血管内皮舒张因子的作用及其对疾病发生发展的影响

自从1980年Furchgott等发现内皮依赖性舒张作用以来,血管内皮就被认为是调节血管平滑肌张力的重要功能单位.血管内皮细胞可通过释放前列环素(PGI_2)、内皮舒张因子(EDRF)、内皮超极化因子(EDHF)、内皮收缩因子(EDCF)等血管活性物质来调节血管平滑肌张力.其中,血管内皮舒张因子具有舒张血管平滑肌和抑制血小板活性的作用,它能介导许多内源性血管活性物质的舒张     

一氧化氮在肺部疾病中的应用研究进展

一氧化氮（简称NO）兼有第二信使物质和神经递质的功能，广泛参与生理功能的调节，对血管及气道平滑肌张力具有调节作用，作为一种血管及支气管扩张剂运用于临床为某些肺部疾病的认识及治疗开辟了新思路。1980年，Furchgott等首先发现乙酸胆碱松弛平滑肌的作用依赖于内皮细胞的完整性，内皮细胞受刺激后，可以产生一种舒张因子，促进血管的舒张，并定名为血管内皮衍化舒张因子（EndothelialderlredrelaxingfactorEDRF）（1）。直到1987年Palmor和Jgnarro等揭示内源性一氧化氮（nitricoxide）是一种内皮衍生舒张因子（EDRF），它具有舒…     

内源性H2S与中枢神经系统的关系

硫化氢(H2S)因被描述为特征性的“臭鸡蛋味”而闻名,并一直被认为是毒性气体,其第一个生理作用的证据是1989年获得的[1],A be等[2]1996年首次通过实验证明内源性H2S可能作为一种神经活性物质而存在。自20世纪90年代以来的研究发现,内源性产生的H2S存在于哺乳动物的多种组织、器     

硫化氢与心血管疾病研究进展

<正>随着生命科学的飞速发展,气体小分子在生命活动中的意义越来越受到高度关注。硫化氢(Hydrogen sulfide,H2S)作为第三种气体信号分子,其在心血管系统的研究价值也倍受关注。它具有重要的生理意义。在心血管系统,它有舒张血管、降低血压、抑制血管平滑肌细胞增殖以及减轻血管重构等多种生物学效应。最近研究证实,内源性H2S直接作用于     

内源性一氧化氮合酶抑制剂与血管内皮功能

在生理和应激状态下,内皮细胞可产生多种生物活性物质,它们在调节血管张力、影响平滑肌细胞增殖、单核细胞粘附、血小板聚集和血栓形成以及维持正常的血管结构和功能等方面起着重要的作用,其中内皮衍生的一氧化氮(nitric oxide,NO)是已知最重要的内源性血管舒张因子.近年来研究发现,内源性一氧化氮合酶(nitric oxide synthase,NOs)抑制剂,如非对称性二甲基精氨酸(asymmetric dimethylarginine,ADMA)和N-单甲基精氨酸(NG-monomethylarginine,NMA),在调节NO合成中起重要作用,与血管内皮功能失调有关.     

气体信号分子H2S对大鼠记忆行为的影响及机制

目的硫化氢(H2S)是一种内源性气体信号分子,在生物体内发挥着广泛的生物学效应。中枢神经系统的H2S作为一个突触调节分子,具有神经保护作用。有研究发现,额颞叶退变性疾病和阿尔茨海默病患者可出现杏仁核依赖的情感记忆异常。神经退行性疾病(如阿尔茨海默病、帕金森病等)患者或动物大脑H2S含量出现异常。但目前对于H2S与学习记忆和情感记忆的关系尚未有相关的报道。本实验研究气体信号分子H2S在大鼠海马区和杏仁核区介导的记忆行为中的作用及机制。方法条件性恐惧记忆和新事物认知实验观察大鼠的记忆行为;脑片膜片钳和场电位技术记录NMDA受体介导的电流及LTP;Western blotting实验研究突触可塑性相关蛋白的表达水平。结果条件性和线索性恐惧学习训练均可明显增加大鼠海马区H2S的含量。H2S合成酶抑制剂可损伤海马依赖的情景性恐惧记忆,和杏仁核依赖的线索性恐惧记忆。外源性补充H2S可剂量依赖性的增强大鼠的记忆行为。同样,外源性给予H2S也可明显增强杏仁核依赖的条件性味觉厌恶记忆,以及海马依赖的新物体认知功能。电生理实验发现,H2S选择性增强海马区含NR2A亚基的NMDA受体介导的电流和NMDA受体依赖的海马LTP;且NR2A特异性阻断剂可取消H2S对LTP和认知功能的增强作用。但选择性增强丘脑-杏仁核通路含NR2B亚基的NMDA受体所介导的电流及NMDA受体依赖性LTP。H2S增强学习记忆的作用与PKA,PKC,CaMKⅡ和CREB等信号通路激活有关。结论作为一种内源性气体信号分子,H2S在海马和杏仁核依赖的记忆行为中扮演着重要角色,为将H2S释放药物开发成为治疗情感障碍性疾病的药物提供新思路。     

