RBFOX2 confers tumor growth by PI3K/AKT and MAPK signaling in gastric cancer.

RNA-binding Fox (RBFOX)2, a member of a family of RNA-binding proteins, is well known as a regulator of alternative pre-mRNA splicing. However, its possible role in gastric cancer is unknown. In this study, we investigated the biologic role and clinical significance of RBFOX2 in gastric cancer growth and elucidated its underlying molecular mechanisms. We found that RBFOX2 was highly expressed in gastric cancer cell lines and tumor tissue compared with the adjacent nontumor tissue. We also found that RBFOX2 overexpression was correlated with poor overall survival in patients with gastric cancers. Multivariate survival analyses revealed that higher RBFOX2 expression was an independent prognostic factor for the overall survival of patients with gastric cancers. Suppression of RBFOX2 by shRNA inhibited gastric cancer cell proliferation, colony formation and induced apoptosis. Mechanism studies revealed that these effects were achieved through the simultaneous modulation of multiple signaling pathways. Knockdown of RBFOX2 expression by shRNA markedly inhibited the phosphorylation of phosphatidylinositol 3-hydroxy kinase, threonine kinase and extracellular signal-regulated kinase and Jun N-terminal kinases proteins. In contrast, the ectopic expression of RBFOX2 had the opposite effects. Moreover, RBFOX2 knockdown also induced the cleavage of caspase-3 and caspase-9 proteins. Collectively, these results demonstrate that RBFOX2 plays a critical role in regulating gastric cancer cell proliferation and survival and may be a potential prognostic biomarker and therapeutic target for gastric cancer.

Establishment of a canine model of pulmonary arterial hypertension induced by dehydromonocrotaline and ultrasonographic study of right ventricular remodeling.

OBJECTIVE: Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs. We aimed to observe the right ventricular size, wall thickness and characteristic functional changes and their associations with PAH in an established model of beagle dogs, and to explore convenient, reliable and sensitive ultrasound indicators for assessing right ventricular remodeling. METHODS: Twenty healthy beagle dogs (8-10 kg) were randomly divided into control group (N-dimethylformamide, n = 10) and dehydromonocrotaline (DHMCT) group (DHMCT, n = 10). N-dimethylformamide or DHMCT was injected through a catheter into the right atrium, and then right heart catheterization, routine echocardiography and two-dimensional speckle tracking imaging (2D-STI) were performed before modeling (0 weeks) and 8, 14 weeks after modeling. Hemodynamic parameters and right ventricular function-related ultrasound data were acquired. At the end of the experiment, the animals were killed and the lung tissues were taken for HE staining. Left and right ventricular walls were separated and weighed respectively, and right ventricular hypertrophy index (RVHI) was measured. The associations of the routine ultrasound data and 2D-STI data at each time point with hemodynamic parameters and RVHI were analyzed. RESULTS: At 0, 8 and 14 weeks, gradual decreases in the right ventricular global longitudinal strain (RVLS) were found in DHMCT group. RVH occurred in DHMCT group, and DHMCT group had a significantly higher RVHI than that of control group (49.83 ± 4.83% vs. 39.80 ± 1.40%, P < .001) and larger pulmonary artery media thickness. RVLS had significant positive correlations with RVSP (r = 0.74, P < .001), mRVP (r = 0.72, P < .001), PASP (r = 0.75, P < .001), mPAP (r = 0.72, P < .001) and PVR (r = 0.68, P < .001). There was a significant positive correlation between RVLS and RVHI (r = 0.74, P < .001). CONCLUSION: The right ventricular function in PAH can be effectively assessed by echocardiography, and RVLS measured by 2D-STI sensitively reflects right ventricular remodeling following PAH.

Pulmonary Artery Denervation Significantly Increases 6-Min Walk Distance for Patients With Combined Pre- and Post-Capillary Pulmonary Hypertension Associated With Left Heart Failure: The PADN-5 Study.

