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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】Exercise training increases basal tone in arterioles distal to chronic coronary occlusion

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    机译 运动训练可增加慢性冠状动脉闭塞远端小动脉的基础张力
    摘要：Endurance exercise training increases basal active tone in coronary arteries and enhances myogenic tone in coronary arterioles of control animals. Paradoxically, exercise training has also been shown to augment nitric oxide production and nitric oxide-mediated relaxation in coronary arterioles. The purpose of the present study was to examine the effect of exercise training on basal active tone of arterioles (~150 µm ID) isolated from the collateral-dependent region of hearts exposed to chronic coronary occlusion. Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Arterioles were isolated from both the collateral-dependent and nonoccluded myocardial regions of sedentary (pen confined) and exercise-trained (treadmill run; 14 wk) pigs. Coronary tone was studied in isolated arterioles using microvessel myographs and standard isometric techniques. Exposure to nominally Ca2+-free external solution reduced resting tension in all arterioles; decreases were most profound (P < 0.05) in arterioles from the collateral-dependent region of exercise-trained animals. Furthermore, nitric oxide synthase (NOS) inhibition (Nω-nitro-l-arginine methylester; 100 µM) unmasked markedly increased nitric oxide-sensitive tone in arterioles from the collateral-dependent region of exercise-trained swine. Blockade of K+ channels revealed significantly enhanced K+ channel contribution to basal tone in collateral-dependent arterioles of exercise-trained pigs. Protein content of endothelial NOS (eNOS) and phosphorylated eNOS (pS1179), determined by immunoblot, was elevated in arterioles from exercise-trained animals with the greatest effect in collateral-dependent vasculature. Taken together, we demonstrate the interaction of opposing exercise training-enhanced arteriolar basal active tone, nitric oxide production, and K+ channel activity in chronic coronary occlusion, potentially enhancing the capacity to regulate blood flow to collateral-dependent myocardium.
  • 2.

    【2hr】Dependence of acetylcholine and ADP dilation of pial arterioles on heme oxygenase after transfusion of cell-free polymeric hemoglobin

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    机译 无细胞聚合性血红蛋白输注后，乙酰胆碱和小动脉小动脉ADP扩张对血红素加氧酶的依赖性
    摘要：Polymers of cell-free hemoglobin have been designed for clinical use as oxygen carriers, but limited information is available regarding their effects on vascular regulation. We tested the hypothesis that the contribution of heme oxygenase (HO) to acetylcholine-evoked dilation of pial arterioles is upregulated 2 days after polymeric hemoglobin transfusion. Dilator responses to acetylcholine measured by intravital microscopy in anesthetized cats were blocked by superfusion of the HO inhibitor tin protoporphyrin-IX (SnPPIX) in a group that had undergone exchange transfusion with hemoglobin 2 days earlier but not in surgical sham and albumin-transfused groups. However, immunoblots from cortical brain homogenates did not reveal changes in expression of the inducible isoform HO1 or the constitutive isoform HO2 in the hemoglobin-transfused group. To test whether the inhibitory effect of SnPPIX was present acutely after hemoglobin transfusion, responses were measured within an hour of completion of the exchange transfusion. In control and albumin-transfused groups, acetylcholine responses were unaffected by SnPPIX but were blocked by addition of the nitric oxide synthase inhibitor Nω-nitro-L-arginine (L-NNA) to the superfusate. In hemoglobin-transfused groups, the acetylcholine response was blocked by either SnPPIX or L-NNA alone. The effect of another HO inhibitor, chromium mesoporphyrin (CrMP), was tested on ADP, another endothelial-dependent dilator, in anesthetized rats. Pial arteriolar dilation to ADP was unaffected by CrMP in controls but was attenuated 62% by CrMP in rats transfused with hemoglobin. It is concluded that 1) polymeric hemoglobin transfusion acutely up-regulates the contribution of HO to acetylcholine-induced dilation of pial arterioles in cats, 2) this upregulation persists 2 days after transfusion when 95% of the hemoglobin is cleared from the circulation, and 3) this acute upregulation of HO signaling is ubiquitous in that similar effects were observed with a different endothelial-dependent agonist (i.e., ADP) in a another species (rat).
  • 3.

