Efficacy of preemptive analgesia treatments for the management of postoperative pain: a network meta-analysis.

BACKGROUND: Preemptive analgesia may improve postoperative pain management, but the optimal regimen is unclear. This study aimed to compare the effects and adverse events of preemptive analgesia on postoperative pain and opioid consumption. METHODS: In this network meta-analysis, 19 preemptive analgesia regimens were compared. Two authors independently searched databases, selected studies, and extracted data. Primary outcomes were the intensity of postoperative pain and opioid consumption. Secondary outcomes included the time to first analgesia rescue and incidence of postoperative nausea or vomiting (PONV). RESULTS: In total, 188 studies were included (13 769 subjects). Ten of 19 regimens reduced postoperative pain intensity compared with placebo, with mean differences 100-point scale ranging from -4.79 (95% confidence interval [CI]: -8.61 to -0.96.) for gabapentin at 48 h to -21.99 (95% CI: -36.97 to -7.02) for lornoxicam at 6 h. Eight regimens reduced opioid consumption compared with placebo, with mean differences ranging from -0.48 mg (95% CI: -0.89 to -0.08) i.v. milligrams of morphine equivalents (IMME) for acetaminophen at 12 h to -2.27 IMME (95% CI: -3.07 to -1.46) for ibuprofen at 24 h. Five regimens delayed rescue analgesia from 1.75 (95% CI: 0.59-2.91) h for gabapentin to 7.35 (95% CI: 3.66-11.04) h for epidural analgesia. Five regimens had a lower incidence of PONV compared with placebo, ranging from an odds ratio of 0.22 (95% CI: 0.11-0.42) for ibuprofen to 0.59 (95% CI: 0.40-0.87) for pregabalin. CONCLUSIONS: Use of preemptive analgesia reduces postoperative pain, opioid consumption, and postoperative nausea or vomiting, and delays rescue analgesia. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021232593.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.

BACKGROUND: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. RESEARCH DESIGN AND METHODS: This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. RESULTS: In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). CONCLUSIONS: Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Efficacy of different analgesia treatments for abdominal surgery: A network meta-analysis.

OBJECTIVE: This study was designed to evaluate the efficacy of analgesia and incidence of postoperative nausea and vomiting (PONV) of several widely used clinical treatments for postoperative analgesia following abdominal surgery through network meta-analysis (NMA) based on published randomized controlled trials (RCTs). METHODS: This NMA was registered on PROSPERO as CRD 42020169606. Primary outcomes were pain scores (visual analog scale) and accumulative opioid consumption, and secondary outcomes assessed the incidence of PONV at 24 h after surgery. RESULTS: A total of 215 RCTs and 15,114 patients were identified in this NMA. In comparison with placebo, use of a preoperative paravertebral block (mean: -12.63, 95% CI: -21.12 to -4.13), continuous wound infiltration (mean: -9.68, 95%CI: -13.15 to -6.22) and postoperative wound infiltration (mean: -6.34, 95%CI: -10.59 to -2.08) had significantly lower pain scores, less opioid consumption (mean: -2.00, 95%CI: -3.52 to -0.48; mean: -1.34, 95%CI: -1.87 to -0.81; mean: -1.41, 95%CI: -2.07 to -0.74, respectively) and lower incidence of PONV (OR: 0.30, 95%CI: 0.13 to 0.67; OR: 0.49, 95%CI: 0.24 to 0.98; OR: 0.55, 95%CI: 0.34 to 0.89, respectively). CONCLUSIONS: The findings from our work provide evidence that preoperative paravertebral block was superior to continuous or postoperative wound infiltration to provide postoperative analgesia, nausea and vomiting after abdominal surgery.

