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您现在的位置：首页>美国卫生研究院文献>American Journal of Physiology - Heart and Circulatory Physiology

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  • 刊频： Twice monthly, Feb. 2012-
  • NLM标题： Am J Physiol Heart Circ Physiol
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  • 1.

    【2hr】Aging enhances pressure-induced arterial superoxide formation

    包量

    机译 衰老促进压力诱导的动脉超氧化物形成
    摘要：The purpose of this study was to investigate the mechanisms that regulate superoxide (O2•−) production as a function of an acute elevation of intravascular pressure and age. Mesenteric arteries isolated from young (6 mo) and aged (24 mo) male Fischer 344 rats were used. O2•− production in vessels in response to 80 (normal pressure, NP) and 180 (high pressure, HP) mmHg was determined by the superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction assay. In vessels exposed to NP, O2•− production was significantly higher in aged than in young vessels (32.7 ± 7.0 vs. 15.4 ± 2.4 nmol·mg−1·30 min−1). HP enhanced O2•− production in vessels of both groups, but the enhancement was significantly greater in aged than in young vessels (63.4 ± 6.7 vs. 32.7 ± 4.3 nmol·mg−1·30 min−1). Apocynin (100 µmol/l) attenuated HP-induced increases in O2•− production in both groups, whereas allopurinol (100 µmol/l) and Nω-nitro-l-arginine methyl ester (100 µmol/l) inhibited the response only in aged vessels. Confocal microscopy showed increases in O2•− in response to HP in endothelial and smooth muscle layers of both groups, with much greater fluorescent staining in aged than in young rats and in the endothelium than in smooth muscle cells. No significant changes in NAD(P)H oxidase gene and protein expressions were observed in vessels of the two groups. Upregulation of protein expression of xanthine oxidase was detected in aged vessels. We conclude that NAD(P)H oxidase contributes importantly to HP-induced enhanced O2•− production in vessels of both young and aged rats, whereas xanthine oxidase and nitric oxide synthase-dependent O2•− production also contribute to the enhancement in mesenteric arteries of aged rats.
  • 2.

    【2hr】Permeability of homotypic and heterotypic gap junction channels formed of cardiac connexins mCx30.2, Cx40, Cx43, and Cx45

    包量

    机译 由心脏连接蛋白mCx30.2，Cx40，Cx43和Cx45形成的同型和异型间隙连接通道的通透性
    摘要：We examined the permeabilities of homotypic and heterotypic gap junction (GJ) channels formed of rodent connexins (Cx) 30.2, 40, 43, and 45, which are expressed in the heart and other tissues, using fluorescent dyes differing in net charge and molecular mass. Combining fluorescent imaging and electrophysiological recordings in the same cell pairs, we evaluated the single-channel permeability (Pγ). All homotypic channels were permeable to the anionic monovalent dye Alexa Fluor-350 (AF350), but mCx30.2 channels exhibited a significantly lower Pγ than the others. The anionic divalent dye Lucifer yellow (LY) remained permeant in Cx40, Cx43, and Cx45 channels, but transfer through mCx30.2 channels was not detected. Heterotypic channels generally exhibited Pγ values that were intermediate to the corresponding homotypic channels. Pγ values of mCx30.2/Cx40, mCx30.2/Cx43, or mCx30.2/Cx45 heterotypic channels for AF350 were similar and approximately twofold higher than Pγ values of mCx30.2 homotypic channels. Permeabilities for cationic dyes were assessed only qualitatively because of their binding to nucleic acids. All homotypic and heterotypic channel configurations were permeable to ethidium bromide and 4,6-diamidino-2-phenylindole. Permeability for propidium iodide was limited only for GJ channels that contain at least one mCx30.2 hemichannel. In summary, we have demonstrated that Cx40, Cx43, and Cx45 are permeant to all examined cationic and anionic dyes, whereas mCx30.2 demonstrates permeation restrictions for molecules with molecular mass over ∼400 Da. The ratio of single-channel conductance to permeability for AF350 was ∼40- to 170-fold higher for mCx30.2 than for Cx40, Cx43, and Cx45, suggesting that mCx30.2 GJs are notably more adapted to perform electrical rather than metabolic cell-cell communication.
  • 3.

