI was produced by injecting LPS 0.2 ml (5 mg/kg) via the trachea in anesthetized rats. PHCD 0.5 ml (2 mg/kg) was intraperitoneally injected at 1 h before establishing the model in group PHCD. Arterial blood samples were collected at 24 h after establishing the model for blood gas analysis and for determination of serum tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) concentrations by enzyme-linked immunosorbent assay. Rats were then sacrificed, and the lungs were removed. The main bronchus was lavaged, and the broncho-alveolar lavage fluid (BALF) was collected for calculation of the percentage of polymorphonuclear neutrophils (PMNs). Lung tissues were obtained for examination of pathological changes and for determination of myeloperoxidase(MPO)activity (by colorimetric assay), wet/dry weight ratio (W/D ratio), and expression of Cav-1 and nuclear factor kappa B (NF-κB) in nucleoprotein (by Western blot). Results Compared with group C, pH value and PaO2 were significantly decreased, the PaCO2, percentage of PMNs in BALF, W/D ratio and MPO activity were increased, the Cav-1 expression was down-regulated, the expression of NF-κB in nucleoprotein was up-regulated, and the serum TNF-α and IL-1β concentrations were increased in group LI (P 0.05). Conclusion The mechanism by which PHC reduces LPS-induced LI may be related to up-regulating the expression of Cav-1 and mitigating inflammatory responses in lung tissues of rats. Key words: Cholinergic antagonists; Caveolin-1; Endotoxemia; Respiratory distress syndrome, adult

Roles of M3 receptor in the effect of penehyclidine hydrochloride upregulated beta-arrestin-1 expression in LPS-stimulated HPMVEC

Background: This study is to investigate the roles of muscarinic receptor 3 (M3 receptor) in the effect of penehyclidine hydrochloride (PHC) upregulated beta-arrestin-1 expression in lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMVEC).Methods: HPMVECs were transfected with a shRNA-containing plasmid that specifically targets M3 receptor mRNA. Cells were collected to measure F-actin contents, levels of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as changes of F-actin cytoskeleton arrangement by Laser scanning confocal. Beta-arrestin-1 protein expressions were determined by Western blot and beta-arrestin-1 mRNA expressions were measured by Real-time PCR.Results: Similar to normal cells, PHC could also increase F-actin contents and beta-arrestin-1 expressions, reduce ICAM-1 and VCAM-1 expressions, and inhibit LPS-stimulated reorganization of F-actin and formation of stress fiber in M3 receptor shRNA group. Compared with normal cells, F-actin cytoskeleton was neat, ICAM-1 and VCAM-1 expressions were decreased, as well as F-actin contents were increased in M3 receptor shRNA group. However, there were no differences in beta-arrestin-1 expressions between normal cell groups and M3 receptor shRNA groups.Conclusion: These results indicate that M3 receptor plays an important role in pulmonary microvascular endothelial barrier function, and knock-out of M3 receptor could attenuate LPS-induced pulmonary microvascular endothelial injury. However, upregulative effect of PHC on beta-arrestin-1 expression is independent with presence of M3 receptor.

Effects of penehyclidine hydrochloride combined with unilateral high-frequency jet ventilation on pulmonary function and inflammatory response during one-lung ventilation in patients with chronic obstructive pulmonary disease