OBJECTIVES: The authors sought to assess the benefits of pulmonary artery denervation (PADN) among combined pre- and post-capillary pulmonary hypertension (CpcPH) patients in a prospective, randomized, sham-controlled trial. BACKGROUND: PADN has been shown to improve hemodynamics of pulmonary arterial hypertension in a series of patients. Additionally, benefits of targeted medical therapy for patients with CpcPH secondary to left-sided heart failure are unknown. METHODS: Ninety-eight CpcPH patients, defined as mean pulmonary arterial pressure ≥25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance (PVR) >3.0 Wood units (WU), were randomly assigned to PADN or sildenafil plus sham PADN. Standard medical therapy for heart failure was administered to all patients in both groups. The primary endpoint was the increase in the 6-min walk distance at the 6-month follow-up. The secondary endpoint was change in PVR. Clinical worsening was assessed in a post hoc analysis. The main safety endpoint was occurrence of pulmonary embolism. RESULTS: At 6 months, the mean increases in the 6-min walk distance were 83 m in the PADN group and 15 m in the sildenafil group (least square mean difference 66 m, 95% confidence interval: 38.2 to 98.8 m; p < 0.001). PADN treatment was associated with a significantly lower PVR than in the sildenafil group (4.2 ± 1.5 WU vs. 6.1 ± 2.9 WU; p = 0.001). Clinical worsening was less frequent in the PADN group compared with the sildenafil group (16.7% vs. 40%; p = 0.014). At the end of the study, there were 7 all-cause deaths and 2 cases of pulmonary embolism. CONCLUSIONS: PADN is associated with significant improvements in hemodynamic and clinical outcomes in patients with CpcPH. Further studies are warranted to define its precise role in the treatment of this patient population. (Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure [PADN-5]; NCT02220335).

Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation.

Uncoupled endothelial nitric oxide synthase (eNOS) produces O2- instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O2- production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O2- burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O2- releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.

Pericardial effusion is correlated with clinical outcome after pulmonary artery denervation for pulmonary arterial hypertension.

OBJECTIVES: Pericardial effusion (PE) is correlated with outcomes in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) was used for treatment of PAH. The present study aimed to analyze the prognostic value of PE for outcomes after PADN in patients with WHO Group I, Group II and Group IV PAH. RESULTS: PE, frequently seen in patients with connective tissue disease, was featured by fast heart rate, decreased exercise capacity, more syncope, worsening pulmonary arterial hemodynamic and right atrium size. PADN procedure resulted in dramatic reduction of PE. After a median of 376 days follow-up, the rate of PAH-related event, all-cause death and rehospitalization increased over the PE amount and occurred in 29.8%, 19.7% and 25.2% of patients with PE, different to 3.4%, 3.4% and 6.8% of patients without PE (p = 0.034, p = 0.041 and p = 0.039, respectively). The reduction of PE during follow-up was similar among three groups. MATERIALS AND METHODS: Between March 2012 and July 2014, a total of 66 consecutive patients (52 ± 16 years) who underwent PADN were stratified by no PE (n = 20), PE < 10 mm (n = 29) and PE ≥ 10 mm (n = 17) according to baseline echocardiograph. Dynamic change of PE and its correlation with PAH-related event after PADN were measured. CONCLUSIONS: PE is associated with increased PAH-related event after PADN. PADN results in significant similar reduction of PE among patients with Group I, Group II and Group IV PAH.

Effects of naftopidil on inhibitory transmission in substantia gelatinosa neurons of the rat spinal dorsal horn in vitro.