    【2hr】Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats

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    机译 作用于CB1受体的内源性大麻素在肝硬化大鼠体内介导心脏收缩功能障碍
    摘要：Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB1 receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB1 receptors have also been implicated in the decreased β-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl4-induced cirrhosis developed decreased cardiac contractility, as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, and tachycardia. Bolus intravenous injection of the CB1 antagonist AM251 (3 mg/kg) acutely increased mean blood pressure, as well as both load-dependent and -independent indexes of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB1-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB1 receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB1-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.
  • 4.

    【2hr】Factors Released from Embryonic Stem Cells inhibit Apoptosis in H9c2 cells through P1-3kinase/Akt but not ERK pathway

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    机译 胚胎干细胞释放的因子通过P1-3激酶/ Akt而不是ERK途径抑制H9c2细胞的凋亡
    摘要：We recently reported that embryonic stem cells-conditioned medium (ES-CM) contains antiapoptotic factors that inhibit apoptosis in the cardiac myoblast, H9c2 cells. However, the mechanisms of inhibited apoptosis remain elusive. In this report, we provide evidences for novel mechanisms involved in the inhibition of apoptosis provided by ES-CM. ES-CM from mouse ES cells was generated. Apoptosis was induced after exposure with H2O2 (400μm) in H9c2 cells followed by replacement with ES-CM or culture medium. H9c2 cells treated with H2O2 were exposed to ES-CM, and ES-CM+cell survival protein phosphatidyl-inositol 3-kinase (PI-3k/Akt) inhibitor, or extracellular signal-regulated kinase (ERK1/2), PD98050. After 24 hours, H9c2 cells treated with ES-CM demonstrated significant increase in cell survival. ES-CM significantly inhibited (p<0.05) apoptosis determined by TUNEL staining, apoptotic ELISA and caspase-3 activity. Importantly, enhanced cell survival and inhibited apoptosis with ES-CM was abolished with . In contrast, PD98050 shows no effect on ES-CM increased cell survival. Furthermore, H2O2 induced apoptosis is associated with decreased levels of phosphorylated (p) Akt activity. Following treatment with ES-CM, we observed a decrease in apoptosis with an increase in pAkt, and increased activity was attenuated with Akt inhibitor, suggesting that the Akt pathway is involved in the decreased apoptosis and cell survival provided by ES-CM. In contrast, we observed no change in ES-CM decreased apoptosis or pERK with PD98050. In conclusion, we suggest that ES-CM inhibited apoposis and is mediatd by Akt but not ERK pathway.
  • 5.

    【2hr】Smooth muscle sparklet CaV channels defined: 1.2 is the number

    包量

    机译 平滑肌小火花CaV通道定义为：1.2是数量
    • 作者：Jonathan H. Jaggar
    • 刊名：American Journal of Physiology - Heart and Circulatory Physiology
    • 2007年第3期
    摘要：
  • 6.

    【2hr】The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow

    包量

    机译 一氧化氮合酶衍生的活性氧在肺血流量增加的羔羊肺动脉舒张改变中的作用
    摘要：Congenital cardiac defects associated with increased pulmonary blood flow (Qp) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Qp and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, 12 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4–6 wk of age. Electron paramagnetic resonance spectroscopy on fourth-generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-ethyl-2-thiopseudourea. Pre-constricted fifth-generation PA rings were relaxed with a NOS agonist (A-23187), a nitric oxide donor [S-nitrosyl amino penicillamine (SNAP)], polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), or H2O2. A-23187-, PEG-SOD-, and H2O2-mediated relaxations were impaired in shunt PA compared with controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A-23187 and SNAP in shunt but not control PA. Inhibition of NOS with nitro-L-arginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A-23187, SOD, and H2O2. We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H2O2, a pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Qp.
  • 7.

