Cardioprotective effect of δ-opioid receptor agonist vs mild therapeutic hypothermia in a rat model of cardiac arrest with extracorporeal life support

Background

To compare the effect of δ-opioid receptor agonist, d-Ala2-d-Leu5 enkephalin (DADLE) with normothermic control and therapeutic hypothermia on post resuscitation myocardial function in a model of extracorporeal life support (ECLS).

Methods

Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32 °C) and DADLE intravenous infusion (1 mg/kg/h). Cooling to 32 °C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS.

Results

DADLE administration resulted in a significantly enhanced recovery of LV systolic function expressed by slope of the LV end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than hypothermia and normothermia. LV stiffness indicated by end-diastolic pressure volume relationship (EDPVR) was significantly lower after DADLE administration (P < 0.01). LV relaxation described by Tau was preserved after DADLE treatment but not after normothermia or mild hypothermia (P < 0.01). Plasma lactate concentrations were lower in DADLE group (P < 0.05). DADLE and not conventional hypothermia significantly increased phosphorylation of the kinases ERK1 and 2 (3.9 ± 0.3 and 3.1 ± 0.5 vs 0.4 ± 0.1 and 0.3 ± 0.1-fold of baseline levels) (P < 0.001). Both DADLE and hypothermia but not normothermia increase phosphorylation of Akt.

Conclusions

DADLE was more effective than mild therapeutic hypothermia in recovering myocardial function and activation of the pro-survival kinases Akt and ERK after ECLS.     

Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor

In the present article, we summarize the preclinical pharmacology of 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327), a highly potent and selective agonist of the δ-opioid receptor. AZD2327 binds with sub-nanomolar affinity to the human opioid receptor (K(i) = 0.49 and 0.75 nM at the C27 and F27 isoforms, respectively) and is highly selective (>1000-fold) over the human μ- and κ-opioid receptor subtypes as well as >130 other receptors and channels. In functional assays, AZD2327 shows full agonism at human δ-opioid receptors ([(35)S]GTPγ EC(50) = 24 and 9.2 nM at C27 and F27 isoforms, respectively) and also at the rat and mouse δ-opioid receptors. AZD2327 is active in a wide range of models predictive of anxiolytic activity, including a modified Geller-Seifter conflict test and social interaction test, as well as in antidepressant models, including learned helplessness. In animals implanted with microdialysis probes and then given an acute stressor by pairing electric shock delivery with a flashing light, there is an increase in norepinephrine release into the prefrontal cortex associated with this acute anxiety state. Both the benzodiazepine anxiolytic standard diazepam and AZD2327 blocked this norepinephrine release equally well, and there was no evidence of tolerance to these effects of AZD2327. Overall, these data support the role of the δ-opioid receptor in the regulation of mood, and data suggest that AZD2327 may possess unique antidepressant and anxiolytic activities that could make a novel contribution to the pharmacotherapy of psychiatric disorders.     

Co-administration of δ- and μ-opioid receptor agonists promotes peripheral opioid receptor function

Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of μ- and δ-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the μ- and δ-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naïve rats and on potassium-evoked release of CGRP from sciatic nerves of naïve rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another μ-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, δ-opioid receptor agonists enhance the effect of μ-opioid receptor agonists in the periphery, and local co-administration of δ- and μ-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain.     

Angiotensin receptor–neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury

Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor–neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia–reperfusion I/R, (III) TH/IRB + IR (0.1/5 mg/kg), (IV) TH/IRB + IR (0.1/10 mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dt_max), and cardiac levels of creatine kinase–MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10 mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.     

Does naloxone alone increase resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model?

Cardiac arrest was induced with asphyxia to identify if naloxone alone increases resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model. The animals were randomized into either a saline group (Sal-gro, treated with normal saline 1 ml iv, n = 8), a low-dose naloxone group (treated with naloxone 0.5 mg/kg iv, n = 8), or a high-dose naloxone group (HN-gro, treated with naloxone 1 mg/kg iv, n = 8) in a blinded fashion during resuscitation. At the end of 10 minutes of asphyxia, cardiopulmonary resuscitation was started, and each drug was administered at the same time. The rate of restoration of spontaneous circulation was seen in 1 of 8, 3 of 8, and 7 of 8 animals in the Sal-gro, LN-gro, and HN-gro, respectively. The rate of restoration of spontaneous circulation in HN-gro was significantly higher than that in Sal-gro (P < .05). Naloxone (1 mg/kg) alone can increase resuscitation rate following asphyxial cardiac arrest in rats.     

What is the optimal dose of epinephrine during cardiopulmonary resuscitation in a rat model?

Objective

Because different species may require different doses of drug to produce the same physiologic response, we were provoked to evaluate the dose-response of epinephrine during cardiopulmonary resuscitation (CPR) and identify what is the optimal dose of epinephrine in a rat cardiac arrest model.