Assessing efficacy of intravenous acetaminophen for perioperative pain control for oocyte retrieval: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effect of preoperative intravenous (IV) acetaminophen versus oral (PO) acetaminophen or placebo on postoperative pain scores and the time to discharge in women undergoing oocyte retrieval. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single academic fertility center. PATIENT(S): Women aged 18-43 years undergoing oocyte retrieval. INTERVENTION(S): Randomization to preoperative 1,000 mg IV acetaminophen and PO placebo (group A), IV placebo and 1,000 mg PO acetaminophen (group B), or IV and PO placebo (group C) MAIN OUTCOME MEASURE(S): Difference in patient-reported postoperative visual analog scale pain scores from baseline and the time to discharge. RESULT(S): Of the 159 women who completed the study, there were no differences in the mean postoperative pain score differences or the time to discharge. Although not statistically significant, the mean postoperative opioid dose requirement in group A was lower than that in groups B and C (0.24 vs. 0.59 vs. 0.58 mg IV morphine equivalents, respectively) due to fewer women in group A requiring rescue pain medication (8% vs. 19% vs. 15%, respectively). Group A also reported less constipation when compared with groups B and C (19% vs. 33% vs. 40%, respectively). The rates of postoperative nausea were similar, and there were no differences in embryology or early pregnancy outcomes between the study groups. CONCLUSION(S): Preoperative IV acetaminophen for women undergoing oocyte retrieval did not reduce postoperative pain scores or shorten the time to discharge when compared with PO acetaminophen or placebo and, thus, cannot currently be recommended routinely in this patient population. CLINICAL TRIAL REGISTRATION NUMBER: NCT03073980.

The Facilitatory Effects of Adjuvant Pharmaceutics to Prolong the Duration of Local Anesthetic for Peripheral Nerve Block: A Systematic Review and Network Meta-analysis.

BACKGROUND: Peripheral nerve block (PNB) with perineural local anesthetic is used for anesthesia or analgesia with many benefits. To extend these benefits, various adjuvant drugs have been used to prolong the duration of analgesia. We aimed to evaluate the effectiveness of various adjuvants at prolonging the duration of sensory and motor blockade for PNB. METHODS: A network meta-analysis of placebo-controlled and active randomized controlled trials was performed comparing 10 adjuvants. Embase, PubMed, Web of Science, and Cochrane library were searched, with articles before May 21, 2020 included. Two authors independently selected studies and extracted data. The primary outcomes were sensory block (SB) and motor block (MB) time, and the secondary outcome was time of first analgesia rescue (FAR). Effect size measures were described as mean differences (MD) with 95% confidence intervals (CIs). Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The study protocol was preregistered with the prospectively registered systematic reviews in health and social care international database (PROSPERO), as number CRD42020187866. RESULTS: Overall 16,364 citations were identified, of which 53 studies were included with data for 3649 patients. In network meta-analyses, 4 of 7 included treatment strategies were associated with more efficacious analgesia compared with placebo therapy, including dexamethasone (SB time: 5.73 hours, 95% CI, 4.16-7.30; MB time: 4.20 hours, 95% CI, 2.51-5.89; time of FAR: 8.71 hours, 95% CI, 6.63-10.79), dexmedetomidine (SB time: 4.51 hours, 95% CI, 3.52-5.50; MB time: 4.04 hours, 95% CI, 2.98-5.11; time of FAR: 5.25 hours, 95% CI, 4.08-6.43), fentanyl (SB time: 3.59 hours, 95% CI, 0.11-7.06; MB time: 4.42 hours, 95% CI, 0.78-8.06), and clonidine (SB time: 2.75 hours, 95% CI, 1.46-4.04; MB time: 2.93 hours, 95% CI, 1.69-4.16; time of FAR: 3.35 hours, 95% CI, 1.82-4.87). In a subgroup analysis, addition of dexamethasone to ropivacaine significantly increased the time of FAR when compared to dexmedetomidine (time of FAR: 5.23 hours, 95% CI, 2.92-7.54) or clonidine (time of FAR: 6.61 hours, 95% CI, 4.29-8.92) with ropivacaine. CONCLUSIONS: These findings provide evidence for the consideration of dexmedetomidine, dexamethasone, and clonidine as adjuvants to prolong the duration of PNB. The addition of dexamethasone to ropivacaine has a longer time of FAR compared with clonidine or dexmedetomidine.

Effect of Preemptive Acetaminophen on Opioid Consumption: A Meta-Analysis.

