Effects of hypothalamic paraventricular nuclei on apoptosis and proliferation of gastric mucosal cells induced by ischemia/reperfusion in rats

AIM: To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei (PVN) on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion (I/R) injury. METHODS: For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals' GI/R injury model was established by clamping the celiac artery for 30min and allowing reperfusing the artery for 30min, 1h, 3h or 6h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times. RESULTS: The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, 1h and 3h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation. CONCLUSION: Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.

Inhibition of central sympathetic nervous tone improves cardiomyocyte contraction by increasing the response of beta 2-adrenergic receptor in aged rats

In the present study,selective β1-adrenergic receptor antagonist CGP20712A and selective β2-adrenergic receptor antagonist ICI 118551 were administered to isolated cardiomyocytes from young （4-6 months）,aged （18-20 months）,and clonidine-pretreated aged （18-20 months） Sprague-Dawley rats.Cardiomyocyte contraction amplitude was measured to assess cardiomyocyte response to the β-adrenergic receptor agonist,isoprenaline.CGP20712A reduced cardiomyocyte contraction amplitude in young and aged groups and significantly reduced contraction amplitude in cells from young rats.ICI 118551 had no effect on cardiomyocyte contraction amplitude in young rats,but significantly decreased contraction amplitude in the aged groups,in particular in the clonidine-pretreated aged rats.Results demonstrated that reduced central sympathetic tone improved cardiomyocyte contraction in aged rats by improving the response of β2-adrenergic receptor to isoprenaline.

Role of mitogen-activated protein kinases in the regulation of paraventricular nucleus to gastric ischemia-reperfusion injuries

Background We investigated the role in electrical stimulations of paraventricular nucleus （PVN） on gastric mucosal cells and the activity of mitogen-activated protein kinases （MAPKs） family members induced by gastric ischemia-reperfusion （GI-R）. And we elucidated the molecular mechanisms of the protection of PVN from GI-R injuries. Methods Sprague-Dawley rats were divided randomly into 4 groups： Group I, the sham-operated GI-R control group; Group II, the sham-operated electrical stimulations to PVN ＋ sham-operated GI-R control group; Group III, the GI-R group; and Group IV, the electrical stimulations to PVN ＋ GI-R group. In all of the experiments, the PVN was stimulated prior to the induction of GI-R. The GI-R model was established by clamping the celiac artery for 30 minutes to induce ischemia and then was released to allow reperfusion for 30 minutes, 1 hour, 3 hours and 6 hours, respectively. The gastric mucosal cellular apoptosis, proliferation, and the expression and activity of MAPKs protein were observed by immunohistochemistry and Western blotting, respectively. Results Compared with the GI-R group, the application of electrical stimulations in the PVN significantly depressed gastric mucosal cellular apoptosis and enhanced gastric mucosal cellular proliferation following the 30-minute, 1-hour and 3-hour intervals of reperfusion; it also promoted the activation of p-ERK during the early phase of reperfusion but inhibited the activation of p-JNK1/2 and p-p38 following the 30-minute, 1-hour and 3-hour intervals of reperfusion. Conclusions The protection of PVN against GI-R injuries may attribute to the inhibition of apoptosis and the promotion of the proliferation of gastric mucosal cells during GI-R. This protective effect is mediated by activating the ERK pathway and depressing the JNK, the JNK. p38 MAPK oathwavs of the oastric mucosal cells.

Protective effect of heme oxygenase-1 on lung injury induced by erythrocyte instillation in rats

Background Intratracheal instillation of blood induces self-repaired acute lung injury. However, the mechanism of repair has been unclear. Heme-oxygenase （HO）-1, which catalyzes heme breakdown, acts as an inducible defense against oxidative stress and plays an important role in inflammation. The objective of this study was to test the role of HO-1 in lung injury caused by intratracheal instillation of red cells. Methods Forty healthy, male Sprague-Dawley rats were randomly divided into five groups： normal group, saline group, erythrocyte group, erythrocyte＋zinc-protoporphyrin （ZnPP, HO-1 inhibitor） group and saline＋ZnPP group. At 2 days after intratracheal instillation of red cells, lung tissues and lavage samples were isolated for biochemical determinations and histological measurements. Results Histological analysis revealed that administration of ZnPP worsened the acute lung injury induced by instilled erythrocytes. HO-1 was over-expressed in the erythrocyte group and in the erythrocyte ＋ ZnPP group. Compared with the erythrocyte ＋ ZnPP group, the levels of total protein, lactate dehydrogenase and tumor necrosis factor-a in the lavage were lower （P 〈0.01）, while the level of interleukin-10 was higher in the erythrocyte group （P 〈0.01）. Conclusion HO-1 protects against erythrocyte-induced inflammatory injury in lung.

Effect of oxytocin on gastric ischemia-reperfusion injury in rats

The effect of peripherally administered oxytocin(OT)on gastric ischemia-reperfusion injury(GI-RI)and its possible mechanism were investigated.The Sprague-Dawley(SD)rats were randomly divided into different treatment groups(n=6).The animal GI-RI model was established by clamping the celiac artery for 30 min to induce ischemia and then released to allow reperfusion for 1 h,and the degree of GI-RI was assessed by scoring the gastric mucosal damage index(GMDI),the gastric fluid output,gastric fluid output,gastric acidity were measured and the surgical preparations of vagotomy and sympathectomy were used to investigate the possible mechanism of OT on GI-RI.The results were as follows.Compared with the control group(NS plus GI-R only,GMDI 121.33P10.40,n=6),the intra peritoneal(ip)administration of oxytocin(20,100μg/0.5 mL)obviously attenuated GI-RI(P<0.05),GMDI were 82.33P14.26,53.5P5.58 respectively(n=6);the gastric fluid output and the gastric acidity(evaluated by pH)of the control group were(430.17P87.36)μL,1.55P0.25(n=6),and those of the OT group were(102.45P48.00)μL,2.65P0.40(n=6)res pectively;differences had statistical significance(P<0.01).The effect of oxytocin was reversed by atosiban,a selective oxytocin receptor antagonist.The GMDI of the group given atosiban 10 min before OT was 138.17P24.06(n=6),which had no significant difference with the control group.Oxytocin further attenuated GI-RI after vagotomy and sympathectomy(GMDI 6.83P8.89,29.67P5.54,n=6),compared with the GI-R group and the oxytocin group(P<0.01).These results indicated that the oxytocin could significantly protect gastric mucosal against injury induced by ischemia-reperfusion,and the oxytocin receptor was involved.This effect of oxytocin may be mediated through the vagus and sympathetic nerve,and then lead to the reduction of gastric juice output and the depression of gastric acidity.

Intermedin in Paraventricular Nucleus Attenuates Sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension

Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.