Endogenous corticotropin-releasing factor potentiates the excitability of presympathetic neurons in paraventricular nucleus via activation of its receptor 1 in spontaneously hypertensive rats.

It is well established that increased excitability of the presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) during hypertension leads to heightened sympathetic outflow and hypertension. However, the mechanism underlying the overactivation of PVN presympathetic neurons remains unclear. This study aimed to investigate the role of endogenous corticotropin-releasing factor (CRF) on the excitability of presympathetic neurons in PVN using Western blot, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) recording, CRISPR/Cas9 technique and patch-clamp technique. The results showed that CRF protein expression in PVN was significantly upregulated in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. Besides, PVN administration of exogenous CRF significantly increased RSNA, heart rate and ABP in WKY rats. In contrast, knockdown of upregulated CRF in PVN of SHRs inhibited CRF expression, led to membrane potential hyperpolarization, and decreased the frequency of current-evoked firings of PVN presympathetic neurons, which were reversed by incubation of exogenous CRF. Perfusion of rat brain slices with artificial cerebrospinal fluid containing CRF receptor 1 (CRFR1) blocker, NBI-35965, or CRF receptor 2 (CRFR2) blocker, Antisauvagine-30, showed that blocking CRFR1, but not CRFR2, hyperpolarized the membrane potential and inhibited the current-evoked firing of PVN presympathetic neurons in SHRs. However, blocking CRFR1 or CRFR2 did not affect the membrane potential and current-evoked firing of presympathetic neurons in WKY rats. Overall, these findings indicate that increased endogenous CRF release from PVN CRF neurons enhances the excitability of presympathetic neurons via activation of CRFR1 in SHRs.

Sulfur dioxide reduces lipopolysaccharide-induced acute lung injury in rats.

INTRODUCTION: Recent studies suggested that sulfur dioxide (SO2) can be produced endogenously by pulmonary vessels and attenuate acute lung injury (ALI) with vasorelaxant effects. This study was conducted to determine whether SO2 can inhibit lung inflammation and relax pulmonary arteries via inhibition of the mitogen-activated protein kinase (MAPK) pathway. MATERIAL AND METHODS: Forty-eight adult male Sprague Dawley rats (250~300 g) were randomly divided into six treatment groups: control (n = 8), control + SO2 (n = 8), control + L-aspartic acid-ß-hydroxamate (HDX) (n = 8), LPS (n = 8), LPS + SO2 (n = 8) and LPS + HDX (n = 8). RESULTS: Six hours after LPS treatment, rats exhibited elevated pulmonary artery hypertension (PAH), marked pulmonary structure injury with elevated pulmonary myeloperoxidase (MPO) activity and increased expression of intercellular adhesion molecule 1 (ICAM-1) and CD11b, along with decreased pulmonary SO2 production and reduced pulmonary aspartate aminotransferase (AAT) activity. Pretreatment with SO2 saline solution significantly reduced, while HDX (AAT inhibitor) aggravated, the pathogenesis of LPS-induced ALI. Moreover, SO2 saline solution significantly down-regulated expression of Raf-1, MEK-1 and phosphorylated ERK (p-ERK). It also prevented pulmonary hypertension in association with an up-regulated SO2/AAT pathway. However, HDX advanced pulmonary hypertension and inflammatory responses in the lung were associated with a down-regulated SO2/AAT pathway. CONCLUSIONS: Our results suggest that SO2 markedly relieved inflammatory responses, in association with Raf-1, MEK-1 and p-ERK during ALI induced by LPS. The down-regulation of the SO2/AAT pathway may be involved in the mechanism(s) of LPS-induced lung injury.

[Mental health of prostatitis patients in China: A statistical analysis of literature].