BACKGROUND: Strategies for reducing postoperative opioid consumption have been explored in many recent studies, due in large part to the recent opioid epidemic. Preemptive analgesia has been proposed as a potential method, but its use is still controversial. OBJECTIVES: This review aimed to evaluate the efficacy of a single dose of acetaminophen as preemptive analgesia for patients undergoing general anesthesia. STUDY DESIGN: A meta-analysis of randomized controlled trials (RCTs). SETTING: The electronic databases of PubMed, EMBASE, Cochrane Library, and the Web of Science were searched. The protocol was previously registered in the PROSPERO database under the registration number CRD 42020165634. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. RCTs that compared preemptive acetaminophen with placebo in surgical patients receiving general anesthesia were included. The risk of bias for each included study was independently assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Six studies with 563 patients were included. Overall, the studies showed a reduction in 24-hour opioid consumption (standardized mean difference [SMD], -1.45; 95% confidence interval [CI], -2.36 to -0.55; P = 0.002), pain scores at 12 hours postoperatively (SMD, -0.86; 95% CI, -1.25 to -0.48; P < 0.0001), and a lower incidence of postoperative nausea (risk ratio [RR] 0.45; 95% CI, 0.34-0.58; P < 0.001) and vomiting (RR 0.39; 95% CI, 0.22-0.72; P = 0.002). LIMITATIONS: The major limitation of this meta-analysis relates to the risk of bias in the limited number of included studies. CONCLUSIONS: Preemptive acetaminophen administration significantly reduces opioid consumption within the initial 24 hours following general anesthesia, with lower pain scores at 12 hours after surgery, and less nausea and vomiting. However, well-conducted RCTs are still needed.

A review on the physiological and pathophysiological role of endothelial glycocalyx.

The glycocalyx is a gel-like layer covering the luminal surface of vascular endothelial cells. It comprises of membrane-attached proteoglycans, glycosaminoglycan chains, glycoproteins, and adherent plasma proteins. The glycocalyx maintains homeostasis of the vasculature, which includes controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion. In the past decades, the number of studies on endothelial glycocalyx has steadily grown. Glycocalyx emerged as an essential part of blood vessels involved in multiple physiological functions. Damage to glycocalyx is associated with many types of diseases. The structure and physiology and pathophysiology of the glycocalyx, as well as the clinical effects of glycocalyx degradation, are addressed throughout this study. We strive in particular to define therapeutic approaches for the survival or reparation of the glycocalyx.

Hsa_circ_0039411 promotes tumorigenesis and progression of papillary thyroid cancer by miR-1179/ABCA9 and miR-1205/MTA1 signaling pathways.

Papillary thyroid cancer (PTC) is a common malignancy in endocrine system worldwide. Increasing evidence has shown that dysregulation of circular RNAs (circRNAs) could contribute to PTC tumorigenesis. The aims of this project are to investigate the potential role and molecular mechanism of hsa_circ_0039411 in PTC. In the project, RT-qPCR was performed to measure the expression profile of hsa_circ_0039411 in PTC tissues and cells. Cell counting kit-8, clonogenic, flow cytometric, and transwell experiments were used to identify the biological role of hsa_circ_0039411 on PTC cell progression. Bioinformatics methods, along with the dual-luciferase reporter test, was used to identify the potential mechanism of hsa_circ_0039411. Hsa_circ_0039411 was identified as enhanced in PTC tissues/cells. Gain-of-function experiments indicated that hsa_circ_0039411 facilitated PTC cell growth, migration, and invasion and inhibited cell apoptosis. Knockdown of hsa_circ_0039411 caused the opposite effects mentioned above. The mechanism exploration showed that hsa_circ_0039411 functioned as a sponge for miR-1179 and miR-1205 to elevate ATP-binding cassette transporter A9 (ABCA9) and metastasis-associated 1 (MTA1) expression at the post-transcriptional level, respectively. Further investigation confirmed that the functions of hsa_circ_0039411 are dependent on its modulation of ABCA9 and MTA1 in PTC cells. This study uncovered a mechanism of hsa_circ_0039411 in PTC, which might act as a novel therapeutic target for PTC.

Corrected QT interval prolongation during anesthetic induction for laryngeal mask airway insertion with or without cisatracurium.