    【2hr】Electromechanics of paced left ventricle simulated by straightforward mathematical model: comparison with experiments

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    机译 用简单的数学模型模拟起搏左心室的机电：与实验的比较
    摘要：Intraventricular synchrony of cardiac activation is important for efficient pump function. Ventricular pacing restores the beating frequency but induces more asynchronous depolarization and more inhomogeneous contraction than in the normal heart. We investigated whether the increased inhomogeneity in the left ventricle can be described by a relatively simple mathematical model of cardiac electromechanics, containing normal mechanical and impulse conduction properties. Simulations of a normal heartbeat and of pacing at the right ventricular apex (RVA) were performed. All properties in the two simulations were equal, except for the depolarization sequence. Simulation results of RVA pacing on local depolarization time and systolic midwall circumferential strain were compared with those measured in dogs, using an epicardial sock electrode and MRI tagging, respectively. We used the same methods for data processing for simulation and experiment. Model and experiment agreed in the following aspects. 1) Ventricular pacing decreased systolic pressure and ejection fraction relative to natural sinus rhythm. 2) Shortening during ejection and stroke work declined in early depolarized regions and increased in late depolarized regions. 3) The relation between epicardial depolarization time and systolic midwall circumferential strain was linear and similar for the simulation (slope = −3.80 ± 0.28 s−1, R2 = 0.87) and the experiments [slopes for 3 animals −2.62 ± 0.43 s−1 (R2 = 0.59), −2.97 ± 0.38 s−1 (R2 = 0.69), and −4.44 ± 0.51 s−1 (R2 = 0.76)]. We conclude that our model of electromechanics is suitable to simulate ventricular pacing and that the apparently complex events observed during pacing are caused by well-known basic physiological processes.
  • 4.

    【2hr】Electromechanical analysis of infarct border zone in chronic myocardial infarction

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    机译 慢性心肌梗死梗死边界区的机电分析
    摘要：To test the hypothesis that alterations in electrical activation sequence contribute to depressed systolic function in the infarct border zone, we examined the anatomic correlation of abnormal electromechanics and infarct geometry in the canine post-myocardial infarction (MI) heart, using a high-resolution MR-based cardiac electromechanical mapping technique. Three to eight weeks after an MI was created in six dogs, a 247-electrode epicardial sock was placed over the ventricular epicardium under thoracotomy. MI location and geometry were evaluated with delayed hyperenhancement MRI. Three-dimensional systolic strains in epicardial and endocardial layers were measured in five short-axis slices with motion-tracking MRI (displacement encoding with stimulated echoes). Epicardial electrical activation was determined from sock recordings immediately before and after the MR scans. The electrodes and MR images were spatially registered to create a total of 160 nodes per heart that contained mechanical, transmural infarct extent, and electrical data. The average depth of the infarct was 55% (SD 11), and the infarct covered 28% (SD 6) of the left ventricular mass. Significantly delayed activation (>mean + 2SD) was observed within the infarct zone. The strain map showed abnormal mechanics, including abnormal stretch and loss of the transmural gradient of radial, circumferential, and longitudinal strains, in the region extending far beyond the infarct zone. We conclude that the border zone is characterized by abnormal mechanics directly coupled with normal electrical depolarization. This indicates that impaired function in the border zone is not contributed by electrical factors but results from mechanical interaction between ischemic and normal myocardium.
  • 5.

    【2hr】Ethanol Inhibits Monocyte Chemotactic Protein-1 Expression in Interleukin-1β-Activated Human Endothelial Cells

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    机译 乙醇抑制白介素1β激活的人内皮细胞中单核细胞趋化蛋白1表达。
    摘要：The aim of this study was to determine the effect of ethanol (EtOH) on endothelial monocyte chemotactic protein-1 (MCP-1) expression. Interleukin-1β (IL-1β) increased the production of MCP-1 by human umbilical vein endothelial cells (HUVEC) from undetectable levels to approximately 900 pg/ml at 24 h. EtOH dose-dependently inhibited IL-1β-stimulated MCP-1 secretion as determined by ELISA; 25±1%, 35±7% and 65±5% inhibition for 1, 10 and 100 mM EtOH, respectively, concomitant with inhibition of monocyte adhesion to activated endothelial cells. Similarly, EtOH dose-dependently inhibited IL-1β-stimulated MCP-1 mRNA expression. Experiments with actinomycin D demonstrated that EtOH decreased the stability of MCP-1 mRNA. In addition, EtOH significantly reduced NF-κB and AP-1 binding activity induced by IL-1β, and inhibited MCP-1 gene transcription. Binding of 125I-MCP-1 to its receptor (CCR2) on THP-1 human monocytic cells was not affected by EtOH treatment. Modulation of the expression of MCP-1 represents a mechanism whereby ethanol could inhibit atherogenesis by blocking the crucial early step of monocyte adhesion and subsequent recruitment to the subendothelial space. These actions of ethanol may underlie, in part, its cardiovascular protective effects in vivo.
  • 6.

