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 ...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.展开更多
Background:Long-term exposure to constant light is becoming a prevalent lifestyle that is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder.Intestinal stem cells(ISCs)are an ...Background:Long-term exposure to constant light is becoming a prevalent lifestyle that is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder.Intestinal stem cells(ISCs)are an important population of cells that maintain homeostasis and function of intestinal tissues.The purpose of this study was to identify the effects of long-term constant light exposure on gastrointestinal function and the potential mechanisms of sympathetic activity on ISC.Methods:Rats housed in a 24 h constant light chamber for 4 weeks were used as the constant light exposure animal model.Hematoxylin-eosin staining and immunohistochemical examination were used to determine the pathological changes of the intestine.Propranolol(ARs inhibitor;40 mg/kg/day),metoprolol(ADRβ1 inhibitor;50 mg/kg/day),and Box5(Wnt5a inhibitor;2μg/day)were used to examine the effect of sympathoexcitation and Wnt signaling pathway on constant light-induced gastrointestinal disorders.Results:We found that 4 weeks of constant light exposure in rats resulted in a decrease in the number of ISC and an increase in sympathetic activity.Intestinal β1-adrenoceptor expression and reactive oxygen species(ROS)were significantly increased,but Wnt5a expression decreased in the continuous light-exposed rats.Similarly,we found that administration of the β1-adrenoceptor antagonist metoprolol for 4 weeks attenuated the effects of continuous light exposure on the intestine,which was rescued by the reintroduction of Wnt5a.Conclusion:Taken together,these data indicate that sympathoexcitation is critical for disruption of ISC under constant light exposure,suggesting that targeting β1-adrenoceptor/oxidative stress/Wnt5a axis may be a potential strategy for ISC disruption induced by prolonged sustained light exposure,providing a new direction for IBS treatment.展开更多
Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rat...Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.展开更多
基金supported by the National Natural Science Foundation of China(81000106 and81470539)
文摘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.
基金supported by the National Natural Science Foundation of China[Nos.32100905 and 82270467]China Postdoctoral Science Foundation[No.2022M713841].
文摘Background:Long-term exposure to constant light is becoming a prevalent lifestyle that is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder.Intestinal stem cells(ISCs)are an important population of cells that maintain homeostasis and function of intestinal tissues.The purpose of this study was to identify the effects of long-term constant light exposure on gastrointestinal function and the potential mechanisms of sympathetic activity on ISC.Methods:Rats housed in a 24 h constant light chamber for 4 weeks were used as the constant light exposure animal model.Hematoxylin-eosin staining and immunohistochemical examination were used to determine the pathological changes of the intestine.Propranolol(ARs inhibitor;40 mg/kg/day),metoprolol(ADRβ1 inhibitor;50 mg/kg/day),and Box5(Wnt5a inhibitor;2μg/day)were used to examine the effect of sympathoexcitation and Wnt signaling pathway on constant light-induced gastrointestinal disorders.Results:We found that 4 weeks of constant light exposure in rats resulted in a decrease in the number of ISC and an increase in sympathetic activity.Intestinal β1-adrenoceptor expression and reactive oxygen species(ROS)were significantly increased,but Wnt5a expression decreased in the continuous light-exposed rats.Similarly,we found that administration of the β1-adrenoceptor antagonist metoprolol for 4 weeks attenuated the effects of continuous light exposure on the intestine,which was rescued by the reintroduction of Wnt5a.Conclusion:Taken together,these data indicate that sympathoexcitation is critical for disruption of ISC under constant light exposure,suggesting that targeting β1-adrenoceptor/oxidative stress/Wnt5a axis may be a potential strategy for ISC disruption induced by prolonged sustained light exposure,providing a new direction for IBS treatment.
基金supported by the National Natural Science Foundation of China(81600333,81770426,81800372,91439120,and 91639105)the Postdoctoral Science Foundation of China(2016M602835,2017M620457)the Postdoctoral Science Foundation of Shaanxi Province,China(2016BSHEDZZ91)
文摘Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.