    【2hr】Microvascular network remodeling in dura mater of ovariectomized pigs: role for angiopoietin-1 in estrogen-dependent control of vascular stability

    包量

    机译 去卵巢猪硬脑膜微血管网络重塑：血管生成素-1在雌激素依赖性血管稳定性控制中的作用
    摘要：Estrogen is a key regulator of vascular responses and angioadaptation in multiple organs and tissues, including brain. However, the consequences of a loss of ovarian steroid hormone secretion on the status of microvascular networks in brain and meninges are largely unknown. Here, using the perfused dura mater model coupled with high-resolution digital epifluorescence and laser scanning confocal microscopy and computer-assisted morphometric analysis, we demonstrate that cessation of ovarian hormone production causes dramatic vascular remodeling in meningeal microvascular networks characterized by a threefold decrease in microvessel density and capillary rarefaction and an almost fourfold increase in vascular permeability. These changes were accompanied by a significant decrease in angiopoietin-1 (Ang-1) expression and Ang-1/Tie-2 ratio (1.4-fold, P < 0.01, and 1.5-fold, P < 0.05, respectively) in ovariectomized animals compared with intact females, but no changes were detected in the expression of estrogen receptors (ER)-α and -β. We conclude that estrogen-dependent control of Ang-1 expression plays an important role in stabilizing meningeal microvessel and maintaining healthy microvascular networks.
  • 8.

    【2hr】Adaptation of coronary microvascular exchange in arterioles and venules to exercise training and a role for sex in determining permeability responses

    包量

    机译 适应性锻炼中小动脉和小静脉中冠状动脉微血管交换的适应以及性别在确定通透性反应中的作用
    摘要：Studies of physical performance and energy metabolism during and following exercise have shown significant sex-specific musculoskeletal adaptations; less is known of vascular adaptations, particularly with respect to exchange capacity. In response to adenosine (ADO), a metabolite produced during exercise, permeability (Ps) of coronary arterioles from female pigs changed acutely; the magnitude and direction of the change (ΔPs) were determined by training status. In the present study Ps to albumin was assessed in arterioles (n = 138) and venules (n = 24) isolated from hearts of male (N = 27) and female (N = 59) pigs in the exercise training group (EX). We evaluated the hypothesis that coronary microvessel exchange adapts to endurance exercise training not by altering basal Ps, per se, but by elevating Ps on exposure to ADO. In contrast, training resulted in a reduction of basal Ps in all arterioles, and in venules from males, with no change in venules from EX females. Exposure to ADO resulted in the predicted increase in Ps except for venules from EX males where Ps was reduced. ΔPs responses of arterioles to mediators of adenylyl cyclase (isoproterenol)- and guanylyl cyclase (atrial natriuretic peptide)-signaling pathways were attenuated in EX pigs relative to pigs in the sedentary group. The adaptation of EX arterioles involves an upregulation of a nitric oxide-dependent pathway since nitric oxide synthase inhibition blocks ΔPs by ADO. Thus adaptation of microvascular exchange capacity to endurance exercise training not only occurs but also involves multiple mechanisms that differ in arterioles and venules with their relative contribution to net flux being a function of sex.
  • 9.

    【2hr】Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption

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    机译 卡那比二醇减轻高糖诱导的内皮细胞炎症反应和屏障破坏
    摘要：A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes. In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-κB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs). HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-κB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs. Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment. Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.
  • 10.

    【2hr】Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans

    包量

    机译 人体皮肤反应性充血的环氧合酶和一氧化氮合酶依赖性
    摘要：We tested the hypothesis that cyclooxygenases (COXs) or COX products inhibit nitric oxide (NO) synthesis and thereby mask potential effects of NO on reactive hyperemia in the cutaneous circulation. We performed laser-Doppler flowmetry (LDF) with intradermal microdialysis in 12 healthy volunteers aged 19–25 yr. LDF was expressed as the percent cutaneous vascular conduction (%CVC) or as the maximum %CVC (%CVCmax) where CVC is LDF/mean arterial pressure. We tested the effects of the nonisoform-specific NO synthase inhibitor nitro-L-arginine (NLA, 10 mM), the nonspecific COX inhibitor ketorolac (Keto, 10 mM), combined NLA + Keto, and NLA + sodium nitroprusside (SNP, 28 mM) on baseline and reactive hyperemia flow parameters. We also examined the effects of isoproterenol, a β-adrenergic agonist that causes prostaglandin-independent vasodilation to correct for the increase in baseline flow caused by Keto. When delivered directly into the intradermal space, Keto greatly augments all aspects of the laser-Doppler flow response to reactive hyperemia: peak reactive hyperemic flow increased from 41 ± 5 to 77 ± 7%CVCmax, time to peak flow increased from 17 ± 3 to 56 ± 24 s, the area under the reactive hyperemic curve increased from 1,417 ± 326 to 3,376 ± 876%CVCmax · s, and the time constant for the decay of peak flow increased from 100 ± 23 to 821 ± 311 s. NLA greatly attenuates the Keto response despite exerting no effects on baseline LDF or on reactive hyperemia when given alone. Low-dose NLA + SNP duplicates the Keto response. Isoproterenol increased baseline and peak reactive flow. These results suggest that COX inhibition unmasks NO dependence of reactive hyperemia in human cutaneous circulation.
  • 11.