    【2hr】Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion

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    机译 一氧化氮清除在血管对无细胞血红蛋白输注的反应中的作用
    摘要：Modified Hb solutions have been developed as O2 carrier transfusion fluids, but of concern is the possibility that increased scavenging of nitric oxide (NO) within the plasma will alter vascular reactivity even if the Hb does not readily extravasate. The effect of decreasing hematocrit from ~30% to 18% by an exchange transfusion of a 6% sebacyl cross-linked tetrameric Hb solution on the diameter of pial arterioles possessing tight endothelial junctions was examined through a cranial window in anesthetized cats with and without a NO synthase (NOS) inhibitor. Superfusion of a NOS inhibitor decreased diameter, and subsequent Hb transfusion produced additional constriction that was not different from Hb transfusion alone but was different from the dilation observed by exchange transfusion of an albumin solution after NOS inhibition. In contrast, abluminal application of the cross-linked Hb produced constriction that was attenuated by the NOS inhibitor. Neither abluminal nor intraluminal cross-linked Hb interfered with pial arteriolar dilation to cromakalim, an activator of ATP-sensitive potassium channels. Pial vascular reactivity to hypocapnia and hypercapnia was unaffected by Hb transfusion. Microsphere-determined regional blood flow indicated selective decreases in perfusion after Hb transfusion in the kidney, small intestine, and neurohypophysis, which does not have tight endothelial junctions. Administration of a NOS inhibitor to reduce the basal level of NO available for scavenging before Hb transfusion prevented further decreases in blood flow to these regions compared with NOS inhibition alone. In contrast, blood flow to skeletal and left ventricular muscle increased, and cerebral blood flow was unchanged after Hb transfusion. This cross-linked Hb tetramer is known to appear in renal lymph but not in urine. We conclude that cell-free tetrameric Hb does not scavenge sufficient NO in the plasma space to significantly affect baseline tone in vascular beds with tight endothelial junctions but does produce substantial constriction in beds with porous endothelium. The data support increasing the molecular size of Hb by polymerization or conjugation to limit extravasation in all vascular beds to preserve normal vascular reactivity.
  • 7.

    【2hr】Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart

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    机译 在5天梗塞的心脏中存活的细胞中外向电流的不同表型
    • 作者：Wen DunPenelope A. Boyden
    • 刊名：American Journal of Physiology - Heart and Circulatory Physiology
    • 2005年第2期
    摘要：We have shown reduced density and altered kinetics in slowly activating K+ currents (IKs) in epicardial border zone (EBZ) cells (IZs) of the 5-day-infarcted canine heart (Jiang M, Cabo, C, Yao J-A, Boyden PA, and Tseng G-N. Cardiovasc Res 48: 34–43, 2000). β-Adrenergic stimulation with isoproterenol increases IKs in normal cells (NZs). In this study, we used a voltage-clamp protocol with an external solution to isolate IKs from contaminating currents to determine the effects of 1 µM isoproterenol on IKs in IZs and NZs. Under our recording conditions, 10 µM azimilide-sensitive currents were stimulated with isoproterenol to compare responsiveness of IKs to isoproterenol in the two cell groups. IKs tail density was reduced 67% in IZs (group I, n = 26) compared with NZs (n = 24, P < 0.05). Isoproterenol-stimulated azimilide-sensitive tail currents were increased 1.72 ± 0.2-fold in NZs and 2.2 ± 0.3-fold in IZs (P > 0.05). In 33% of IZs (group II, n = 13), native currents showed no tail currents; however, isoproterenol-stimulated azimilide-sensitive currents were voltage dependent, fast activating, and large in amplitude compared with group I IZs, similar to “lone” KCNQ1 currents. Using short clamp pulses, we also found an increase in sustained currents sensitive to tetraethylammonium chloride (TEA) and no change in C-9356-sensitive currents in IZs with little or no transient outward current. In some IZs where IKs is downregulated, the effect of isoproterenol on IKs was similar to that on IKs in NZs. In others, the existence of lone KCNQ1-type currents, which are sensitive to β-adrenergic stimulation, is consistent with our findings of an increased KCNQ1-to-KCNE1 mRNA ratio (Jiang et al.). Accompanying altered IKs in IZs are an enhanced TEA-sensitive current and a normal C-9356-sensitive current.
  • 8.

    【2hr】Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets

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    机译 容量超负荷肥大中的舒张功能障碍与肌层薄板的异常剪切有关
    摘要：Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 ± 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 ± 2 vs. 21 ± 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/dtmax: 2,476 ± 203 vs. 2,330 ± 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/dtmin: −2,466 ± 190 vs. −2,076 ± 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 ± 2 vs. 43 ± 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 ± 33 vs. 244 ± 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer (P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload (P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.
  • 9.