Objective To evaluate the effects of penehyclidine hydrochloride (PHCD) combined with high-frequency jet ventilation (HFJV) of the operated lungs on pulmonary function and inflammatory response during one-lung ventilation (OLV) in patients with chronic obstructive pulmonary disease (COPD). Methods Sixty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients of both sexes with COPD, aged 40-64 yr, with body mass index of 17-26 kg/m2, scheduled for elective video-assisted thoracoscopic surgery under general anesthesia, were divided into 4 groups (n=15 each) using a random number table method: conventional group (group C), PHCD group (group P), HFJV group (group H) and PHCD combined with HFJV group (group PH). After induction of anesthesia, the patients were intubated with a double-lumen tube and then mechanically ventilated, with inspired oxygen concentration 100%, oxygen flow rate 2 L/min, tidal volume 6-8 ml/kg, respiratory rate 10-14 breaths/min, and respiratory rate was set at 12-16 breaths/min and PETCO2 was maintained at 40-45 mmHg during OLV.PHCD 0.01 mg/kg was intravenously injected before intubation in P and PH groups.The ventilation mode was changed to OLV after beginning of skin incision in each group.Ventilation of the lung on the operated side was performed by means of HFJV(driving pressure 0.5 kg/cm2)during OLV in P and PH groups.The pneumodynamic parameters such as airway peak pressure (Ppeak), airway plateau pressure (Pplat), airway resistance (Raw) and dynamic lung compliance (Cdyn) were monitored immediately before skin incision (T1) and at 60 and 120 min of OLV (T2, 3). Arterial blood samples were obtained at T2 for blood gas analysis, and oxygenation index (OI), respiratory index (RI), physiologic dead space fraction (VD/VT) and alveolar-arterial oxygen gradiant (A-aDO2) were calculated.Venous blood samples were drawn at T3 for determination of the serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-8 by enzyme-linked immunosorbent assay.The occurrence of pulmonary complications was recorded within 72 h after operation. Results Compared with group C, the serum concentrations of TNF-α, IL-6 and IL-8, Ppeak, Pplat, Raw, RI, VD/VT, A-aDO2 and incidence of pulmonary complications were significantly decreased, and Cdyn and OI were increased in group P and group PH (P<0.05), and the serum concentrations of TNF-α, IL-6 and IL-8, RI, VD/VT, A-aDO2 and incidence of pulmonary complications were significantly decreased, and OI was increased in group H (P<0.05). Compared with group P or group H, the serum concentrations of TNF-α, IL-6 and IL-8, RI, VD/VT, A-aDO2 and incidence of pulmonary complications were significantly decreased, and OI was increased in group PH (P<0.05). Conclusion PHCD combined with HFJV of the operated lung produces better efficacy in improving respiratory function, inhibiting inflammatory responses, reducing lung injury and is more helpful in improving prognosis than either alone in the patients with COPD. Key words: Cholinergic antagonists; High-frequency jet ventilation; Pulmonary disease, chronic obstructive; Respiratory function tests; Systemic inflammatory response syndrome

Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats

Penehyclidine hydrochloride (PHC) is a selective M1 and M3 receptor antagonist. This study was designed to investigate the effect of PHC on acute lung injury (ALI) induced by severe acute pancreatitis (SAP) and the expression of hypoxia-inducible factor-1α (HIF-1α) in rats. A total of 45 healthy adult male SD rats were randomly divided into 3 groups: an S group, sham operation; an ALI group, pancreatitis-associated acute lung injury (PALI); and a P group, PALI treated with PHC. Rats from the ALI and P groups were used to establish a model of acute lung injury associated with SAP by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Rats in the P group, reflecting acute lung injury caused by SAP, were treated with PHC immediately following SAP. Rats in the S and ALI groups were injected with the same amount of 0.9% sodium chloride solution. After modeling, the rats were sacrificed at 12h. The wet/dry weight (W/D) ratios of lung tissue were calculated. Pathological changes in pancreatic and lung tissues were scored. The expression levels of TLR4 and NF-κB p65 in lung tissue were detected by Western blot. RT-PCR was used to detect HIF-1α mRNA in lung tissue. The HIF-1α, IL-1β, and IL-6 expression levels in lung tissues and serum amylase levels were detected by ELISA. The results showed extensive infiltration of neutrophils, alveolar hemorrhage and necrosis and fat necrosis in the pancreatic tissue of rats in the PALI and P groups. Their pancreatic tissue injury scores were significantly higher than the score of the S group (P<0.01). However, no statistically significant difference was observed in the serum amylase levels of the P and ALI groups (P>0.05). The W/D ratios of lung tissue in the ALI and P group rats were significantly higher than those in the S group (P<0.05). Compared with those of the ALI group rats, the lung tissue pathological changes of the P group were significantly improved, and the lung W/D value was significantly lower than that of the ALI group (P<0.05). Compared with those of the S group, the TLR4, NF-κB p65, HIF-1α mRNA, and HIF-1α expression levels in the lung tissue of the ALI and P groups were significantly higher (P<0.01), and the TLR4, NF-κB p65, HIF-1α mRNA, HIF-1α, IL-1β and IL-6 expression levels in the P group were significantly lower than those in the ALI group (P<0.05). The current work indicates that PHC could not alleviate the damage to pancreatic tissue caused by SAP. However, PHC did suppress HIF-1α, IL-1β and IL-6 expression levels and reduced the acute lung injury induced by SAP in rats, which might depend on suppression of the expression of inflammatory factors, such as HIF-1α.