    【2hr】High Resolution Imaging of Murine Myocardial Infarction With Delayed Enhancement and Cine Micro-CT

    包量

    机译 延迟增强和Cine Micro-CT对小鼠心肌梗死的高分辨率成像
    摘要：ObjectiveTo determine the feasibility of delayed enhancement µCT imaging to quantify myocardial infarct size in experimental mouse models.
  • 12.

    【2hr】Cytochrome P450 Epoxygenases Protect Endothelial Cells from Apoptosis Induced by Tumor Necrosis Factor-α via MAPK and PI3K/Akt Signaling Pathways

    包量

    机译 细胞色素P450环氧酶通过MAPK和PI3K / Akt信号通路保护内皮细胞免受肿瘤坏死因子-α诱导的凋亡。
    摘要：Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor (TNF)-α induced apoptosis in bovine aortic endothelial cells (BAECs). CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-α induction of endothelial cell apoptosis as evaluated by DNA laddering and FACS analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-α. The anti-apoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the PI3K/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-α induced ERK1/2 dephosphorylation in a time-dependent manner, and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-α. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-α. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling.
  • 13.

    【2hr】Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles

    包量

    机译 慢性一氧化氮合酶抑制作用钝化冠状动脉而非小动脉的内皮依赖性功能
    摘要：Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1–3 mo (8.3 ± 0.6 mg · kg−1 · day−1). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with L-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. L-NAME, Indo, and L-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles.
  • 14.

    【2hr】Cellular and Molecular Determinants of Altered Ca2+ Handling in the Failing Rabbit Heart

    包量

    机译 失败的兔子心脏中改变的Ca2 +处理的细胞和分子决定因素
    摘要：Myocytes from the failing myocardium exhibit depressed and prolonged Ca2+ transients ([Ca2+]i transients) that are, in part, responsible for contractile dysfunction and unstable repolarization. In order to better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with AP duration prolongation that was especially pronounced at low stimulation frequencies. The L-type calcium channel current (ICa,L) density (−0.964±0.172 vs. −0.745±0.128 pA/pF at +10 mV) and NCX (2.1±0.8 vs. 2.3±0.8 pA/pF at +30 mV) currents were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72±0.07 µM and 0.56±0.04 µM in normal and failing hearts correspondingly, p<0.05) with slowed rates of decay and reduced Ca2+ spark amplitudes (p<0.0001) in myocytes isolated from failing compared to control hearts. Inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing compared to control hearts (p<0.05). The mRNA levels of the α1C subunit, ryanodine receptor (RyR) and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly down regulated in the failing compared with the control hearts (p<0.05). α1C protein levels were unchanged, RyR, SERCA2a and PLB were significantly down regulated (p<0.05), while NCX protein was significantly up regulated (p<0.05). These results support a prominent role for the sarcoplasmic reticulum in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the the depressed [Ca2+]i and the altered action potential profile phenotype.
  • 15.

    【2hr】Spatial Heterogeneity of the Restitution Portrait in Rabbit Epicardium

    包量

    机译 兔心外膜恢复肖像的空间异质性
    摘要：Spatial heterogeneity of repolarization can provide a substrate for reentry to occur in myocardium. This heterogeneity may result from spatial differences in APD restitution. The restitution portrait (RP) measures many aspects of rate-dependent restitution: the dynamic restitution curve (RC), S1-S2 RC, and short-term memory response. We used the RP to characterize epicardial patterns of spatial heterogeneity of restitution that were repeatable across animals. NZW rabbit ventricles were paced from either the epicardial apex, mid-ventricle, or base, and optical action potentials were recorded from the same three regions. A perturbed downsweep pacing protocol was applied that measured the RP over a range of cycle lengths from 1000-140 ms. The time constant of short-term memory measured close to the stimulus was dependent on location. In the mid-ventricle the mean time constant was 19.1±1.1 sec, but it was 39% longer at the apex (p<0.01) and 23% longer at the base (p=0.03). The S1-S2 RC slope was dependent on pacing site (p=0.015), with steeper slope when pacing from the apex than from the base. There were no significant repeatable spatial patterns in steady-state APD at all cycle lengths or in dynamic RC slope. These results indicate that transient patterns of epicardial heterogeneity of APD may occur following a change in pacing rate. Thus, it may affect cardiac electrical stability at the onset of a tachycardia or during a series of ectopic beats. Differences in restitution with respect to pacing site suggest that vulnerability may be affected by the location of reentry or ectopic foci.
  • 16.