OBJECTIVE: To know the basic status of researches on the mental health of prostatitis patients in China by statistical analysis of the literature published in the past two decades and provide some reference for such studies. METHODS: Using the bibliometrics method, we performed statistical analyses on the publication years, journals, and authors of the articles published in the core journals concerning the mental health of prostatitis patients in China as well as on the topics of the identified studies using their titles, key words and abstracts. RESULTS: Totally, 226 related studies were identified, of which 31 (by 29 authors) were published in the Chinese core journals. As for the topics of the included studies, 102 (45.13%) focused on the role and significance of psychotherapy in the treatment of prostatitis, 52 (23.01%) on the correlation of psychological factors with prostatitis, and 23 (10.18%) on the correlation of psychopathic factors with prostatitis complicated by sexual dysfunction. Most of the articles on the mental health of prostatitis patients were published in National Journal of Andrology. CONCLUSIONS: Studies on the mental health of prostatitis patients in China are carried out in varied institutions and different directions but, however, need to be furthered and deepened. For this condition, a comprehensive therapeutic mode of "prevention-communication-treatment" is coming into being, and the methodology for related researches is gradually turning from linear to stereoscopic.

The cardioprotective effect of naringenin against ischemia-reperfusion injury through activation of ATP-sensitive potassium channel in rat.

Naringenin (Nari) has antioxidative and anti-atherosclerosis effects, and activation of ATP-sensitive potassium channel (KATP) can offer cardiac protection. We hypothesized that Nari protects the heart against ischemia-reperfusion (I-R) injury through activation of KATP. Isolated hearts from adult male Sprague-Dawley rats experienced a 30-min global ischemia followed by 60-min reperfusion (120 min for the infarct size determination). The hearts were treated with Nari (NARI); Nari plus glibenclamide (GLI), a non-specific ATP-sensitive potassium channel blocker (NARI+GLI); and Nari plus 5-hydroxy decanoic acid (5-HD), a mitochondrial membrane ATP-sensitive potassium channel blocker (NARI+5-HD). The left ventricular pressure, lactate dehydrogenates (LDH) in coronary effluent, superoxide dismutase (SOD) and malondialdehyde (MDA) in myocardium, and myocardial infarct area were measured. Nari above 2.5 µmol/L improved the recovery of left ventricular function, decreased LDH in coronary effluent, and reduced myocardial infarct area. The SOD activity was increased and MDA was decreased in Nari-treated myocardium. The cardioprotective effect of Nari was canceled by GLI and 5-HD. In conclusion, Nari has a cardioprotective effect against I-R injury, which may be carried out through activating ATP-sensitive potassium channels in both cell and mitochondrial membrane, and enhancing myocardial antioxidant capacity.

The anti-arrhythmic effect of chronic intermittent hypobaric hypoxia in rats with metabolic syndrome induced with fructose.

This study investigated the anti-arrhythmic effects from chronic intermittent hypobaric hypoxia (CIHH) and the cellular mechanisms in rats with metabolic syndrome. Male Sprague-Dawley rats were randomly distributed among the control, fructose-fed (fed with 10% fructose in the drinking water to induce metabolic syndrome), CIHH (42 days of hypobaric hypoxia treatment simulating an altitude of 5000 m a.s.l.: PB = 404 mm Hg, PO2 = 84 mm Hg, 6 h per day), and the CIHH plus fructose (CIHH-F) groups. In anesthetized rats, the arrhythmia score was determined after 30 min of cardiac ischemia followed by 120 min of reperfusion. Action potentials (AP) were recorded from isolated ventricular papillary muscles. The arrhythmia score was much lower in CIHH-F rats than in the fructose-fed rats. Under basic conditions, AP duration (APD) was significantly shortened in fructose-fed rats, but obviously prolonged in CIHH rats compared with that of the control rats. During ischemia, the AP amplitude, the maximal rate of rise of phase 0, APD, and resting potential, were lower in the control, fructose-fed, and CIHH-F groups, but were not changed in the CIHH rats. The lower AP during ischemia did not recover after washout for the fructose-fed rats. In conclusion, CIHH protects the heart against ischemia-reperfusion induced arrhythmia in rats with metabolic syndrome. This effect of CIHH is possibly related to baseline prolongation of the AP and attenuation of AP reduction during ischemia-reperfusion.

Enhanced vasorelaxation effect of endogenous anandamide on thoracic aorta in renal vascular hypertension rats.