急性颅脑外伤患者血清镁离子浓度变化及硫酸镁治疗效果

镁离子是体内重要的阳离子,在中枢神经系统(CNS)中具有重要的代谢和调节功能,其浓度的降低直接影响了脑细胞功能,与脑损害有着密切的关系.近年来,镁离子作为一种强有力的内源性脑组织保护剂,越来越受到重视.镁离子作为血管舒张因子和神经保护剂的治疗作用在动物实验中得到证实.     

气体信号分子 H2 S 与缺血性脑损伤的关系

硫化氢（ hydrogen sulfide,H2 S）是一种具有臭鸡蛋气味的气体,数百年来,人们普遍认为硫化氢是有害气体,其毒性作用已被大量报道。然而,自20世纪末以来,Abe等［1］首次通过实验证明,内源性H2 S可能作为一种神经活性物质而存在。同时,Kimura［2］对H2 S的不断研究中证实,脑组织内存在相对较高浓度的H2 S, H2 S能促进N-甲基-D-天冬氨酸（ NMDA）受体的活性,诱导海马突触的长时程增强效应（ long-term potentia-tion,LTP）,提示气体H2 S在神经系统发挥着重要的生物学功能。 H2 S与多种缺血性脑损伤疾病有着密切的关系,但机制尚不够清楚。因此,H2 S在神经系统的生成、生理作用、机制及其与缺血性脑血管病的关系有待进一步研究。     

硫化氢促进结肠癌细胞的生长

<正>硫化氢(H2S)是一种具有广泛生物学效应的气体信号分子[1],我们曾报道了H2S具有促血管新生的能力[2-3],而血管新生可促进肿瘤细胞的增殖和扩散。结肠癌细胞能表达合成H2S的两个酶:胱硫醚-β-合酶(CBS)和胱硫醚-γ-裂解酶(CSE),其中CSE含量远大于CBS的含量[4]。本实验通过干扰内源性H2S的生成来探讨其对肿瘤生长的影响。     

血管紧张肽-（1-7）的生物学作用

血管紧张肽(Ang)-(1-7)作为AngⅡ的内源性拮抗因子,可能在肾脏生理和病理生理中起着一定的作用,通过与结核蜡酸合酶结合发挥改善胰岛素抵抗、保护血管内皮、扩张血管、降低血压、防止动脉粥样硬化、改善心肌重构、调节心肌细胞功能、抑制血管平滑肌细胞和心脏成纤维细胞增殖、保护肾小管细胞、增强缓激肽活性、调节水电解质平衡及利尿等与AngⅡ截然相反的生物学效应,且在体内外均能拮抗AngⅡ的活性。     