    【2hr】Caveolin-1 abolishment attenuates the myogenic response in murine cerebral arteries

    包量

    机译 Caveolin-1的消除减弱了鼠脑动脉的肌源性反应。
    摘要：Intravascular pressure-induced vasoconstriction (the “myogenic response”) is intrinsic to smooth muscle cells, but mechanisms that underlie this response are unresolved. Here we investigated the physiological function of arterial smooth muscle cell caveolae in mediating the myogenic response. Since caveolin-1 (cav-1) ablation abolishes caveolae formation in arterial smooth muscle cells, myogenic mechanisms were compared in cerebral arteries from control (cav-1+/+) and cav-1-deficient (cav-1−/−) mice. At low intravascular pressure (10 mmHg), wall membrane potential, intracellular calcium concentration ([Ca2+]i), and myogenic tone were similar in cav-1+/+ and cav-1−/− arteries. In contrast, pressure elevations to between 30 and 70 mmHg induced a smaller depolarization, [Ca2+]i elevation, and myogenic response in cav-1−/− arteries. Depolarization induced by 60 mM K+ also produced an attenuated [Ca2+]i elevation and constriction in cav-1−/− arteries, whereas extracellular Ca2+ removal and diltiazem, an L-type Ca2+ channel blocker, similarly dilated cav-1+/+ and cav-1−/− arteries. Nω-nitro-l-arginine, an nitric oxide synthase inhibitor, did not restore myogenic tone in cav-1−/− arteries. Iberiotoxin, a selective Ca2+-activated K+ (KCa) channel blocker, induced a similar depolarization and constriction in pressurized cav-1+/+ and cav-1−/− arteries. Since pressurized cav-1−/− arteries are more hyperpolarized and this effect would reduce KCa current, these data suggest that cav-1 ablation leads to functional KCa channel activation, an effect that should contribute to the attenuated myogenic constriction. In summary, data indicate that cav-1 ablation reduces pressure-induced depolarization and depolarization-induced Ca2+ influx, and these effects combine to produce a diminished arterial wall [Ca2+]i elevation and constriction.
  • 17.

    【2hr】Differential effects of lower body negative pressure and upright tilt on splanchnic blood volume

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    机译 下半身负压和直立倾斜对内脏血容量的不同影响
    摘要：Upright posture and lower body negative pressure (LBNP) both induce reductions in central blood volume. However, regional circulatory responses to postural changes and LBNP may differ. Therefore, we studied regional blood flow and blood volume changes in 10 healthy subjects undergoing graded lower-body negative pressure (−10 to −50 mmHg) and 8 subjects undergoing incremental head-up tilt (HUT; 20°, 40°, and 70°) on separate days. We continuously measured blood pressure (BP), heart rate, and regional blood volumes and blood flows in the thoracic, splanchnic, pelvic, and leg segments by impedance plethysmography and calculated regional arterial resistances. Neither LBNP nor HUT altered systolic BP, whereas pulse pressure decreased significantly. Blood flow decreased in all segments, whereas peripheral resistances uniformly and significantly increased with both HUT and LBNP. Thoracic volume decreased while pelvic and leg volumes increased with HUT and LBNP. However, splanchnic volume changes were directionally opposite with stepwise decreases in splanchnic volume with LBNP and stepwise increases in splanchnic volume during HUT. Splanchnic emptying in LBNP models regional vascular changes during hemorrhage. Splanchnic filling may limit the ability of the splanchnic bed to respond to thoracic hypovolemia during upright posture.
  • 18.