Effects of penehyclidine hydrochloride on activities of NF-κB and AP-1 during actue lung injury induced by blunt chest trauma-hemorrhagic shock and resuscitation in rats

Objective To investigate the effects of penehyclidine hydrochloride on activities of nuclear factor kappa B(NF-κB) and activator protein-1 (AP-1) during actue lung injury induced by blunt chest trauma-hemorrhagic shock and resuscitation (HSR) in rats. Methods Thirty male Sprague-Dawley rats, aged 8 weeks, weighing 250-300 g, were randomly assigned into 3 equal groups (n = 10 each) using a random number table: sham operation group (group S), blunt chest trauma-HSR group (group THSR) and penehyclidine hydrochloride group (group PHCD). The model of actue lung injury induced by blunt chest trauma-HSR was induced by dropping a 300 g weight onto a precordium in anesthetized rats.Blood was withdrawn via the femoral artery 5 min later until MAP was decreased to 35-45 mmHg within 15 min and maintained at this level for 60 min, followed by resuscitation.In PHCD group, PHCD 2 mg/kg was injected intravenously at 60 min after hemorrhagic shock.At 6 h after the model was established, blood samples were obtained for measurement of concentrations of tumor necrosis factor-alpha (TNF-α) in serum.The lungs were then removed for determination of lung water content, myeloperoxidase (MPO) activaty (by colorimetric assay), NF-κB and AP-1 activaties (using electrophoretic mobility shift assay) in lung tissues, and for microscopic examination of pathologic changes (under light microscope). The left lung was lavaged, and lung permeability index (LPI) was calculated. Results Compared with S group, lung water content, LPI, serum TNF-α level and activites of MPO, NF-κB and AP-1 were significantly increased in THSR and PHCD groups.Compared with THSR group, lung water content, LPI, serum TNF-α concentrations and activites of MPO, NF-κB and AP-1 were significantly decreased in PHCD group.The pathological damage to lung tissues was significantly reduced in PHCD group as compared with THSR group. Conclusion PHCD can inhibit activities of NF-κB and AP-1 in lung tissues, thus mitigating acute lung injury induced by blunt chest trauma-HSR in rats. Key words: NF-κappa B; Transcription factor AP-1; Cholinergic antagonists; Thoracic injury; Shock, hemorrhagic; Respiratory distress syndrome, adult

Effect of penehyclidine hydrochloride on heart rate variability in hysteroscopy.

In order to evaluate the effect of different doses of penehyclidine hydrochloride (penehyclidine) on heart rate (HR) and HR variability (HRV) in hysteroscopy, 180 patients (American Society of Anesthesiologists grade I-II) were randomized equally to three groups: 0.5 mg penehyclidine and intravenous anesthesia (group I), 1.0 mg penehyclidine and intravenous anesthesia (group II) and saddle anesthesia combined with intravenous anesthesia (control group). HR and HRV, including total power (TP), low-frequency power (LF), high-frequency power (HF) and the LF to HF ratio (LF/HF), were recorded prior and subsequent to the induction of anesthesia (T0 and T1, respectively), following the start of surgery (T2) and following completion of surgery (T3). HR was lower at T2 than at T0 in the control patients, but no differences were observed in groups I and II. The HR at T2 was increased in group II compared with that in group I. TP in group II was significantly higher compared with that in group I at T2. At T1 and at T2, the LF and HF values were lower in group I than those in the controls. Patients in group II also had higher LF and HF at T2 than patients in group I. The HF was higher at T2 than that at T0 in the controls; however, the HF and LF did not change significantly within groups I and II. No significant differences were observed in the LF/HF ratio among the three groups. At a dose of 0.5 mg, penehyclidine stabilized HRV and did not alter the autonomic nervous modulation of HR. A penehyclidine dose of 1.0 mg may be superior to a dose of 0.5 mg in maintaining HR, but is less effective at balancing sympathetic and parasympathetic activity.