Emerging evidence has indicated that anandamide (AEA) is able to stimulate vasorelaxation in both spontaneously hypertensive rats (SHRs) and L-NAME-induced hypertensive rats. Yet it remains unknown whether AEA modulates vasomotion of the aorta in renovascular hypertensive (RVH) rats. The aim of present study is to explore the effect of AEA on the relaxation of thoracic aortas in two-kidney one-clip (2K1C)-induced RVH rats. It is demonstrated that AEA stimulates a pronounced relaxation in the aortas of 2K1C rats compared with sham rats. The enhanced relaxation caused by AEA in aortas from 2K1C rats was diminished in the presence of the cannabinoid receptor-1 (CB1 ) antagonist AM251 and the CB2 receptor antagonist AM630. Likewise, the vasodilation action of AEA was blocked in L-NAME-treated or endothelium-denuded aortas. The Western blot results revealed that the expression of CB1 and CB2 receptors was increased in the 2K1C rat aortas compared with sham rats. The phosphorylation of endothelial nitric oxide synthase (p-eNOS) at the activation site Ser1177 was enhanced in AEA-treated rings from 2K1C rats in both time-dependent and dose-dependent manners. The augmented p-eNOS expression was inhibited by the co-treatment with AM251 or AM630. Taken together, the present study demonstrated that AEA enhanced endothelium-dependent aortic relaxation through activation of both CB1 and CB2 receptors and P-eNOS/NO pathway in 2K1C rats.

Chronic intermittent hypobaric hypoxia ameliorates ischemia/reperfusion-induced calcium overload in heart via Na/Ca2+ exchanger in developing rats.

BACKGROUND/AIMS: Chronic intermittent hypobaric hypoxia (CIHH) protects the heart against ischemia/reperfusion (I/R) injury. This study investigated the calcium homeostasis mechanism and the role of Na(+)/Ca(2+) exchanger (NCX) in the cardiac protective effect of CIHH in developing rats. METHODS: Neonatal male rats received CIHH treatment or no treatment (control) in a hypobaric chamber simulating 3000-meter altitude for 42 days. The left ventricular function of isolated hearts was evaluated after 30 minutes of ischemia and 60 minutes of reperfusion. Myocardial infarct size, intracellular Ca(2+) concentration ([Ca(2+)]i), Na(+)-Ca(2+) exchanger currents (I(Na/Ca)) in ventricular myocytes, and NCX1 protein level in the sarcolemmal membrane were determined. RESULTS: The recovery of cardiac function after I/R was improved, with the myocardial infarct size reduced, in CIHH rats compared with control rats (p<0.05). These effects were attenuated by Bay K8644, an L-type Ca(2+) channel agonist, or ryanodine, a sarcoplasmic reticulum Ca(2+) channel receptor activator. Furthermore, the increases in [Ca(2+)]i during I/R were blunted in CIHH rats, but this effect was abolished by Bay K8644 or chelerythrine, a protein kinase C (PKC) inhibitor. The I(Na/Ca) was decreased and the reversal potential of INa/Ca was shifted toward negative potential during simulated ischemia in the control cardiomyocytes (p<0.05). The inhibition of NCX1 protein expression during I/R was smaller in the CIHH rats than in the control rats (p<0.05). CONCLUSION: These data suggest that CIHH protects developing rat hearts during I/R by enhancing the resistance against calcium overload and by preserving normal I(Na/Ca) and NCX1 protein. PKC activation might be involved in this protective process of CIHH.

Inhibition of carotid sinus baroreflex in neonatal rats exposed to chronic intermittent hypobaric hypoxia.

Chronic intermittent hypobaric hypoxia (CIHH) facilitates carotid sinus baroreflex (CSB) in adult rats, but the effect of CIHH on CSB in young rats is not known. The purpose of present study was to investigate the effect of CIHH on CSB in the young rat treated with CIHH from neonatal age, and the role of nitric oxide (NO) and Ca²âº in the effect of CIHH. Neonatal male Sprague-Dawley rats were randomly divided into three groups: 42-day CIHH treatment group (CIHH42), 56-day CIHH treatment group (CIHH56), and an age-matched control group (control). CIHH neonatal rats with the maternal rats were exposed to a simulated high-altitude hypoxia in a hypobaric chamber mimicking 5,000-m altitude (O2 at 11.1%) for 42 or 56 days, 6 h per day, respectively. Isolated carotid sinus perfusion technique was used to test CSB of the rats. After 42-day and 56-day CIHH exposure, the CSB of the rats was inhibited significantly, manifesting as decrease of peak slope (PS) and reflex decrease (RD), and increase of threshold pressure (TP), equilibrium pressure (EP) and saturation pressure (SP). This inhibitory effect was canceled by L-type calcium channel activator Bay K 8644, but not by nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The data showed that CIHH inhibited CSB in anesthetized young rats through blocking L-type calcium channels in carotid sinus baroreceptor.