OBJECTIVE: Naftopidil is used clinically for the treatment of voiding disorders in benign prostatic hyperplasia. Previous in vivo experiments in which naftopidil was applied intrathecally abolished rhythmic bladder contraction, suggesting that naftopidil might inhibit a voiding reflex through interaction with spinal dorsal horn neurons. Here we aimed to clarify the mechanism of action of naftopidil on dorsal horn neurons. METHODS: Whole-cell patch-clamp recordings were performed using substantia gelatinosa neurons of adult rat spinal cord slices. Miniature or evoked inhibitor and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were analyzed. RESULTS: Bath-applied naftopidil increased the frequency but not the amplitude of miniature IPSCs (mIPSCs) in 38% of neurons tested; in contrast, the effect of naftopidil on miniature EPSCs (mEPSCs) were mild and observed in only 2 out of 19 neurons. Naftopidil enhanced the amplitude of both GABAergic and glycinergic evoked-IPSCs (eIPSCs) that were elicited by focal stimuli in the presence of either the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). CONCLUSIONS: Although naftopidil was developed as an alpha-1 adrenoceptor antagonist, our previous spinal cord slice experiments showed that the activation of an alpha-1 adrenoceptor in substantia gelatinosa increases the frequency of mIPSCs. This result suggested that, under our conditions, naftopidil may interact with a receptor(s) other than an alpha-1 adrenoceptor in the spinal dorsal horn. The present results suggested that naftopidil enhances the release of GABA and glycine by activating inhibitory interneuron terminals in the spinal dorsal horn via a receptor other than an alpha-1 adrenoceptor, thereby modulating sensory transmission in the substantia gelatinosa.

Spontaneous Coronary Artery Dissection as a Cause of Acute Myocardial Infarction in Young Female Population: A Single-center Study.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic but a rare and extremely dangerous clinical entity, it has a high prevalence in young female population with acute myocardial infarction (AMI). The previous reports were restricted to other countries' population, but rare in China. Hence, this study aimed to focus on the characteristics of SCAD as a cause of young female AMI population in Jiangsu, China. METHODS: This study enrolled young female AMI patients aged ≤50 years who underwent coronary angiography (CAG) and intracoronary imaging in our center between January 2013 and December 2016. Their clinical presentations, risk factors, and CAG characteristics were analyzed. RESULTS: A total of 60 young female AMI (<7 days) patients were enrolled. From their CAG and intracoronary imaging results, the prevalence of SCAD in young female AMI population was 35% (21/60), the prevalence of coronary atherosclerostic heart disease was 65% (39/60). In the SCAD group, 43% (9/21) presented with non-ST-elevation myocardial infarction (NSTEMI) and the remainder presenting as STEMI. SCAD usually occurred in a single vessel (20/21, 95%), especially in left anterior descending artery (14/21, 67%). Eighteen patients (18/21, 86%) underwent conservative treatment, whereas the remaining three patients (3/21, 14%) underwent percutaneous coronary intervention. Regarding the angiographic results of SCAD lesions, intramural hematoma was discriminated in 95% (20/21), and Type I imaging was observed in 5% (1/21), Type II was observed in 67% (14/21), and Type III was 29% (6/21). The average stenosis in the group was 76.9% ± 20.6%, and the mean lesion length was 36.6 ± 8.6 mm. CONCLUSIONS: SCAD has a high prevalence in young female AMI population in Jiangsu, China. Discriminating the cause of AMI in young female population is very important.

Clinical Outcome of Double Kissing Crush Versus Provisional Stenting of Coronary Artery Bifurcation Lesions: The 5-Year Follow-Up Results From a Randomized and Multicenter DKCRUSH-II Study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions).

BACKGROUND: Provisional stenting is effective for anatomic simple bifurcation lesions. Double kissing crush stenting reduces the 1-year rate of target lesion revascularization. This study aimed to investigate the 5-year clinical results of the DKCRUSH-II study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions). METHODS AND RESULTS: A total of 370 patients with coronary bifurcation lesions who were randomly assigned to either the double kissing crush or provisional stenting group in the DKCRUSH-II study were followed for 5 years. The primary end point was the occurrence of a major adverse cardiac event at 5 years. Patients were classified by simple and complex bifurcation lesions according to the DEFINITION criteria (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents). At 5 years, the major adverse cardiac event rate (23.8%) in the provisional stenting group was insignificantly different to that of the double kissing group (15.7%; P=0.051). However, the difference in the target lesion revascularization rate between 2 groups was sustained through the 5-year follow-up (16.2% versus 8.6%; P=0.027). The definite and probable stent thrombosis rate was 2.7% in each group (P=1.0). Complex bifurcation was associated with a higher rate of target lesion revascularization (21.6%) at 5 years compared with 11.1% in patients with a simple bifurcation (P=0.037), with an extremely high rate in the provisional stenting group (36.8% versus 12.5%, P=0.005) mainly because of final kissing balloon inflation (19.4% versus 5.2%; P=0.036). CONCLUSIONS: The double kissing crush stenting technique for coronary bifurcation lesions is associated with a lower rate of target lesion revascularization. The optimal stenting approach based on the lesions' complexity may improve the revascularization for patients with complex bifurcations. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org. Unique identifier: ChiCTR-TRC-0000015.

Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system.

BACKGROUND: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. METHODS: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. RESULTS: PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. CONCLUSIONS: PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue.

Pulmonary artery denervation for treatment of a patient with pulmonary hypertension secondary to left heart disease.

Pulmonary hypertension (PH) predicts poor outcome in patients with left heart disease. A 62-year-old man was referred for heart failure associated with ischemic cardiomyopathy. He received a diagnosis of combined postcapillary and precapillary PH secondary to left heart disease on the basis of hemodynamic parameters. After the pulmonary artery denervation procedure was performed, hemodynamic parameters were markedly improved, which resulted in a significant increase in functional capacity.

Hemodynamic, functional, and clinical responses to pulmonary artery denervation in patients with pulmonary arterial hypertension of different causes: phase II results from the Pulmonary Artery Denervation-1 study.

BACKGROUND: The mechanisms underlying pulmonary arterial hypertension (PAH) are multifactorial. The efficacy of pulmonary artery denervation (PADN) for idiopathic PAH treatment has been evaluated. This study aimed to analyze the hemodynamic, functional, and clinical responses to PADN in patients with PAH of different causes. METHODS AND RESULTS: Between April 2012 and April 2014, 66 consecutive patients with a resting mean pulmonary arterial pressure ≥25 mm Hg treated with PADN were prospectively followed up. Target drugs were discontinued after the PADN procedure. Hemodynamic response and 6-minute walk distance were repeatedly measured within the 1 year post PADN follow-up. The clinical end point was the occurrence of PAH-related events at the 1-year follow-up. There were no PADN-related complications. Hemodynamic success (defined as the reduction in mean pulmonary arterial pressure by a minimal 10% post PADN) was achieved in 94% of all patients, with a mean absolute reduction in systolic pulmonary arterial pressure and mean pulmonary arterial pressure within 24 hours of -10 mm Hg and -7 mm Hg, respectively. The average increment in 6-minute walk distance after PADN was 94 m. Worse PAH-related events occurred in 10 patients (15%), mostly driven by the worsening of PAH (12%). There were 8 (12%) all-cause deaths, with 6 (9%) PAH-related deaths. CONCLUSIONS: PADN was safe and feasible for the treatment of PAH. The PADN procedure was associated with significant improvements in hemodynamic function, exercise capacity, and cardiac function and with less frequent PAH-related events and death at 1 year after PADN treatment. Further randomized studies are required to confirm the efficacy of PADN for PAH. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline.

OBJECTIVES: This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms. BACKGROUND: SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear. METHODS: Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution. RESULTS: PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction. CONCLUSIONS: PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.

Two-year clinical outcomes after coronary drug-eluting stent placement in Chinese men and women: a multicenter, prospective registry study.

BACKGROUND: Previous studies have reported a discrepancy in baseline characteristics and outcomes after percutaneous coronary intervention between men and women. However, this finding has never been verified in the Chinese population. The present study analyzed two-year clinical outcomes after placement of coronary drug-eluting stents in Chinese men and women. METHODS: From January 2005 to December 2010, a total of 3804 Chinese patients (2776 men, 1028 women) who underwent drug-eluting stent implantation were studied prospectively. The primary endpoint was the composite major adverse cardiac event (MACE) rate, including myocardial infarction, cardiac death, and target vessel revascularization at two years. Stent thrombosis served as the safety endpoint. Propensity score matching was used to compare the adjusted MACE rate between the two groups. RESULTS: At two-year follow-up, unadjusted rates of myocardial infarction, non-ST segment elevation myocardial infarction, target vessel revascularization, and MACE were significantly different between men (6.84%, 4.6%, 13.1%, and 21.7%, respectively) and women (3.8% [P = 0.001], 2.0% [P < 0.001] 10.3% [P = 0.025], and 16.3% [P < 0.001], respectively). After propensity score matching, there were no significant differences in composite MACE and individual endpoints at two years between the genders. CONCLUSION: Despite all the unfavorable risk factor clustering in women and complex coronary disease in men, the two-year clinical outcomes after coronary stent placement were comparable between Chinese women and men.

Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension).

OBJECTIVES: This study was designed to test the safety and efficacy of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PA hypertension (IPAH) not responding optimally to medical therapy. BACKGROUND: Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main PA. We previously demonstrated that PADN completely abolished the experimentally elevated PA pressure responses to occlusion of the left interlobar PA. METHODS: Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group. PADN was performed at the bifurcation of the main PA, and at the ostial right and left PA. Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed. The primary endpoints were the change of PA pressure (PAP), tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up. RESULTS: Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001). CONCLUSIONS: We report for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy. Further randomized study is required to confirm the efficacy of PADN. (First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension [PADN-1] study; chiCTR-ONC-12002085).

Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo.

AIMS: The study sought to assess the effect of percutaneous pulmonary artery denervation (PADN) on balloon-occlusion-induced acute pulmonary arterial hypertension (PAH) in vivo. The PADN is a minimally invasive and endovascular catheter-based interventional therapy using radiofrequency ablation to abolish the pulmonary arterial baroreceptors to pressure response. METHODS AND RESULTS: To examine the efficacy of balloon-occlusion-induced PAH, twenty Mongolian dogs were randomly assigned to one of two groups: group 1 (left distal pulmonary basal trunk occlusion) and group 2 (left pulmonary interlobar artery occlusion). Afterwards, PADN treatment at the main pulmonary artery bifurcation level with left pulmonary interlobar artery occlusion in all 20 dogs was conducted. Haemodynamic parameters were measured at baseline and during balloon occlusion as well as the PADN treatment at different time points: one, two, three, five, and ten minutes. Before the PADN treatment, most haemodynamic parameters of the pulmonary artery remained unchanged in group 1 with distal pulmonary basal trunk occlusion. However, in group 2 with the occlusion of the left pulmonary interlobar artery, mean pulmonary arterial pressure, mean right ventricular pressure, and pulmonary vessel resistance gradually increased, and mean absolute difference reached peak at five minutes (Δ16.6 mmHg, Δ14.1 mmHg and Δ1,144 dye/s/cm5, respectively; each p<0.01). These haemodynamic parameters at five minutes induced by left pulmonary interlobar artery occlusion were completely abolished with the PADN treatment compared to baseline (Δ0.3 mmHg, Δ0.2 mmHg, and Δ34 dye/s/cm5, respectively). CONCLUSIONS: Balloon occlusion of the left pulmonary interlobar artery led to a significant increase of haemodynamic parameters of the pulmonary artery. The pressure responses were completely abolished by the PADN treatment at the main bifurcation area of the left pulmonary artery.

Identification of 5-HT receptor subtypes enhancing inhibitory transmission in the rat spinal dorsal horn in vitro.