Effect of penehyclidine hydrochloride on endotoxemia-induced intestinal injury in neonatal rats

Objective To investigate the effect of penehyclidine hydrochloride on endotoxemia-induced intestinal injury in neonatal rats. Methods Ninety healthy neonatal Sprague-Dawley rats, aged 7 days, weighing 16-20 g, were randomly divided into 3 groups (n=30 each) using a random number table: control group (group C), lipopolysaccharide (LPS) group, and penehyclidine hydrochloride group (group P). Endotoxemia was induced by intraperitoneal LPS 5 mg/kg in LPS and P groups. In group P, penehyclidine 2 mg/kg was injected intraperitoneally at 30 min before and after LPS injection. The equal volume of normal saline was given in group C. At 2, 6 and 12 h after LPS or normal saline administration, 10 rats in each group were randomly chosen and sacrificed. The ileum was removed to detect wet/dry lung weight ratio (W/D ratio) and contents of tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), hypoxia-inducible factor 1 alpha (HIF-1α) and glutamine (Gln), and for examination of the pathologic changes of the ileum with light microscope. Results Compared with group C, the W/D ratio and contents of TNF-α, IL-6 and HIF-1α were significantly increased, and the content of Gln was decreased at each time point in LPS and P groups. Compared with group LPS, the W/D ratio and contents of TNF-α, IL-6 and HIF-1α were significantly decreased, the content of Gln was increased at each time point, and the pathologic changes of the ileum were mitigated in group P. Conclusion Penehyclidine hydrochloride can reduce endotoxemia-induced intestinal injury in the neonatal rats, and down-regulated expression of HIF-1α, up-regulated expression of Gln and attenuated inflammatory responses may be involved in the mechanism. Key words: Cholinergic antagonists; Endotoxemia; Intestine; Infant, newborn

Effects of penehyclidine hydrochloride on hemorrhagic shock-induced acute lung injury in rats

Objective To observe the effects of penehyclidine hydrochloride (PHC) on hemorrhagic shock/resuscitation-induced acute lung injury in rats.Methods Fifteen healthy adult Sprague-Dawley rats were randomly allocated equally into three groups:groups P,C and S.The rats in group S received sham operation,and those in groups P and C were subjected to bloodletting for shock,then shock state maintained for 60 min,and resuscitation was done with autoblood.The rats in group P received PHC treatment (0.03 mg/kg) before resuscitation of hemorrhagic shock,and those in group C and group S received 1.0 ml normal saline instead.Blood samples were collected via the carotid artery for interleukin-8 (IL-8),tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) monitoring at the time of subsequence carotid arteriopuncture (T0),before shock induction (T1),5 min after shock (T2),before resuscitation of shock (T3),5 min (T4),30 min (T5),1.5 h (T6) and 2.5 h (T7) after mean arterial pressure (MAP) reached expected resuscitation goal.The arterial blood gas analyses were detected at T0,T3 and T7.The morphological changes of lungs were observed under microscope.Results The ratio of PO2/FiO2 in groups P and C were significantly lower than in group S at T7 [(289.5 ± 67.1) mmHg (1 mmHg =0.133 kPa),(280.0 ±73.3) mmHg vs.(458.1 ±31.0) mmHg,P ＜0.01].There was marked diversity among group P,C and S in the morphological score (4.4 ± 1.7,7.4 ± 1.9 vs.0.8 ± 1.1,P ＜0.01) ; The peak concentrations of IL-8 [(7.35 ±0.14),(8.44 ±0.13) ng/L vs.(3.75 ±0.06) ng/L,P ＜0.01],TNF-α [(8.45 ±0.24,(9.69 ±0.52) ng/L vs.(4.19 ± 0.04) ng/L,P＜0.01] and NF-κB [(272.34 ± 12.60),(310.00 ± 16.47) ng/L vs.(133.98 ± 1.91) ng/L,P ＜ 0.01] respectively,with significant difference among three groups.Conclusion Treatment of PHC might have a protective effect against lung injury induced by hemorrhagic shock/resuscitation.Its action mechanisms are probably involved in the suppression of inflammatory factor production and inhibition of the NF-κB pathway. Key words: Hemorrhagic shock ; Acute lung injury; Penehyclidine hydrochloride ; Inflammatory cytokine

Protective effects of penehyclidine hydrochloride on liver injury induced by cardiopulmonary bypass in Guangxi bama miniature pig