Opioid receptors mediate enhancement of ACh-induced aorta relaxation by chronic intermittent hypobaric hypoxia.

The present study was designed to investigate the role of opioid receptors in the vasorelaxation effect of chronic intermittent hypobaric hypoxia (CIHH) in thoracic aorta rings and the underlying mechanism in rats. Adult male Sprague-Dawley (SD) rats were randomly divided into 2 groups: CIHH treatment group and control group. The rats in CIHH group were exposed to hypoxia in a hypobaric chamber (simulated 5 000 m altitude) for 28 days, 6 h per day. The rats in control group were kept in the same environment as CIHH rats except no hypoxia exposure. The relaxation of thoracic aorta rings was recorded by organ bath perfusion technique, and expression of opioid receptors was measured by Western blot. Results are shown as follows. (1) The acetylcholine (ACh)-induced endothelium-dependent relaxation of thoracic aorta in CIHH rats was increased obviously in a concentration-dependent manner compared with that in control rats (P < 0.05). (2) This enhancement of ACh-induced relaxation in CIHH rats was abolished by naloxone, a non-specific opioid receptor blocker (P < 0.05). (3) The expressions of δ, µ and κ opioid receptors in thoracic aorta of CIHH rats were up-regulated compared with those in control rats (P < 0.05). (4) The enhancement of CIHH on relaxation of thoracic aorta was reversed by glibenclamide, an ATP-sensitive potassium channel (KATP) blocker (P < 0.05). The results suggest that opioid receptors are involved in CIHH-enhanced ACh-induced vasorelaxation of thoracic aorta through KATP channel pathways.

Effects of anandamide on potassium channels in rat ventricular myocytes: a suppression of I(to) and augmentation of K(ATP) channels.

Anandamide is an endocannabinoid that has antiarrhythmic effects through inhibition of L-type Ca(2+) channels in cardiomyocytes. In this study, we investigated the electrophysiological effects of anandamide on K(+) channels in rat ventricular myocytes. Whole cell patch-clamp technique was used to record K(+) currents, including transient outward potassium current (I(to)), steady-state outward potassium current (I(ss)), inward rectifier potassium current (I(K1)), and ATP-sensitive potassium current (I(KATP)) in isolated rat cardiac ventricular myocytes. Anandamide decreased I(to) while increasing I(KATP) in a concentration-dependent manner but had no effect on I(ss) and I(K1) in isolated ventricular myocytes. Furthermore, anandamide shifted steady-state inactivation curve of I(to) to the left and shifted the recovery curve of I(to) to the right. However, neither cannabinoid 1 (CB(1)) receptor antagonist AM251 nor CB(2) receptor antagonist AM630 eliminated the inhibitory effect of anandamide on I(to). In addition, blockade of CB(2) receptors, but not CB(1) receptors, eliminated the augmentation effect of anandamide on I(KATP). These data suggest that anandamide suppresses I(to) through a non-CB(1) and non-CB(2) receptor-mediated pathway while augmenting I(KATP) through CB(2) receptors in ventricular myocytes.

Sulfur dioxide attenuates LPS-induced acute lung injury via enhancing polymorphonuclear neutrophil apoptosis.