Objective This study was performed to observe the occurrence of corrected QT (QTc) interval prolongation during anesthetic induction for laryngeal mask airway insertion and the effects of cisatracurium administration on the QTc interval. Methods Eighty-eight patients were assigned to two groups: the cisatracurium administration group (n = 45) and non-cisatracurium administration group (n = 43). The QTc interval was continuously recorded by a 12-lead Holter electrocardiogram beginning in the hospital ward and continuing until after anesthetic induction. Results In the cisatracurium administration group, the QTc interval significantly increased from 417.9 ± 27.9 to 451.6 ± 32.5 ms after arrival in the operating room and significantly decreased to 432.4 ± 32.5 ms after a 15-minute rest; it significantly increased to 459.7 ± 23.8 ms again after propofol and fentanyl injection. However, the QTc interval decreased after cisatracurium injection. In the non-cisatracurium administration group, the QTc interval initially showed changes similar to those in the cisatracurium group until fentanyl and propofol were injected. Conclusions The QTc interval was significantly prolonged on arrival in the operating room and after propofol and fentanyl injection. The QTc interval did not significantly change by laryngeal mask airway insertion regardless of the administration of cisatracurium.

Role of the Lateral Habenula in Pain-Associated Depression.

Patients with chronic pain have significantly higher incidences of depression and anxiety than the average person. However, the mechanism underlying this link has not been elucidated in terms of how chronic pain causes significant mood changes and further develops into severe anxiety or depression. The serotonergic system in the raphe nuclei is an important component in both pain processing and the pathogenesis of depression. Since the lateral habenular nucleus (LHb) controls the raphe nuclei, it may participate in the regulation of pain-associated depression. Thus, the aim of the current study was to investigate the role of the LHb in this pathophysiological process. We used chronic constriction injury (CCI) of the sciatic nerve in rats as a model for neuropathic pain and assessed the changes potentially related to the mood disorders. The forced swim test (FST) and sucrose preference test (SPT) were performed to determine the behavioral changes 28 days after pain surgery. Expression of ß calmodulin-dependent protein kinase type II (ßCaMKII) in the LHb, cytochrome-c oxidase (COX) activity in the LHb and dorsal raphe nucleus (DRN) and serotonin (5-HT) levels in the DRN were measured. We found an increasing in LHb activity and ßCaMKII expression, and a decrease in neuronal activity in the DRN and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the CCI rats. These effects were accompanied by the depression-like behaviors. Lesions in the LHb improved the pain threshold and depression-like behavior in the rats. These results suggest that the LHb may play a role in pain-associated depression by affecting the activity of 5-HT neurons in the DRN. Furthermore, we showed that increases in the LHb-DRN pathway activity were a common neurobiological mechanisms for pain and depression, which may explain the coexistence of pain and depression.

20-Hydroxyeicosatetraenoic Acid Is a Key Mediator of Angiotensin II-induced Apoptosis in Cardiac Myocytes.

Cardiomyocyte apoptosis is involved in a variety of cardiac stresses, including ischemia-reperfusion injury, heart failure, and cardiomyopathy. Both Angiotensin II (Ang II) and 20-hydroxyeicosatetraenoic acid (20-HETE) induce apoptosis in cardiomyocytes. Here, we examined the relationship between 20-HETE and Ang II in cardiomyocyte apoptosis. Apoptosis was examined using flow cytometry in primary cultured rat cardiomyocytes treated with control, Ang II, and Ang II plus HET0016 (a 20-HETE formation inhibitor). The results demonstrated that the treatment of cardiomyocytes with Ang II or 20-HETE significantly increased the percentage of apoptotic cells and that Ang II-induced apoptosis was markedly attenuated by HET0016 or losartan (an AT1 receptor antagonist). In apoptotic mechanism experiments, Ang II or 20-HETE treatment significantly reduced mitochondrial membrane potential, indicating that a mitochondria-dependent mechanism is involved. Ang II-induced alteration in mitochondrial membrane potential was significantly attenuated by HET0016. Treatment of cardiomyocytes with Ang II also increased superoxide production, and this effect of Ang II was attenuated by HET0016. Treatment of cardiomyocytes with Ang II significantly increased CYP4A1 expression and 20-HETE production, as measured by Western blot, real-time RT-PCR, and mass spectrometric analysis. All results suggest that 20-HETE may play a key role in Ang II-induced apoptosis in cardiomyocytes by a mitochondrial superoxide-dependent pathway.

BN52021 protects rat cardiomyocyte from doxorubicin induced cardiotoxicity.