Objective To investigate the effects of penehyclidine hydrochloride on liver injury induced by cardiopulmonary bypass (CPB) in Guangxi bamaminiature pig.Methods Twenty-seven Bama miniature pigs weighted 32-40 kg were chosen,three pigs were used for sampling blood,another twentyfour pigs were used for cardiopulmonary bypass (CPB).Twenty-four pigs were randomly divided into three groups (n=8 each):group Sham,group Mod,and group PHC.Propofol,fentanyl and vecuronium were continued by intravenous injection and inhaled isoflurane interruptly for anesthesic maintain.CPB was performed on mild hypothermic beating heart for 120 min.Pnehyclidine hydrochloride 0.1 mg/kg was injected intravenously before 10 min CPB.Blood samples were collected for aspartate aminotransferase (AST),alanine transaminase (ALT),direct bilirubin (DB) and total bilirubin (TB) before CPB (T0),after CPB 1 h (T1),CPB cease (T2) and operation cease (T3).The content of ATP,MDA and SOD in liver tissue at befor and after CPB were measured and the pathologic change of liver was evaluated by electron microscope.Results The levels of ALT,AST,DB and TB in group Mod and group PHC were significantly higher at T1-T3 than those in group Sham (P ＜ 0.05).ATP,SOD were lower and MDA was higher significantly in group Mod and group PHC after CPB than that in group Sham (P ＜ 0.05).Compared with the group Mod,The levels of ALT,AST,DB,TB and MDA were lower and ATP,SOD were higher significantly respectively in group PHC (P ＜ 0.05).The electron microscopec examination showed that histologic damage was significantly reduced in group PHC compared with group Mod.Conclusion Pnehyclidine hydrochloride can attenuate Iiver injury induced by CPB,antioxygen to remove oxygen free radical in liver may be the mechanism. Key words: Penehyclidine hydrochloride ; Cardiopulmonary bypass ; Liver injury ; Antioxygen

Effects of penehyclidine hydrochloride on acute lung injury induced by blunt chest trauma-hemorrhagic shock and resuscitation in rats

Objective To investigate the effects of penehyclidine hydrochloride (PHC) on acute lung injury induced by blunt chest trauma-hemorrhagic shock and resuscitation in rats.Methods Forty male SpragueDawley rats,aged 8 weeks,weighing 250-300 g,were randomly assigned into 4 equal groups (n =10 each) using a random number table:sham operation group (S group),blunt chest trauma combined with hemorrhagic shock and resuscitation group (group THSR),PHC for prevention group (group P1)and PHC for treatment group (group P2).ALI was induced by dropping a 300 g weight onto a precordial protective shield to direct the impact force away from the heart and toward the lungs in anesthetized rats in THSR,P1 and P2 groups.Blood was withdrawn via the femoral artery 5 min later until MAP was decreased to 35-45 mmHg within 15 min and maintained at this level for 60 min,followed by resuscitation.In P1 group,PHC 2 mg/kg was injected intravenously at 30 min before blunt chest trauma.In P2 group,PHC 2 mg/kg was injected intravenously at 60 min after hemorrhagic shock.At 6 h after the model was established,arterial blood samples were obtained for blood gas analysis and for measurement of concentrations of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum by ELISA.Oxygenation index (OI) was calculated.The animals were sacrificed and bronchoalveolar lavage fluid (BALF) was collected for determination of white blood cell count and protein concentrations.Lungs were removed for examination of pathological changes and ultrastructure and for determination of Toll-like receptor (TLR4) and phosphor-p38 mitogen activated protein kinase (p-p38MAPK) expression (by Western blot).Results Compared with group S,PaO2 and OI were significantly decreased,PaCO2,protein concentrations in BALF,white blood cell count,and IL-6 and IL-1β concentrations in serum were increased,and TLR4 and p-p38MAPK expression was up-regulated in THSR,P1 and P2 groups.Compared with group THSR,PaO2 and OI were significantly increased,PaCO2,protein concentrations in BALF,white blood cell count,and IL-6 and IL-lβ concentrations in serum were decreased,TLR4 and p-p38MAPK expression was down-regulated in P1 and P2 groups.No significant differences were found in the parameters mentioned above between P1 and P2 groups.Conclusion PHC can mitigate acute lung injury induced by blunt chest trauma-hemorrhagic shock and resuscitation in rats,and inhibited activation of TLR4/ p38MAPK signaling pathway and attenuated inflammatory responses are involved in the mechanism. Key words: Cholinergic antagonists; Thoracic injury; Shock, Hemorrhagic; Respiratory distress syndrome, adult