BACKGROUND: 5-hydroxytryptamine (5-HT) is one of the major neurotransmitters widely distributed in the CNS. Several 5-HT receptor subtypes have been identified in the spinal dorsal horn which act on both pre- and postsynaptic sites of excitatory and inhibitory neurons. However, the receptor subtypes and sites of actions as well as underlying mechanism are not clarified rigorously. Several electrophysiological studies have been performed to investigate the effects of 5-HT on excitatory transmission in substantia gelatinosa (SG) of the spinal cord. In the present study, to understand the effects of 5-HT on the inhibitory synaptic transmission and to identify receptor subtypes, the blind whole cell recordings were performed from SG neurons of rat spinal cord slices. RESULTS: Bath applied 5-HT (50 µM) increased the frequency but not amplitudes of spontaneous inhibitory postsynaptic currents (sIPSCs) in 58% of neurons, and both amplitude and frequency in 23% of neurons. The frequencies of GABAergic and glycinergic mIPSCs were both enhanced. TTX (0.5 µM) had no effect on the increasing frequency, while the enhancement of amplitude of IPSCs was eliminated. Evoked-IPSCs (eIPSCs) induced by focal stimulation near the recording neurons in the presence of CNQX and APV were enhanced in amplitude by 5-HT. In the presence of Ba(2+) (1 mM), a potassium channel blocker, 5-HT had no effect on both frequency and amplitude. A 5-HT(2A) receptor agonist, TCB-2 mimicked the 5-HT effect, and ketanserin, an antagonist of 5-HT(2A) receptor, inhibited the effect of 5-HT partially and TCB-2 almost completely. A 5-HT(2C) receptor agonist WAY 161503 mimicked the 5-HT effect and this effect was blocked by a 5-HT(2C) receptor antagonist, N-desmethylclozapine. The amplitudes of sIPSCs were unaffected by 5-HT(2A) or 5-HT(2C) agonists. A 5-HT(3) receptor agonist mCPBG enhanced both amplitude and frequency of sIPSCs. This effect was blocked by a 5-HT(3) receptor antagonist ICS-205,930. The perfusion of 5-HT(2B) receptor agonist had no effect on sIPSCs. CONCLUSIONS: Our results demonstrated that 5-HT modulated the inhibitory transmission in SG by the activation of 5-HT(2A) and 5-HT(2C) receptors subtypes located predominantly at inhibitory interneuron terminals, and 5-HT(3) receptors located at inhibitory interneuron terminals and soma-dendrites, consequently enhanced both frequency and amplitude of IPSCs.

Inhibition of membrane Na+ channels by A type botulinum toxin at femtomolar concentrations in central and peripheral neurons.

Recent studies have demonstrated that the botulinum neurotoxins inhibit the release of acetylcholine, glutamate, GABA, and glycine in central nerve system (CNS) neurons. The Na(+) current (I(Na)) is of major interest because it acts as the trigger for many cellular functions such as transmission, secretion, contraction, and sensation. Thus, these observations raise the possibility that A type neurotoxin might also alter the I(Na) of neuronal excitable membrane. To test our idea, we examined the effects of A type neurotoxins on I(Na) of central and peripheral neurons. The neurotoxins in femtomolar to picomolar concentrations produced substantial decreases of the neuronal I(Na), but interestingly the current inhibition was saturated at about maximum 50% level of control I(Na). The inhibitory pattern in the concentration-response curve for the neurotoxins differed from tetrodotoxin (TTX), local anesthetic, and antiepileptic drugs that completely inhibited I(Na) in a concentration-dependent manner. We concluded that A type neurotoxins inhibited membrane Na(+)-channel activity in CNS neurons and that I(Na) of both TTX-sensitive and -insensitive peripheral dorsal ganglion cells were also inhibited similarly to a maximum 40% of the control by the neurotoxins. The results suggest evidently that A2NTX could be also used as a powerful drug in treating epilepsy and several types of pain.

Inhibition of Membrane Na+ Channels by A Type Botulinum Toxin at Femtomolar Concentrations in Central and Peripheral Neurons.

Recent studies have demonstrated that the botulinum neurotoxins inhibit the release of acetylcholine, glutamate, GABA, and glycine in central nerve system (CNS) neurons. The Na+ current (INa) is of major interest because it acts as the trigger for many cellular functions such as transmission, secretion, contraction, and sensation. Thus, these observations raise the possibility that A type neurotoxin might also alter the INa of neuronal excitable membrane. To test our idea, we examined the effects of A type neurotoxins on INa of central and peripheral neurons. The neurotoxins in femtomolar to picomolar concentrations produced substantial decreases of the neuronal INa, but interestingly the current inhibition was saturated at about maximum 50% level of control INa. The inhibitory pattern in the concentration-response curve for the neurotoxins differed from tetrodotoxin (TTX), local anesthetic, and antiepileptic drugs that completely inhibited INa in a concentration-dependent manner. We concluded that A type neurotoxins inhibited membrane Na+-channel activity in CNS neurons and that INa of both TTX-sensitive and-insensitive peripheral dorsal ganglion cells were also inhibited similarly to a maximum 40% of the control by the neurotoxins. The results suggest evidently that A2NTX could be also used as a powerful drug in treating epilepsy and several types of pain.