The aim of this study was to assess the role of platelet activating factor (PAF) antagonist BN52021 in doxorubicin induced cardiotoxicity and to explore the mechanisms. H9c2 cardiomyocytes were employed to investigate the effect of BN52021 on doxorubicin induced cell viability and cell apoptosis. Signaling pathway of caspase 3, cytochrome c, calcium and p38 mitogen-activated protein (MAPK) was determined during the doxorubicin induced apoptosis. Our results showed BN52021 pretreatment could protected cell death induced by doxorubicin in H9c2 cardiomyocytes. Decrease concentration of [Ca(2+)] and expression of phosphorylated P38 MAPK were accounted for the protection effect. Inhibition of signaling pathway of calcium and p38 MAPK showed similar effect exerted by BN52021 in doxorubicin induced cell apoptosis. Our results demonstrated BN52021 protected against doxorubicin induced cell death in H9c2 cardiomyocytes by calcium and p38 MAPK signaling in vitro. These finding may give insight on the treatment of doxorubicin induced cardiomyopathy.

High salt-diet reduces SLC14A1 gene expression in the choroid plexus of Dahl salt sensitive rats.

Elevated Na(+) concentration ([Na(+)]) in the cerebrospinal fluid (CSF) contributes to the development of salt-sensitive hypertension. CSF is formed by the choroid plexus (CP) in cerebral ventricles, and [Na(+)] in CSF is controlled by transporters in CP. Here, we examined the effect of high salt diet on the expression of urea transporters (UTs) in the CP of Dahl S vs Dahl R rats using real time PCR. High salt intake (8%, for 2 weeks) did not alter the mRNA levels of UT-A (encoded by SLC14A2 gene) in the CP of either Dahl S or Dahl R rats. In contrast, the mRNA levels of UT-B (encoded by SLC14A1 gene) were significantly reduced in the CP of Dahl S rats on high salt diet as compared with Dahl R rats or Dahl S rats on normal salt diet. Reduced UT-B expression was associated with increased [Na(+)] in the CSF and elevated mean arterial pressure (MAP) in Dahl S rats treated with high salt diet, as measured by radiotelemetry. High salt diet-induced reduction in UT-B protein expression in the CP of Dahl S rats was confirmed by Western blot. Immunohistochemistry using UT-B specific antibodies demonstrated that UT-B protein was expressed on the epithelial cells in the CP. These data indicate that high salt diet induces elevations in CSF [Na(+)] and in MAP, both of which are associated with reduced UT-B expression in the CP of Dahl S rats, as compared with Dahl R rats. The results suggest that altered UT-B expression in the CP may contribute to an imbalance of water and electrolytes in the CSF of Dahl S rats on high salt diet, thereby leading to alterations in MAP.

WITHDRAWN:Expression of the angiotensin II, rac GTPase activating protein 1, signal transducer and activator of transcription 3 signaling pathway in patients with permanent atrial fibrillation and rheumatic heart disease.

Ahead of Print article withdrawn by publisher.

Combination use of platelets and recombinant activated factor VII for increased hemostasis during acute type a dissection operations.

BACKGROUND: Refractory blood loss is a common problem in surgeries for acute type A aortic dissections. Significant evidence has supported the benefit of using recombinant activated factor VII (rFVIIa) to control of intractable bleeding in patients after cardiac surgery. In this prospective clinical study, we present a novel method to achieve intraoperative hemostasis by using a combination of platelets and rFVIIa during operations for acute type A aortic dissections. METHODS: Between May 2009 and August 2012, 71 patients with acute type A dissections who underwent emergency surgery were prospectively included and allocated to one of the following two intervention groups for hemostasis: 3 units platelets combined with 2.4 mg rFVIIa (n = 25), and conventional methods (n = 46). RESULTS: The patients who received the combination of platelets and rFVIIa required fewer transfusions of red blood cells (6.2 ± 3.1 units vs 9.8 ± 2.8 units; p < 0.05), fresh frozen plasma (736.9 ± 178.3 ml vs 1264.3 ± 245.2 ml, p < 0.05), platelet concentrates (3 units vs 5.0 ± 1.8 units, p < 0.001), and cryoprecipitate (2.8 ± 0.9 units vs 8.2 ± 2.3 units, p < 0.05). These patients also required less time for sternal closure (76.9 ± 17.2 min vs 102.3 ± 10.7 min, p < 0.05) compared with the conventional therapy patients. There was no statistically significant difference in the incidence of serious adverse events between these two groups. CONCLUSIONS: Using a combination of platelets and rFVIIa is an effective strategy for achieving hemostasis during acute type A dissection surgery. This hemostatic strategy does not appear to be associated with an increase in postoperative adverse events.