AIM: We speculated that the enhanced apoptosis of polymorphonuclear neutrophil (PMN) might be responsible for the inhibition of PMN infiltration in the lung. This study was designed to investigate the effects of sulfur dioxide (SO(2)) on PMN apoptosis in vivo and in vitro, which may mediate the protective action of SO(2) on pulmonary diseases. METHODS: Acute lung injury (ALI) was induced by intratracheally instillation of lipopolysaccharide (LPS, 100 µg/100 g, in 200 µL saline) in adult male SD rats. SO(2) solution (25 µmol/kg) was administered intraperitoneally 30 min before LPS treatment. The rats were killed 6 h after LPS treatment. Lung tissues were collected for histopathologic study and SO(2) concentration assay. Bronchoalveolar lavage fluid (BALF) was collected for the measurement of PMN apoptosis. For in vitro experiments, rat peripheral blood PMNs were cultured and treated with LPS (30 mg/L) and SO(2) (10, 20 and 30 µmol/L) for 6 h, and apoptosis-related protein expression was detected by Western blotting, and apoptosis rate was measured with flow cytometry. RESULTS: LPS treatment significantly reduced the SO(2) concentrations in the lung tissue and peripheral blood, as compared with the control group. Pretreatment with SO(2) prevented LPS-induced reduction of the SO(2) concentration in the lung tissue and peripheral blood. LPS treatment significantly reduced PMN apoptosis both in vivo and in vitro, which could be prevented by the pretreatment with SO(2). The protein levels of Caspase-3 and Bax was significantly increased, but Bcl-2 was decreased by the pretreatment with SO(2), as compared with LPS administration alone. CONCLUSION: SO(2) plays an important role as the modulator of PMN apoptosis during LPS-induced ALI, which might be one of the mechanisms underlying the protective action of SO(2) on pulmonary diseases.

CIHH protects the heart against left ventricular remodelling and myocardial fibrosis by balancing the renin-angiotensin system in SHR.

AIM: The aim of our study was to clarify the cardioprotection of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in spontaneously hypertensive rats (SHR). MAIN METHODS: Adult male rats were divided into normal blood pressure Wistar-Kyoto rats (WKY) control (WKY-CON), WKY rats with CIHH treatment (WKY-CIHH), SHR control (SHR-CON) and SHR with CIHH treatment (SHR-CIHH) groups. SHR-CIHH and WKY-CIHH rats were subjected to hypobaric hypoxia simulating 4000-m altitude for 35 days, 5 h per day. Arterial blood pressure and cardiac function parameters, including ejection fraction, fractional shortening and left ventricular (LV) wall thickness, were evaluated. Cardiac pathomorphology and myocardial fibrosis were determined. The expression of angiotensin-converting enzyme (ACE), ACE2, Ang II, Ang1-7, AT1 receptor, Mas receptor, IL-6, TNF-α，IL-10, SOD and MDA were assayed in myocardium. KEY FINDINGS: CIHH significantly decreased arterial blood pressure, alleviated LV hypertrophy, and improved cardiovascular function in SHR (P < 0.05-0.01). Also, CIHH protected SHR heart against morphological changes and fibrosis. In addition, CIHH significantly down-regulated the ACE/Ang II/AT1 receptor axis and up-regulated the ACE2/Ang1-7/Mas axis of renin-angiotensin system (RAS) in SHR (P < 0.05-0.01). CIHH significantly reduced IL-6, TNF-α, and MDA levels, but increased IL-10 and SOD in SHR myocardium (P < 0.05-0.01). SIGNIFICANCE: The CIHH treatment protected the heart of SHR against LV remodelling and myocardial fibrosis, which might be carried out through a balance in the ACE/Ang II/AT1 axis and the ACE2/Ang1-7/Mas axis of the RAS to reduce inflammation, and inhibit oxidative stress.

Chronic intermittent hypobaric hypoxia decreases beta-adrenoceptor activity in right ventricular papillary muscle.

Chronic intermittent hypobaric hypoxia (CIHH) has an effective cardiac protection against ischemia-reperfusion injury. However, the underlying mechanisms are not fully known. It has been shown that blockade of beta-adrenergic receptor exerts anti-arrhythmic action and improves cardiac remodeling in ischemic myocardium. Thus we determined the influence of CIHH on beta-adrenergic receptor activity in right ventricular papillary muscle of rats. We found that the action potential duration in right ventricular papillary muscle was significantly longer in CIHH rats than in control rats. Activation of beta-adrenergic receptor with dl-isoproterenol dose-dependently increased action potential duration and the contractility in right ventricular papillary muscle. In CIHH rats, the prolonged effect of dl-isoproterenol on action potential duration and the positive inotropic effect were significantly decreased compared with that in control rats. Furthermore, radioligand-binding experiments revealed that the density and affinity of beta-adrenergic receptor in right ventricular myocardium was significantly lower in CIHH rats. In addition, Western blot analysis revealed that the membrane-bound G protein G(s)alpha expression level in cardiac myocardium was significantly lower in CIHH rats than that in control rats. Collectively, these data suggest that CIHH suppresses beta-adrenergic receptor action in right ventricular papillary muscle through decreasing receptor density and affinity, as well as membrane-bound G(s)alpha. This mechanism may be involved in the cardiac protective effect of CIHH.