Hydrogen sulphide and angiogenesis: mechanisms and applications

In vascular tissues, hydrogen sulphide (H(2)S) is mainly produced from L-cysteine by the cystathionine gamma-lyase (CSE) enzyme. Recent studies show that administration of H(2)S to endothelial cells in culture stimulates cell proliferation, migration and tube formation. In addition, administration of H(2)S to chicken chorioallantoic membranes stimulates blood vessel growth and branching. Furthermore, in vivo administration of H(2)S to mice stimulates angiogenesis, as demonstrated in the Matrigel plug assay. Pathways involved in the angiogenic response of H(2)S include the PI-3K/Akt pathway, the mitogen activated protein kinase pathway, as well as ATP-sensitive potassium channels. Indirect evidence also suggests that the recently demonstrated role of H(2)S as an inhibitor of phosphodiesterases may play an additional role in its pro-angiogenic effect. The endogenous role of H(2)S in the angiogenic response has been demonstrated in the chicken chorioallantoic membranes, in endothelial cells in vitro and ex vivo. Importantly, the pro-angiogenic effect of vascular endothelial growth factor (but not of fibroblast growth factor) involves the endogenous production of H(2)S. The pro-angiogenic effects of H(2)S are also apparent in vivo: in a model of hindlimb ischaemia-induced angiogenesis, H(2)S induces a marked pro-angiogenic response; similarly, in a model of coronary ischaemia, H(2)S exerts angiogenic effects. Angiogenesis is crucial in the early stage of wound healing. Accordingly, topical administration of H(2)S promotes wound healing, whereas genetic ablation of CSE attenuates it. Pharmacological modulation of H(2)S-mediated angiogenic pathways may open the door for novel therapeutic approaches.     

Potential importance of alterations in hydrogen sulphide (H2S) bioavailability in diabetes

Despite its long-standing reputation as a foul smelling and toxic gas that is associated with the decay of biological matter,hydrogen sulphide (H2S) has emerged as an important regulator of cardiovascular homoeostasis. H2S promotes a number of cellular signals that regulate metabolism, cardiac function and cell survival. Endogenous H2S bioavailability is regulated by several enzymes involved in the biosynthesis of cysteine. This study by Brancaleone et al. in the current issue of the British Journal of Pharmacology provides novel insights into the impairment of H2S biosynthesis in the setting of diabetes mellitus. The authors report that enzymic H2S biosynthesis is impaired in a murine model of type 1 diabetes and the attenuation in H2S bioavailability is associated with impaired vascular reactivity. This study has profound implications for the use of pharmacological agents to augment endogenous H2S synthesis or agents that release H2S to augment the levels of this gaseous signalling molecule in cardiovascular disease.     

Direct stimulation of K(ATP) channels by exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells

ATP-sensitive K+ (K(ATP)) channels in vascular smooth muscle cells (VSMC) are important targets for endogenous metabolic regulation and exogenous drug therapy. H2S, as a novel gasotransmitter, has been shown to relax rat aortic tissues via opening of K(ATP) channels. However, interaction of H2S, exogenous-applied or endogenous-produced, with K(ATP) channels in resistance artery VSMC has not been delineated. In the present study, using the whole-cell and single-channel patch-clamp technique, we demonstrated that exogenous H2S activated K(ATP) channels and hyperpolarized cell membrane in rat mesenteric artery VSMC. H2S enhanced the amplitude of whole-cell K(ATP) currents with an EC50 value of 116 +/- 8.3 microM and increased the open probability of single K(ATP) channels. H2S hyperpolarized membrane potentials by -12 mV in nystatin-perforated VSMC. Furthermore, inhibition of endogenous H2S production with D,L-propargylglycine (PPG) reduced whole-cell K(ATP) currents. PPG alone had no effect on unitary K(ATP) channel currents in cell-free membrane patches. In addition, effects of H2S on K(ATP) channels and membrane potentials were independent of cGMP-mediated phosphorylation. This study demonstrated modulation of K(ATP) channel activity by exogenous and endogenous H2S in resistance artery VSMC, thus helping elucidate cardiovascular functions of this endogenous gas.     

Hydrogen sulphide in heart and systemic circulation

In the mammalian cardiovascular system, H(2)S joins carbon monoxide (CO) and endothelial derived relaxing factors, (EDRFs)-nitric oxide (NO), as the third gasotransmitter. In the vasculature, cystathionine-γ-lyase (CSE) is the main enzyme responsible for H(2)S biosynthesis starting from the substrate e.g. L-cysteine. There is a growing body of evidence that supports a role for H(2)S in regulating the vascular homeostasis. H(2)S (NaHS) is known to induce a concentration-dependent relaxation of large conduit arteries. Interestingly, H(2)S also relaxes peripheral resistance vessels such as mesenteric arteries suggesting a role for H(2)S also in the regulation of vascular resistance and systemic blood pressure. This vasodilatory effect is dependent on the activation of K(ATP) channels. However, a cross-talk exists between the L-Argine/NO and L-cysteine/H(2)S pathways. Furthermore, it has been shown that H(2)S acts as an endogenous non-selective inhibitor of phosphodiesterase activity. Compelling evidence links H(2)S to regulation of erectile function while it remains unclear whether the L-cysteine/H(2)S pathway plays a pathogenetic role in erectile dysfunction. Despite the rapid growth of the field, it should be noted that several aspects of H(2)S physiology in the cardiovascular system remain unsolved and the lack of reliable inhibitors and donors remains a major limitation.     