The effect of penehyclidine hydrochloride on pulmonary interstitial fibrosis induced by paraquat in rats

Objective To investigate the effect of penehyclidine hydrochloride(PHC) on pulmonary interstitial fibrosis(PIF) induced by paraquat (PQ) in rats.Methods Forty-eight male SD rats were randomly divided into four groups,control group(Con group),model group(Mod group),PHC group and dexamethasone(Dex) group.Then every group was randomly divided into 7th day and 22th day subgroup,there were 6 rats in every group.20％ PQ (18 mg/kg,diluted to 1 ml) was injected peritoneally to make poisoning model,while in the Con group 1 ml normal saline was used.30 min after exposed to PQ,rats in PHC group and Dex group were respectively intraperitoneally injected with PHC (0.1 mg/kg) and Dex (3 mg/kg),and then repeated injection once per 24 h,all intervention drug were diluted to 1 ml with normal saline.Rats in Con group and Mod group at corresponding time points were given with equal volume of normal saline.On the 7th day and 22th day respectively,experimental animals were killed to detect the partial pressure of oxygen in artery (PaO2) and partial pressure of carbon dioxide in artery (PaCO2),the lung wet/dry ratio (W/D),the pathological changes of lung tissue by hematoxylin-eosin (HE) staining and Masson staining,and the transforming growth factor-β1 (TGF-β1) expression in lung tissue with immunohistochemistry.Results Comparing with Con group,the PaO2 was significantly lower[(79±6) mm Hg/(78±8) mm Hg vs(39±6) mm Hg/(44±5) mm Hg,(46±4) mm Hg/(52±5) mm Hg,(54±6) mm Hg/(60±6) mm Hg(1 mm Hg=0.133 kPa)],the PaCO2[(44±7) mm Hg/(45±7) mm Hg vs(92±5) mm Hg/(82±4) mm Hg,(84±8) mm Hg/(73±8) mm Hg,(75±7) mm Hg/(65±7) mm Hg],pulmonary W/D[(2.60±0.25)/(2.58±0.22) vs(5.67±0.61)/(4.57±0.39),(4.25±0.44)/(3.85±0.34),(3.69±0.40)/(3.40±0.28)] and TGF-β1[(136±7)/(140±7) vs(215±23)/(322±29),(193±11)/(246±16),(186±11)/(214±14)] expression was significantly increased in rats exposed to PQ.The morphological changes presented acute pulmonary inflammatiuon on the 7th day,while on the 22th day,PIF appeared.Penehyclidine hydrochloride and Dex,could significantly increase PaO2,decrease PaCO2.Inhibit lung inflammation infiltration,reduce PIF,significantly reduce lung W/D and TGF-β1 expression in the lung tissue,and there were no obvious difference in PHC group and Dex group.Conclusions PHC can inhibitting the expression of TGF-31,then reduce lung inflammation infiltration and suppress the occurrence of PIF of PQ poisoning in rats. Key words: Penehyclidine hydrochloride; Pulmonary interstitial fibrosis; Paraquat; Transforming growth factor-β1

Effect of penehyclidine hydrochloride on β-arrestin-1 expression in lipopolysaccharide-induced human pulmonary microvascular endothelial cells

β-arrestins are expressed proteins that were first described, and are well-known, as negative regulators of G protein-coupled receptor signaling. Penehyclidine hydrochloride (PHC) is a new anti-cholinergic drug that can inhibit biomembrane lipid peroxidation, and decrease cytokines and oxyradicals. However, to date, no reports on the effects of PHC on β-arrestin-1 in cells have been published. The aim of this study was to investigate the effect of PHC on β-arrestin-1 expression in lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cells (HPMEC). Cultured HPMEC were pretreated with PHC, followed by LPS treatment. Muscarinic receptor mRNAs were assayed by real-time quantitative PCR. Cell viability was assayed by the methyl thiazolyl tetrazolium (MTT) conversion test. The dose and time effects of PHC on β-arrestin-1 expression in LPS-induced HPMEC were determined by Western blot analysis. Cell malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured. It was found that the M3 receptor was the one most highly expressed, and was activated 5 min after LPS challenge. Furthermore, 2 μg/mL PHC significantly upregulated expression of β-arrestin-1 within 10 to 15 min. Compared with the control group, MDA levels in cells were remarkably increased and SOD activities were significantly decreased in LPS pretreated cells, while PHC markedly decreased MDA levels and increased SOD activities. We conclude that PHC attenuated ROS injury by upregulating β-arrestin-1 expression, thereby implicating a mechanism by which PHC may exert its protective effects against LPS-induced pulmonary microvascular endothelial cell injury.