    【2hr】Longer muscle lengths recapitulate force suppression in swine carotid artery

    包量

    机译 较长的肌肉长度可恢复猪颈动脉的力量抑制
    摘要：Cyclic nucleotide can relax arterial smooth muscle without reductions in myosin regulatory light chain (MRLC) phosphorylation, a process termed force suppression. Smooth muscle contractile force also depends on tissue length. It is not known how tissue length affects force suppression. Swine carotid artery rings were equilibrated at various lengths (as a fraction of Lo, the optimal length for force development). They were then frozen during contractile activation with or without forskolin-induced relaxation. Frozen tissue homogenates were then analyzed for Ser19-MRLC phosphorylation and Ser16-heat shock protein 20 (HSP20) phosphorylation (HSP20 is the proposed mediator of force suppression). Higher values of MRLC phosphorylation were required to induce a histamine contraction at longer tissue lengths. At 1.4 Lo, the dependence of force on MRLC phosphorylation observed with histamine stimulation alone was shifted to the right, a response similar to that observed during force suppression at 1.0 Lo. The rightward shift in the dependence of force on MRLC phosphorylation seen with histamine stimulation alone at 1.4 Lo was not associated with increased HSP20 phosphorylation. Addition of forskolin to histamine-stimulated tissues at 1.4 Lo induced a relaxation associated with increased HSP20 phosphorylation and reduced MRLC phosphorylation, i.e., there was no additional force suppression. At shorter tissue lengths (0.6 Lo), the dependence of force on MRLC phosphorylation with histamine stimulation alone was steep, a response similar to that observed during normal contractile activation at 1.0 Lo. Addition of forskolin induced force suppression at 0.6 Lo. The sensitivity of swine carotid to the concentration of histamine was greater at longer tissue lengths compared with shorter tissue lengths, suggesting a physiological mechanism to restore optimal tissue length. These data suggest that longer tissue lengths induced a force suppression-like state that was 1) not additive with forskolin and 2) not associated with HSP20 phosphorylation. Further research is required to determine this length-dependent mechanism.
  • 19.

    【2hr】P2X purinergic receptor-mediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure

    包量

    机译 心肌病的Calsequestrin模型的心肌细胞中P2X嘌呤能受体介导的离子电流：对心力衰竭的治疗意义
    摘要：P2X purinergic receptors, activated by extracellular ATP, mediate a number of cardiac cellular effects and may be important under pathophysiological conditions. The objective of the present study was to characterize the P2X receptor-mediated ionic current and determine its role in heart failure using the calsequestrin (CSQ) model of cardiomyopathy. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and CSQ mice. The P2X agonist 2-methylthio-ATP (2-meSATP) induced an inward current that was greater in magnitude in CSQ than in WT ventricular cells. The novel agonist, MRS-2339, an N-methanocarba derivative of 2-chloro-AMP relatively resistant to nucleotidase, induced a current in the CSQ myocyte similar to that by 2-meSATP. When administered via a miniosmotic pump (Alzet), it significantly increased longevity compared with vehicle-injected mice (log rank test, P = 0.02). The improvement in survival was associated with decreases in the heart weight-to-body weight ratio and in cardiac myocyte cross-sectional area [MRS-2339-treated mice: 281 ± 15.4 (SE) μm2, n = 6 mice vs. vehicle-treated mice: 358 ± 27.8 μm2, n= 6 mice, P < 0.05]. MRS-2339 had no vasodilator effect in mouse aorta ring preparations, indicating that its salutary effect in heart failure is not because of any vascular unloading. The cardiac P2X current is upregulated in the CSQ heart failure myocytes. Chronic administration of a nucleotidase-resistant agonist confers a beneficial effect in the CSQ model of heart failure, apparently via an activation of the cardiac P2X receptor. Cardiac P2X receptors represent a novel and potentially important therapeutic target for the treatment of heart failure.
  • 20.

    【2hr】Circulating levels of Cytochrome c after Resuscitation from Cardiac Arrest: A Marker of Mitochondrial Injury and Predictor of Survival

    包量

    机译 心脏骤停复苏后细胞色素c的循环水平：线粒体损伤的标志和存活的预测因子
    摘要：BackgroundCalcium overload and reactive oxygen species can injure mitochondria during ischemia and reperfusion. We hypothesized that mitochondrial injury occurs during cardiac resuscitation causing cytochrome c release to the cytosol and bloodstream while activating apoptotic pathways.
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