Methods

Rat cardiac arrest was induced via asphyxia, and then the effects of different doses of epinephrine (0.04, 0.2, and 0.4 mg/kg IV, respectively) and saline on the outcome of CPR were compared (n = 10/each group). The primary outcome measure was restoration of spontaneous circulation (ROSC), and the secondary was the change of spontaneous respiration and hemodynamics after ROSC.

Results

Rates of ROSC were 9 of 10, 8 of 10, 7 of 10, and 1 of 10 in the low-dose, medium-dose, and high-dose epinephrine groups and saline group, respectively. The rates of withdrawal from the ventilator within 60 minutes in the low-dose (7 of 9) and medium-dose epinephrine groups (7 of 8) were higher than in the high-dose epinephrine group (1 of 7, P < .05). Mean arterial pressures were comparable, but the heart rate in the high-dose epinephrine group was the lowest among epinephrine groups after ROSC. These differences in part of time points reached statistical significance (P < .05).

Conclusion

Different doses of epinephrine produced the similar rate of ROSC, but high-dose epinephrine inhibited the recovery of spontaneous ventilation and caused relative bradycardia after CPR in an asphyxial rat model. Therefore, low and medium doses of epinephrine were more optimal for CPR in a rat asphyxial cardiac arrest model.     

Effect of function exercises on paralysis in treatment of stroke

Background:Incidenceofparalysisinstrokeisveryhighanddrugtherapyisoftenadopted.Butignoranceoffunctionexercisewillinfluenceprognosisofdisease,evenleadtorelapse.Objective:Toinvestigatetheeffectoffunctionexercisesonparalysisintreatmentofstroke.Unit:AffiliatedHospitalofMedicalCollege,NorthChinaU-niversity.Subjects:120casesofstrokeinacutephasewereinvestigatedincluding90casesofcerebralthrombosis,30casesofcerebralhemorrhage.Allcaseshaddifferentdegreesofmotiondysfunctionandweredependentonothers.Pa…     

Effect of β-sodium aescinate on hypoxia-inducible factor-1α expression in rat brain cortex after cardiopulmonary resuscitation

BACKGROUND:

This study was undertaken to investigate the expression of hypoxia-inducible factor-1α (HIF-1α) in rat cerebral cortex and the effects of β-sodium aescinate (SA) administration after return of spontaneous circulation (ROSC).

METHODS:

Sixty rats were divided into three groups: SA group, injected intraperitoneally with SA instantly after ROSC; control group, injected intraperitoneally with normal saline; and sham-operated group, without cardiac arrest or SA. The cardiac arrest model was established using asphyxiation and intravenous potassium chloride. Blood was sampled 1, 6, 12, and 24 hours after ROSC. Protein and mRNA levels of HIF-1α, VEGF and EPO were detected in the cerebral cortex by immunohistochemistry and real-time RT-PCR; serum levels of NSE and S100β were determined by enzyme-linked immunosorbent assays.

RESULTS:

Serum S100β and NSE were significantly increased in the control group versus the sham-operated group 1, 6, 12 and 24 hours after ROSC (P<0.05). Protein and mRNA levels of HIF-1α, VEGF and EPO were significantly increased in the control rats (P<0.05). Serum NSE and S100β were significantly decreased in the SA group versus the control group 1, 6, 12 and 24 hours after ROSC (P<0.05). Protein and mRNA levels of HIF-1α, VEGF and EPO were significantly increased in the SA group (P<0.05).

CONCLUSIONS:

The expression of HIF-1α is increased in rat cerebral cortex after ROSC, and SA up-regulates the expression of HIF-1α. The up-regulation of HIF-1α improves the resistance of the cortex to ischemia and hypoxia and contributes to neuroprotection, possibly because of up-regulation of EPO and VEGF expression.KEY WORDS: Cardiopulmonary resuscitation, HIF-1α, Erythropoietin, Vascular endothelial growth factor, β-sodium aescinate, Neuroprotection     

Effect of mild hypothermia on the oxidative stress induced myocardlal injury after cardiopulmonary resuscitation北大核心CSCD

Objective To observe the effects of mild hypothermia on the myocardial mitochondrial injmy induced by oxidative stress after restoration of spontaneous circulation (ROSC) in rat of cardiac arrest model. Methods Eighteen male Wistar rats were randomly (raudom number) divided into normal temperature group and mild hypothermia group after ROSC. Ultrasound was used to measure the left ventricular ejection fraction (EF), shortening fraction (FS) and stroke volume (SV). The levels of glutethione (GSH), malondialdehyde (MDA) and adenosine triphosphate (ATP) in myocardium were detected. The ultramicroscopic structure of myocardial mitochondria was observed under transmission electron microscope at 4 h after ROSC. Results There were no significant differences in basic life support (BIS) time, dosage of epinephrine and number of defibrillation attempt between two groups (P > 0.05). The concentrations of GSH and ATP in myocardium of rats in hypothermia group were significantly higher than those in normal temperature group, while the level of MDA was significantly lower in hypothermia group than that in normal temperature group. Echocardiographic findings showed that hypothermia could significantly improve the EF, FS and SV after ROSC. The hypothermia decreased the myocardial mitochondria injury rather than normothermia [mitochondrial injury score: (0. 21 ±0.04) vs. ( 0.42 ±0. 08), P <0. 05]. Conclusions In this model, mild hypothermia can decrease myocardial oxidative stress injury, improving the cardiac function after ROSC.     