Effect of penehyclidine hydrochloride on level of angiopoietin-1 and tyrosine kinase receptor-2 during endotoxin-induced acute lung injury in rats

Objective To evaluate the effect of penehyclidine hydrochloride (PHC) on the level of angiopoietin-1 (Ang-1) and tyrosine kinase receptor-2 (Tie-2) during endotoxin-induced acute lung injury (ALI) in rats.Methods Forty adult male Sprague-Dawley rats,weighing 180-220 g,were randomly divided into 4 groups using a random number table (n =10 each):control group (group C),ALI group,low-dose PHC group (group L-PHC) and high-dose PHC group (group H-PHC).ALI was induced with iv injection of lipopolysaccharide 5.0 mg/kg via the tail vein.In L-PHC and H-PHC groups,PHC 0.6 and 2 mg/kg were injected,respectively,via the tail vein at 1 and 24 h after lipopolysaccharide injection.The rats were sacrificed at 48 h after the initial injection of PHC to measure the lung water content,protein concentration in bronchoalveolar lavage fluid (BALF),and the expression of Ang-1,Tie-2 and phosphorylated Tie-2 in lung tissues.The morphological changes of lung tissues were observed under light microscope and the ultrastructural changes of alveolar epithelial barrier under transmission electron microscope.Results Compared with group C,the lung water content and protein concentrations in BALF were significantly increased,and the expression of Ang-1 and phosphorylated Tie-2 was down-regulated in the other three groups (P ＜ 0.05).Compared with group ALI,the lung water content and protein concentrations in BALF were significantly decreased,and the expression of Ang-1 and phosphorylated Tie-2 was up-regulated in H-PHC group (P ＜ 0.05),and no significant changes were found in the parameters mentioned above in group L-PHC (P ＞0.05).The damage to lung tissues was significantly reduced in group H-PHC as compared with group ALI.Conclusion PHC can improve the permeability of pulmonary microvascular and reduce injury to alveolar epithelial barrier,thus ameliorating endotoxin-induced ALI in rats,and the effect is dose-related and up-regulation of Ang-1 expression and inhancement of Tie-2 activity are involved in the mechanism. Key words: Cholinergic antagonist ; Respiratory distress syndrome, adult ; Endotoxemia; Angiopoietin-1 ; Receptor, protein-tyrosine kinases

Effects of penehyclidine hydrochloride on expression of Toll like receptor-4 and nuclear factor kappa B in a rat model of sepsis-induced acute lung injury

Objective To evaluate the effects of penehyclidine hydrochloride (PHC) on the expression of Toll like receptor-4 (TLR4) and nuclear factor kappa B (NF-κcB) in a rat model of sepsis-induced acute lung injury (ALI).Methods Seventy-two adult male Sprague-Dawley rats,weighing 180-220 g,were randomly divided into 3 groups (n =24 each) using a random number table:shame operation group (group S),ALI group and PHC group.Sepsis-induced ALl was induced by cecal ligation and puncture in anesthetized rats.In group PHC,PHC 0.45 mg/kg was intramuscularly injected immediately after cecal ligation and puncture.At 6,12,24 and 36 h after ligation,the broncho-alveolar lavage fluid (BALF) was collected for detection of TNF-α and IL-6 concentrations and the lungs were removed for determination of the expression of TLR4 (using RT-PCR and Western blot) and NF-κBp65 (using Western blot) in lung tissues and for microscopic examination.The pathological changes of lungs were scored.The wet to dry lung weight (W/D) ratio was calculated and the activity of myeloperoxidase (MPO) in lung tissues was measured.Results As compared with S group,the IL-6 concentrations in BALF at 6,12 and 24 h after ligation,TNF-α concentration in BALF at 6 and 12 h after ligation,and the expression of TLR4 and NF-κBp65,pathological scores,W/D ratio and MPO activity at each time point were significantly increased in ALI group (P ＜ 0.05).Compared with ALI group,the TNF-α concentration in BALF at 6 and 12 h after ligation,and IL-6 concentrations in BALF,the expression of TLR4 and NF-κBp65,pathological scores,W/D ratio and MPO activity at each time point were significantly decreased in group PHC (P ＜ 0.05).Conclusion PHC inhibits NF-κB activation and decreases inflammatory responses through blocking TLR4 expression in lung tissues,thus attenuating sepsis-induced ALI in rats. Key words: Cholinergic antagonists; Sepsis; Respiratory distress syndrome, adult ; Toll-like receptor 4; NF-kappa B