Surgical approach for the treatment of aortoesophageal fistula combined with dual aortic aneurysms: a case report.

Aortoesophageal fistula is a rare disease with a high mortality rate. The disease is with high mortality due to aneurysm rupture, and thus successfully managed cases are rarely reported. Here, we report a case of aortoesophageal fistula caused by a huge descending aneurysm and another smaller aneurysm found in the aortic arch. Such case was relatively rare in the cardiovascular field. Due to the limited experience, it was difficult to determine the proper therapeutic strategy. For this case, for the dual aneurysm, we surgically inserted an aortic endovascular stent-graft to exclusive the aneurysm and simultaneously repair the other aortic arch aneurysm. The patient had an uneventful recovery and was discharged after 1 month antibiotics therapy for the palliative treatment of the esophageal fistula. She survived for 8 months at home before dying of massive hematemesis. Here, we present the operative method and our therapeutic experience for this extremely rare case.

GABAB receptor gene transfer into the nucleus tractus solitarii induces chronic blood pressure elevation in normotensive rats.

BACKGROUND: Increasing evidence indicates that GABAergic neurons in the nucleus of the solitary tract (NTS) play a significant role in the arterial baroreceptor reflex and control of cardiovascular homeostasis. However, the role of these neurons in the development of hypertension is not yet fully clear. METHODS AND RESULTS: In the present study, we first confirmed that GABAB receptor (GBR) expression is enhanced in the NTS of SHR as compared with WKY rats using real-time RT-PCR and western blots. To study the functional consequence of upregulated GBR expression, GBR was overexpressed in the NTS by bilateral microinjection of the AAV2-GBR1 viral vector into the NTS of WKY rats. Immunofluorescence staining and western blots demonstrated that microinjection of AAV2-GBR1 into the NTS of WKY rats resulted in a significant increase in GBR1 expression in the NTS neurons. Overexpression of GBR in the NTS induced a chronic elevation in blood pressure and heart rate in the normotensive WKY rats. In an acute study, the pressor response to baclofen microinjected into the NTS was enhanced in SHR as compared with WKY rats. CONCLUSIONS: GBR1 expression is enhanced in the NTS of SHR vs. WKY rats and overexpression of this gene in the NTS results in chronic elevation of blood pressure and heart rate in normotensive rats.

Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons.

Several studies have focused on the beneficial effects of peripheral angiotensin-(1-7) [Ang-(1-7)] in the regulation of cardiovascular function, showing its counterregulatory effect against the actions of angiotensin II (ANG II). However, its actions in the central nervous system are not completely understood. In the present study, we investigated the intracellular mechanisms underlying the action of ANG-(1-7) using the patch-clamp technique in neurons cultured from the hypothalamus of neonatal spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Superfusion of neurons with ANG II (100 nM) significantly increased neuronal firing in both strains of rats, and this chronotropic effect of ANG II was significantly enhanced in prehypertensive SHR neurons compared with WKY rat neurons. The enhanced chronotropic effect of ANG II was attenuated by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY 294002 (10 µM). Superfusion of neurons with ANG-(1-7) (100 nM) did not alter the neuronal firing rate in either SHR or WKY neurons; however, it significantly attenuated the chronotropic action of ANG II exclusively in prehypertensive SHR neurons. This counterregulatory effect of ANG-(1-7) on ANG II action in prehypertensive SHR neurons was attenuated by cotreatment with either A-779, a Mas receptor antagonist, or bisperoxovanadium, a phosphatase and tensin homologue deleted on chromosome ten (PTEN) inhibitor. In addition, incubation of WKY and prehypertensive SHR neurons with ANG-(1-7) significantly increased PTEN activity. The data demonstrate that ANG-(1-7) counterregulates the chronotropic action of ANG II via a PTEN-dependent signaling pathway in prehypertensive SHR neurons.