Hydrogen sulfide: a novel signaling molecule in the vascular system

Hydrogen sulfide (H2S) is an endogenous gasotransmitter produced in mammalian cells. It is responsible for physiological functions in many organs and systems, with attention focused mainly on the cardiovascular and nervous systems. In the vascular system, H2S produces biphasic effects in regulation of vascular tone. At lower concentrations, it induces vasoconstriction predominantly via decreasing cyclic adenosine monophosphate in smooth muscle cell and inhibiting the production and bioavailability of nitric oxide. At higher concentrations, it produces vasorelaxation mainly through opening of KATP channels and induction of intracellular acidification. Scavenging reactive oxygen species and elevation of cyclic guanosine monophosphate are also implicated in the vasorelaxant response. This review presents an overview of the current knowledge of H2S in the vascular system, with special emphasis and discussion on the involvement of various signaling pathways and ion channels based on current understanding and reported literature till date.     

YC-1 stimulates the expression of gaseous monoxide-generating enzymes in vascular smooth muscle cells

The benzylindazole derivative 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) is an allosteric stimulator of soluble guanylate cyclase (sGC) that sensitizes the enzyme to the gaseous ligands carbon monoxide (CO) and nitric oxide (NO). In this study, we examined whether YC-1 also promotes the production of these gaseous monoxides by stimulating the expression of the inducible isoforms of heme oxygenase (HO-1) and NO synthase (iNOS) in vascular smooth muscle cells (SMCs). YC-1 increased HO-1 mRNA, protein, and promoter activity and potentiated cytokine-mediated expression of iNOS protein and NO synthesis by SMCs. The induction of HO-1 by YC-1 was unchanged by the sGC inhibitor, 1H-(1,2,4)oxadiazolo[4,3-alpha]quinozalin-1-one (ODQ) or by the protein kinase G inhibitors (8R,9S,11S)-(-)-2-methyl-9-methoxyl-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta9(cde)trinen-1-one (KT 5823) and YGRKKRRQRRRPPLRKKKKKH-amide (DT-2) and was not duplicated by 8-bromo-cGMP or the NO-independent sGC stimulator 5-cyclopropyl-2[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-yl] pyrimidin-4-ylamine (BAY 41-2272). However, the YC-1-mediated induction of HO-1 was inhibited by the phosphatidylinositol-3-kinase (PI3K) inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002). In contrast, the enhancement of cytokine-stimulated iNOS expression and NO production by YC-1 was prevented by ODQ and the protein kinase A inhibitor (9S,10S, 12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12-epoxy-1H-diindolo(1,2,3-fg:3',2',1'-kl)pyrrolo(3,4-i)(1,6)-benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) and was mimicked by 8-bromo-cGMP and BAY 41-2272. In conclusion, these studies demonstrate that YC-1 stimulates the expression of HO-1 and iNOS in vascular SMCs via the PI3K and sGC-cGMP-protein kinase A pathway, respectively. The ability of YC-1 to sensitize sGC to gaseous monoxides and simultaneously stimulate their production through the induction of HO-1 and iNOS provides a potent mechanism by which the cGMP-dependent and -independent biological actions of this agent are amplified.     