Polydatin attenuates ischemia/reperfusion-induced apoptosis in myocardium of the rat.

The aim of the present study was to investigate the effect of polydatin on apoptosis induced by ischemia/reperfusion (I/R) in rat myocardium and to explore the underlying mechanism. Adult male Sprague-Dawley (SD) rats were randomly divided into control, I/R and polydatin (50 mumol/L) groups. On the Langendorff apparatus, isolated rat heart was subjected to 30-min global ischemia followed by 60-min reperfusion. TUNEL labeling and flow cytometric techniques were used for the measurement of apoptosis and the expression of Bcl-2 and Bax protein in cardiomyocytes of rat. The results showed: (1) Compared with those in the control group, the number of TUNEL-positive cells and apoptosis rate were increased in I/R group; (2) Compared with that in the I/R group, the number of TUNEL-positive cells was significantly decreased in the polydatin group [(18.1+/-4.0)% vs (35.1+/-5.4)%, P<0.01]; (3) Apoptosis rate assayed by flow cytometry in I/R group was significantly higher than that in polydatin group [(15.43+/-4.55)% vs (8.66+/-3.18)%, P<0.01]; (4) Expression level of Bax protein was higher in I/R group than that in polydatin group (P<0.05), while the level of Bcl-2 protein and Bcl-2/Bax ratio were higher in polydatin group than those in I/R group (P<0.05, P<0.01), respectively. The results obtained suggest that polydatin exerts an inhibitory effect on I/R-induced apoptosis through increasing Bcl-2 protein expression and decreasing Bax protein expression in myocardium of the rat.

Chronic Intermittent Hypobaric Hypoxia Ameliorates Renal Vascular Hypertension Through Up-regulating NOS in Nucleus Tractus Solitarii.

Chronic intermittent hypobaric hypoxia (CIHH) is known to have an anti-hypertensive effect, which might be related to modulation of the baroreflex in rats with renal vascular hypertension (RVH). In this study, RVH was induced by the 2-kidney-1-clip method (2K1C) in adult male Sprague-Dawley rats. The rats were then treated with hypobaric hypoxia simulating 5000 m altitude for 6 h/day for 28 days. The arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured before and after microinjection of L-arginine into the nucleus tractus solitarii (NTS) in anesthetized rats. Evoked excitatory postsynaptic currents (eEPSCs) and spontaneous EPSCs (sEPSCs) were recorded in anterogradely-labeled NTS neurons receiving baroreceptor afferents. We measured the protein expression of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS) in the NTS. The results showed that the ABP in RVH rats was significantly lower after CIHH treatment. The inhibition of ABP, HR, and RSNA induced by L-arginine was less in RVH rats than in sham rats, and greater in the CIHH-treated RVH rats than the untreated RVH rats. The eEPSC amplitude in NTS neurons receiving baroreceptor afferents was lower in the RVH rats than in the sham rats and recovered after CIHH. The protein expression of nNOS and eNOS in the NTS was lower in the RVH rats than in the sham rats and this decrease was reversed by CIHH. In short, CIHH treatment decreases ABP in RVH rats via up-regulating NOS expression in the NTS.

Impaired Hypothalamic Regulation of Sympathetic Outflow in Primary Hypertension.

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.

Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.

Background Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 ( OXR 1) is upregulated in the paraventricular nucleus ( PVN ) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats ( OZR s). We hypothesized that silencing OXR 1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZR s. Methods and Results An adeno-associated virus ( AAV ) vector containing a short hairpin RNA (sh RNA ) targeting rat OXR 1 was designed to silence OXR 1 expression in the PVN . The AAV - OXR 1-sh RNA or scrambled sh RNA was injected into the PVN in OZR s. The arterial blood pressure in free-moving OZR s was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free-moving OZR s treated with AAV - OXR 1-sh RNA had markedly lower OXR 1 expression and lower mean arterial blood pressure, heart rate, and ratio of low- to high-frequency components of heart rate variability compared with OZR s treated with scrambled sh RNA . Furthermore, AAV - OXR 1-sh RNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN . In addition, treatment with AAV - OXR 1-sh RNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZR s and attenuated the excitatory effect of orexin A on the firing activity of these neurons. Conclusions These data suggest that chronic downregulation of OXR 1 expression in the PVN reduces sympathetic vasomotor tone in obesity-related hypertension.