Effect of different therapeutic time windows of mild hypothermia on neurological protection from ventricular fibrillation in rabbit models北大核心CSCD

Objective To investigate the effects of mild hypothermia on post-resuscitation neurological outcome after ventricular fibrillation (VF) in rabbits. Methods Forty-five adult New Zealand rabbits were induced VF by direct current of electricity. The rabbits were randomly(random number) divided into following groups: normothermic resuscitation group (NR), mild hypothermia pre-arrest group (HP), mild hypothermia resuscitation 30 min group (HRe30), mild hypothermia resuscitation 90 min group (HRe90), normothermic sham group (NS), and hypothermia sham group (HS). The rabbits of NR group were observed for 600 min in room temperature after restoration of spontaneous circulation (ROSC). The mild hypothermia was induced by surface cooling, and maintained for 600 min after the aimed low temperature reached. The arterial blood samples were collected for determining neuron-specific enolase (NSE) and thioredoxin (Trx) and the mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and left ventricular pressure raise and fall rate (dp/dtmax) were observed at 15 min before CA, and 30 min, 60 min, 120 min, 360 min and 600 min after ROSC. After the animals were sacrificed at 600 min after ROSC, the whole brain of animals was harvested and observed under light microscope to calculate the apoptotic index of the hippocampal CA1 neurons by using TUNEL method. One-way ANOVA was used to determine the statistical significance between two groups, a two-tailed value of P<0.05 was considered statistically significant. Results (1) Hemodynamically compared with normal temperature groups, HR was lower in hypothermia groups. Compared with NR, HRe30, and HRe90 group, LVEDP was higher in HP group at 30 min after ROSC(3.40.8 vs. 4.61.0, 4.10.5, 4.30.2, F=9.85, P=0.019).In HP group, the level of+dp/dtmax was higher than that in NR, HRe30 and HRe90 groups at 30 min and 120 min after ROSC. In HP group, the level of -dp/dtmax was higher than that of NR group at 30 min, 60 min, 120 min, 360 min and 600 min after ROSC. (2) Serologically compared with HP, HRe30 and HRe90 group, NSE levels were higher in NR group at 60 min, 120 min and 360 min after ROSC. Compared with NR, HRe30, and HRe90 group, Trx levels in NR group were lower at 60 min,120 min, 360 min and 600 min after ROSC. Compared with HP group, Trx levels in HRe30 and HRe90 groups were higher at 60 min, 120 min, 360 min and 600 min after ROSC. (3) Pathologically compared with NR group, histopathological changes in hippocampus CA1 area were milder found in HP, HRe30 and HRe90 groups. AI (%) was lower in HP, HRe30 and HRe90 groups than that in NR group[(62.2510.43)% vs. (20.615.02)%, (25.083.92)%, (30.337.15)%, P=0.001]. Concusions This study shows that hypothermia should be initiated as soon as possible, and especially early intra-arrest cooling appears to be significantly better than post-ROSC cooling and normothermia. © 2018 Chinese Medical Association. All Rights Reserved.     

Effects of mild hypothermia on autophagy in hippocampal CAI neurons in rats after CPR北大核心CSCD

Objective To establish the cardiac arrest-cardiopulmonary resuscitation model in rats, and to observe the effect of mild hypothermia on autophagy in hippocampal CAI neurons after ROSC. Methods A total of 36 Wistar rats were randomly divided into two groups: normal temperature treatment group (NT group) and mild hypothermia treatment group ( HT group). To establish the cardiac arrest- cardiopulmonary resuscitation ( CA-CPR) model in rats by epicardial electrical stimulation induced ventricular fibrillation, and to sacrifice 3 animals in each group to obtain the brain cortex in 2nd and 4th hours after ROSC in order to observe the expression of p-AMPK by electron microscope and LC3 granules through Western blot. The neurological deficit score (NDS) was assessed in 24, 48, 72 hours respectively after ROSC. To sacrifice the animals so as to take the cerebrum in 72 hours after ROSC, then calculate the apoptotic index of the hippocampal CAI neurons, which were dyed through TUNEL method. Results The expression of p-AMPK, Beclin-1 and LC3-E/LC3- I ratio in Normothermia group were all lower than the Mild hypothermia group (P < 0. 05 ) , the neurons plasma of hippocampal CAI area in the Hypothermia group demonstrated obvious LC3 granules formation, the NDS score of the Normothermia group and the Mild hypothermia group in ROSC24h, ROSC48h, ROSC72h were 320vs205, 285vsl40, 266vsl20, respectively. The apoptotic index of the hippocampal CA1 area in the Normothemia group in ROSC72h was higher than the Mild hypothermia group, ( P < 0. 05 ). Conclusions Mild hypothermia after cardiopulmonary resuscitation promotes autophagy of the hippocampal CA1 area neurons in rats and reduce neuronal apoptosis.     