Absence of ligand-induced regulation of kinin receptor expression in the rabbit

The induction of B(1) receptors (B(1)Rs) and desensitization or down-regulation of B(2) receptors (B(2)Rs) as a consequence of the production of endogenous kinins has been termed the autoregulation hypothesis. The latter was investigated using two models based on the rabbit: kinin stimulation of cultured vascular smooth muscle cells (SMCs) and in vivo contact system activation (dextran sulphate intravenous injection, 2 mg kg(-1), 5 h). Rabbit aortic SMCs express a baseline population of B(1)Rs that was up-regulated upon interleukin-1beta treatment ([(3)H]-Lys-des-Arg(9)-BK binding or mRNA concentration evaluated by RT - PCR; 4 or 3 h, respectively). Treatment with B(1)R or B(2)R agonists failed to alter B(1)R expression under the same conditions. Despite consuming endogenous kininogen (assessed using the kinetics of immunoreactive kinin formation in the plasma exposed to glass beads ex vivo) and producing hypotension mediated by B(2)Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B(1)Rs in conscious animals (RT - PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 microg kg(-1), 5 h) was an effective B(1)R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve. We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B(1)Rs. Kinin receptor antagonists (icatibant combined to B-9858, 50 microg kg(-1) of each) failed to prevent or reduce the effect of LPS on B(1)R expression. Dextran sulphate or LPS treatments did not persistently down-regulate vascular B(2)Rs (jugular vein contractility assessed ex vivo). The kinin receptor autoregulation hypothesis is not applicable to primary cell cultures derived from a tissue known to express B(1)Rs in a regulated manner (aorta). The activation of the endogenous kallikrein-kinin system is ineffective to induce B(1)Rs in vivo in an experimental time frame sufficient for B(1)R induction by LPS.     

Regulation and function of cyclic nucleotide phosphodiesterases in pathological vascular remodeling

Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures. Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting) or biological(lipids,diabetes,smoking,or virus) injuries. It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts,leukocytes,and platelets. One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype. Synthetic SMCs are proliferatory,migratory,secretory and inflammatory,playing key roles in the pathogenesis of vascular remodeling. In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI_2) and nitric oxide(NO) that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype. Cyclic nucleotides cAMP and cGMP are primary mediators of PGI_2 and NO,respectively,and play critical roles in control vascular structural integrity and function. Cyclic nucleotides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase(PDE) isozymes catalyzing the degradation reaction. To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11). PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type. Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes. We then explored the functional roles and underlying mechanisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodeling in vitro and in vivo using a variety of gain-of-or loss-of-function approaches. For example,we found that Ca~(2+)/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE 1C is selectively expressed in synthetic SMCs in vitro and in various vascular disease models in vivo. PDE 1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism.PDE 1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models. These findings suggest that PDE 1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling. Inhibiting PDE 1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.     

Sildenafil stimulates the expression of gaseous monoxide-generating enzymes in vascular smooth muscle cells via distinct signaling pathways

Sildenafil is a cGMP-specific phosphodiesterase type 5 inhibitor that augments cGMP accumulation following the activation of soluble guanylate cyclase (sGC). In this study, we investigated whether sildenafil promotes the production of the sGC-stimulatory gases, carbon monoxide and nitric oxide, by stimulating the expression of the inducible isoforms of heme oxygenase (HO-1) and nitric oxide synthase (iNOS) in vascular smooth muscle cells (SMCs). Sildenafil increased HO-1 expression and potentiated cytokine-mediated expression of iNOS and NO synthesis by SMCs. The induction of HO-1 was unaffected by the sGC inhibitor 1H-(1,2,4)oxadiazolo[4,3-α]quinozalin-1-one (ODQ) or the protein kinase G inhibitor (8R,9S,11S)-(-)-2-methyl-9-methoxyl-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta9(cde)trinen-1-one (KT 5823). However, the sildenafil-mediated increase in HO-1 promoter activity was abolished by mutating the antioxidant responsive elements in the promoter or by overexpressing a dominant-negative mutant of NF-E2-related factor-2 (Nrf2). Furthermore, the induction of HO-1 by sildenafil was accompanied by an increase in reactive oxygen species (ROS) and blocked by N-acetyl-l-cysteine and rotenone. In contrast, the enhancement of cytokine-stimulated NO synthesis by sildenafil was prevented by ODQ and the protein kinase A inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg:3',2',1'-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) and duplicated by lipophilic analogs of cGMP. In conclusion, these studies demonstrate that sildenafil stimulates the expression of HO-1 and iNOS via the ROS-Nrf2 and sGC-cGMP pathway, respectively. The ability of sildenafil to block the catabolism of cGMP while stimulating the synthesis of sGC-stimulatory gaseous monoxides through the induction of HO-1 and iNOS provides a potent mechanism by which cGMP-dependent vascular actions of this drug are amplified.