Neuroprotective effect of penehyclidine hydrochloride on focal cerebral ischemia-reperfusion injury.

Penehyclidine hydrochloride can promote microcirculation and reduce vascular permeability. However, the role of penehyclidine hydrochloride in cerebral ischemia-reperfusion injury remains unclear. In this study, in vivo middle cerebral artery occlusion models were established in experimental rats, and penehyclidine hydrochloride pretreatment was given via intravenous injection prior to model establishment. Tetrazolium chloride, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and immunohistochemical staining showed that, penehyclidine hydrochloride pretreatment markedly attenuated neuronal histopathological changes in the cortex, hippocampus and striatum, reduced infarction size, increased the expression level of Bcl-2, decreased the expression level of caspase-3, and inhibited neuronal apoptosis in rats with cerebral ischemia-reperfusion injury. Xanthine oxidase and thiobarbituric acid chromogenic results showed that penehyclidine hydrochloride upregulated the activity of superoxide dismutase and downregulated the concentration of malondialdehyde in the ischemic cerebral cortex and hippocampus, as well as reduced the concentration of extracellular excitatory amino acids in rats with cerebral ischemia-reperfusion injury. In addition, penehyclidine hydrochloride inhibited the expression level of the NR1 subunit in hippocampal nerve cells in vitro following oxygen-glucose deprivation, as detected by PCR. Experimental findings indicate that penehyclidine hydrochloride attenuates neuronal apoptosis and oxidative stress injury after focal cerebral ischemia-reperfusion, thus exerting a neuroprotective effect.

The effect of penehyclidine hydrochloride on lung ventilation function during gynecologic laparoscopic surgery

Objective To investigate the effect of preoperative penehyclidine hydrochloride on lung ventilation function during gynecologic laparoscopic surgery.Methods 42 patients scheduled for gynecologic laparoscopic surgery were randomly divided into 2 groups.Penehyclidine hydrochloride 20 μg/kg was administered in experimental group (P) and normal saline was injected in control group (N) 10 min after intubation.HR,MAP,SpO2,PETCO2,Raw,Ppeak,Pplat and pulmonary compliance (Compl)were monitored and recorded immediately before (T0)and at 5 (T1),30 (T2),60 (T3) and 90 (T4) min after injection.Results During operation,Ppeak,Pplat,Raw showed an ascend trend while Compl descended in both groups.And the value of Raw at T1,T2,T3,T4 in group P was lower than that at correspoinding time point in group N [(14.8±1.4),(14.6±1.6),(14.6±1.3),(14.4±1.2) cm H2O·L-1·s-1 vs (16.2±1.6),(16.1±1.8),(16.1±1.9),(16.1±1.7) cm H2O·L-1· s-1)](1 cm H2O=0.098 kPa).The Compl in group P was higher than that in group N [T3:(30.2±3.5) vs (27.3±4.8),P=0.033; T4:(29.9±3.6) ml/cm H2O vs (27.2±4.1) ml/cm H2O,P=0.031].Compared to To,SBP,DBP and SpO2 showed no difference during operation,while HR decreased significantly during operation (P=0.000) in both groups.Conclusions Application of penehyclidine hydrochloride during gynecologic laparoscopic surgery can improve the lung ventilation function,results in an increase in Compl and decrease in Raw without obvious disturbance in hemodvnamics. Key words: Penehyclidine; Laparoscopic; Lung function