Effect of rehabilitation nursing on recovery of linguistic function in stroke aphasia

BACKGROUND:Lalopathycomplicatedinstrokecanre-coveryorberestoredbylinguisticcorrectivetraining.OBJECTIVE:Toobservetheeffectofrehabilitationnursingonrecoveryoflinguisticfunctioninstrokeaphasia.UNIT:DepartmentofRehabilitation,AffiliatedHospitalofLuzhouMedicalCollege.SUBJECTS:32patientswithstrokeaphasiawereinvestigatedincluding18malesand14femalesaged46-77(mean:61)yearsoldwithdiseasecourseover1monthinallcases.Allcasescon-formedtodiagnosisstandardspassedbyChinesemedicalassocia-tionfou…     

Effect of early enteral and parenteral nutrition on visceral ischemic lesion of rat burn model

AIM:To compare the effects of early enteral nutrition and early parenteral nutrition on ameliorating visceral ischemia and relieving free radical damage.METHODS:66 Wistar rats were divided into 3 groups:control group (C),parenteral nutrition group(PN) and enteral nutrition group(EN),PN and EN groups made up of 30% TBSAⅢ degree bum model,We delivered nutrient solution with same calorie and calorie-nitrogen ratio via vein or enteral tract respectively.Blood flow of liver,kidney and change of SOD of heart,liver and kidney at 6,12,24,48,72h after burn were tested.RESULTS:Tissue blood flow and SOD of EN group were higher than those of PN group in many phase(P&;lt;0.05-0.01).CONCLUSION:Early enternal nutrition can relieve the increase of visceral vascular permeability and damage of oxygen free radical.     

Effects of myoblast transfer of human erythro-poietin gene on the erythropoiesis in a rat model of renal failure

Anemia is an invariable symptom of end-stage renalfailure. Erythropoietin (Epo) has been used to improvethe quality of life of patients with end-stage renal failure,but repeated injection of Epo requires patients frequenthospital visits and easily spreads the infectious diseases.In order to investigate whether Epo gene therapy iseffective to renal anemia, we conduct this research work.Firstly, the retrovirus vector (pLEpoSN) containing     

Cardioprotective effect of therapeutic hypothermia at 34°C against ischaemia/reperfusion injury mediated by PI3K and nitric oxide in a rat isolated heart model

Aim

Therapeutic hypothermia (TH) is widely used as a cardioprotective treatment for cardiac arrest. TH at 30-32 °C during ischaemia and reperfusion has a cardioprotective effect. The aims of the study were to examine whether TH at 34 °C with late induction (immediately after the start of reperfusion) has a cardioprotective effect and to determine if this effect is mediated by nitric oxide (NO) and phosphatidylinositol 3′-kinase (PI3K).

Methods

Langendorff perfusion of Sprague-Dawley rat hearts was initiated at 75 mmHg at 37 °C. Left ventricle infarct sizes were evaluated by triphenyltetrazolium chloride staining after Langendorff perfusion in 6 groups (each n = 7): control group; ischaemia group, with 34 °C TH during ischaemia for 30 min and reperfusion for 180 min; reperfusion group, with 34 °C TH induced solely during the reperfusion period; the l-NAME (NO synthase inhibitor), LY294002, and wortmannin (PI3K inhibitors) groups, which were treated similarly to the reperfusion group with the addition of each compound.

Results

TH reduced the left ventricle infarct size from 54.2 ± 14.8% of the control group to 11.9 ± 6.3% (ischaemia group, p < 0.001) and to 23.5 ± 10.5% (reperfusion group, p < 0.001). l-NAME, LY294002, and wortmannin reversed the cardioprotective effect of TH induced during reperfusion to 42.5 ± 10.6% (p = 0.009), 40.9 ± 4.1% (p = 0.021), and 51.9 ± 13.0% (p < 0.001), respectively. Circulatory temperatures reached 34 °C within 5 min in all groups subjected to TH.

Conclusions

TH of 34 °C showed a cardioprotective effect even with late initiation of cooling during reperfusion. The effect was mediated by NO and PI3K.