Poly[tris-(µ(3)-5-amino-isophthalato)diaqua-dicerium(III)].

In the title complex, [Ce(2)(C(8)H(5)NO(4))(3)(H(2)O)(2)](n), each Ce ion is in nine-coordinated environment. Eight O atoms from six ligands participate in coordination, in addition to one O atom from a water mol-ecule. Both carboxyl-ate groups from the ligands chelate the Ce atoms, forming two four-membered rings. The 5-amino-isophthalate ligands also bridge the Ce centers, forming a two-dimensional network, and O-H⋯O and N-H⋯O hydrogen bonds complete the structure.

Chronic intermittent hypobaric hypoxia ameliorates diabetic nephropathy through enhancing HIF1 signaling in rats.

AIM: Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had anti-diabetes effect. The present study was to explore the renal protective effect of CIHH in diabetic rats. METHODS: Sprague-Dawley rats were randomly divided into three groups: diabetes mellitus group (DM, induced by high-fat diet combined with low-dose streptozotocin), diabetes plus CIHH treatment group (DM+CIHH, simulated 5000-m altitude, 6h per day for 28days, after diabetes model confirmed) and control group (CON). Systolic arterial blood pressure (SAP), blood biochemicals, urinary albumin, and histopathology of kidney were determined. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, protein levels of hypoxia induced factors (HIFs) and transforming growth factor ß1 (TGF-ß1) in kidney were assayed. RESULTS: The increased SAP, urinary albumin, hyperplasia of glomerular, fibrosis in mesangial and glomerular, and abnormal lipid metabolism in diabetic rats were ameliorated by CIHH treatment. And decreased superoxide dismutase (SOD) activity and increased malondialdehyde (MDA) level in diabetic kidney were reversed in CIHH-treated DM rats. In addition up-regulated TGF-ß1 and down-regulated HIF1α in diabetic kidney returned back to normal level in CIHH-treated DM rats. CONCLUSIONS: These data demonstrated for the first time that CIHH had protective effects against the early stage damage of diabetic nephropathy through activating HIF1 signaling, improving anti-oxidation and inhibiting TGF-ß1 signaling in diabetic rats.

Anti-diabetes effect of chronic intermittent hypobaric hypoxia through improving liver insulin resistance in diabetic rats.

AIM: Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. The present study was to investigate the anti-diabetes effect of CIHH in type-2 diabetic rats for the first time. MAIN METHODS: Sprague-Dawley rats were randomly divided into 4 groups: control group (CON), diabetes mellitus group (DM, induced by high-fat diet combined with low-dose streptozotocin), CIHH treatment group (CIHH, simulated 5000-m altitude, 6h per day for 28 days), and diabetes mellitus plus CIHH treatment group (DM+CIHH). Histopathology of liver, systolic arterial blood pressure (SAP), blood biochemicals, glucose and insulin tolerance were determined. The expression of proteins associated with insulin signaling pathway as well as hypoxia induced factors were assayed. KEY FINDINGS: Diabetic rats showed impaired glucose tolerance, dyslipidemia, hepatic steatosis and hepatic insulin resistance in addition to increased SAP. However, SAP, serum triglyceride and cholesterol were decreased, and hepatic steatosis and insulin resistance were improved in DM+CIHH rats. Furthermore, the protein expression of glucokinase (GCK), insulin receptor substrates (IRS-1 and IRS-2), and HIF1α were increased, while the expression of phosphoenolpyruvate carboxykinase (PEPCK), was markedly reduced in DM+CIHH rats. SIGNIFICANCE: We conclude that CIHH treatment has anti-diabetes effects through ameliorating insulin resistance via hepatic HIF-insulin signaling pathway in type-2 diabetic rats.