Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especi...Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.Conclusion It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance,cardiac dysfunction,and remodeling possibly via inactivating NLRP3 inflammasome.展开更多
Background Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular ...Background Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated. Methods Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups： angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, 13 adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed. Results The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats. Conclusions Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.展开更多
Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following ...Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups： sham （with the left anterior descending coronary artery exposed but without ligation）, MI （left anterior descending coronary artery ligation）, and MI plus NRG-1 （left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 （10 lag/kg, once daily for 7 days））. At 4 weeks after MI, echocardi- ography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening, mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 （neuronal specific pro- tein）, nerve growth factor, choline acetyltransferase （vagus nerve marker）, and vesicular acetylcholine transporter （cardiac vagal nerve fiber marker） in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG- 1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury.展开更多
目的研究心肌梗死(简称心梗)后大鼠心脏Sema 3A及其受体neuropilin-1(NP-1)和电生理的变化。方法50只大鼠随机分为心梗组(n=30)和假手术组(n=20)。用结扎左冠状动脉前降支的方法制备大鼠心梗模型。8周后,测定大鼠梗死周边区心室颤动(简...目的研究心肌梗死(简称心梗)后大鼠心脏Sema 3A及其受体neuropilin-1(NP-1)和电生理的变化。方法50只大鼠随机分为心梗组(n=30)和假手术组(n=20)。用结扎左冠状动脉前降支的方法制备大鼠心梗模型。8周后,测定大鼠梗死周边区心室颤动(简称室颤)阈值和有效不应期;应用蛋白质印迹法和逆转录聚合酶链反应技术检测梗死周边区Sema 3A及其受体的蛋白和mRNA的表达。结果心梗后8周,大鼠梗死周边区心肌室颤阈值降低(7.1±4.1 V vs 13.0±2.1 V,P<0.05),有效不应期延长(76±9 ms vs 61±8 ms,P<0.05)。大鼠心脏梗死周边区Sema 3A蛋白和mRNA的相对值都显著的降低。但是,Sema 3A的受体蛋白和mRNA的相对值都明显的升高。结论心梗后大鼠心脏梗死周边区发生电重构;梗死周边区Sema 3A明显减少,Sema 3A的受体明显增加。展开更多
基金supported by the National Natural Science Foundation of China(No.81370282).
文摘Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.Conclusion It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance,cardiac dysfunction,and remodeling possibly via inactivating NLRP3 inflammasome.
基金This study was supported by grants trom Natural Science Foundation of China （No. 30971223） and Nantong Society Development Project （No. 2010008）.
文摘Background Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated. Methods Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups： angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, 13 adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed. Results The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats. Conclusions Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.
基金supported by a grant from the National Key Basic Research Development Program,the“973”Program,No.2012CB518604the National Natural Science Foundation of China,No.81260052+1 种基金the Natural Science Foundation of Hubei Province,No.2014CKB497,2014BKB075,and 2015BKA339the Natural Science Foundation of Henan Province of China,No.201602262
文摘Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction （MI）. Increasing evidence indicates that neuregulin-1 （NRG-1） improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups： sham （with the left anterior descending coronary artery exposed but without ligation）, MI （left anterior descending coronary artery ligation）, and MI plus NRG-1 （left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 （10 lag/kg, once daily for 7 days））. At 4 weeks after MI, echocardi- ography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening, mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 （neuronal specific pro- tein）, nerve growth factor, choline acetyltransferase （vagus nerve marker）, and vesicular acetylcholine transporter （cardiac vagal nerve fiber marker） in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG- 1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury.
文摘目的研究心肌梗死(简称心梗)后大鼠心脏Sema 3A及其受体neuropilin-1(NP-1)和电生理的变化。方法50只大鼠随机分为心梗组(n=30)和假手术组(n=20)。用结扎左冠状动脉前降支的方法制备大鼠心梗模型。8周后,测定大鼠梗死周边区心室颤动(简称室颤)阈值和有效不应期;应用蛋白质印迹法和逆转录聚合酶链反应技术检测梗死周边区Sema 3A及其受体的蛋白和mRNA的表达。结果心梗后8周,大鼠梗死周边区心肌室颤阈值降低(7.1±4.1 V vs 13.0±2.1 V,P<0.05),有效不应期延长(76±9 ms vs 61±8 ms,P<0.05)。大鼠心脏梗死周边区Sema 3A蛋白和mRNA的相对值都显著的降低。但是,Sema 3A的受体蛋白和mRNA的相对值都明显的升高。结论心梗后大鼠心脏梗死周边区发生电重构;梗死周边区Sema 3A明显减少,Sema 3A的受体明显增加。