    【2hr】Role of adenosine A1 and A3 receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury

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    机译 腺苷A1和A3受体在调节线粒体呼吸链损伤后心肌细胞稳态中的作用
    摘要：Activation of either the A1 or the A3 adenosine receptor (A1R or A3R, respectively) elicits delayed cardioprotection against infarction, ischemia, and hypoxia. Mitochondrial contribution to the progression of cardiomyocyte injury is well known; however, the protective effects of adenosine receptor activation in cardiac cells with a respiratory chain deficiency are poorly elucidated. The aim of our study was to further define the role of A1R and A3R activation on functional tolerance after inhibition of the terminal link of the mitochondrial respiratory chain with sodium azide, in a state of normoxia or hypoxia, compared with the effects of the mitochondrial ATP-sensitive K+ channel opener diazoxide. Treatment with 10 mM sodium azide for 2 h in normoxia caused a considerable decrease in the total ATP level; however, activation of adenosine receptors significantly attenuated this decrease. Diazoxide (100 µM) was less effective in protection. During treatment of cultured cardiomyocytes with hypoxia in the presence of 1 mM sodium azide, the A1R agonist 2-chloro-N6-cyclopentyladenosine was ineffective, whereas the A3R agonist 2-chloro-N6-iodobenzyl-5′-N-methylcarboxamidoadenosine (Cl-IB-MECA) attenuated the decrease in ATP level and prevented cell injury. Cl-IB-MECA delayed the dissipation in the mitochondrial membrane potential during hypoxia in cells impaired in the mitochondrial respiratory chain. In cells with elevated intracellular Ca2+ concentration after hypoxia and treatment with NaN3 or after application of high doses of NaN3, Cl-IB-MECA immediately decreased the elevated intracellular Ca2+ concentration toward the diastolic control level. The A1R agonist was ineffective. This may be especially important for the development of effective pharmacological agents, because mitochondrial dysfunction is a leading factor in the pathophysiological cascade of heart disease.
  • 10.

    【2hr】Antagonistic regulation of swelling-activated Cl− current in rabbit ventricle by Src and EGFR protein tyrosine kinases

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    机译 Src和EGFR蛋白酪氨酸激酶对兔心室肿胀激活的Cl-电流的拮抗作用
    摘要：Regulation of swelling-activated Cl− current (ICl,swell) is complex, and multiple signaling cascades are implicated. To determine whether protein tyrosine kinase (PTK) modulates ICl,swell and to identify the PTK involved, we studied the effects of a broad-spectrum PTK inhibitor (genistein), selective inhibitors of Src (PP2, a pyrazolopyrimidine) and epidermal growth factor receptor (EGFR) kinase (PD-153035), and a protein tyrosine phosphatase (PTP) inhibitor (orthovanadate). ICl,swell evoked by hyposmotic swelling was increased 181 ± 17% by 100 μM genistein, and the genistein-induced current was blocked by the selective ICl,swell blocker tamoxifen (10 μM). Block of Src with PP2 (10 μM) stimulated tamoxifen-sensitive ICl,swell by 234 ± 27%, mimicking genistein, whereas the inactive analog of PP2, PP3 (10 μM), had no effect. Moreover, block of PTP by orthovanadate (1 mM) inhibited ICl,swell and prevented its stimulation by PP2. In contrast with block of Src, block of EGFR kinase with PD-153035 (20 nM) inhibited ICl,swell. Several lines of evidence argue that the PP2-stimulated current was ICl,swell: 1) the stimulation was volume dependent, 2) the current was blocked by tamoxifen, 3) the current outwardly rectified with both symmetrical and physiological Cl− gradients, and 4) the current reversed near the Cl− equilibrium potential. To rule out contributions of other currents, Cd2+ (0.2 mM) and Ba2+ (1 mM) were added to the bath. Surprisingly, Cd2+ suppressed the decay of Cd2+ plus Ba2+ eliminated time-dependent ICl,swell, and currents between −100 and −100 mV. Nevertheless, these divalent ions did not eliminate ICl,swell or prevent its stimulation by PP2. The results indicate that tyrosine phosphorylation controls ICl,swell, and regulation of ICl,swell by the Src and EGFR kinase families of PTK is antagonistic.
  • 11.

    【2hr】Sexual dimorphism in the permeability response of coronary microvessels to adenosine

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    机译 冠状微血管对腺苷渗透性反应的性二态性
    摘要：Gender influences volume regulation via several mechanisms; whether these include microvascular exchange, especially in the heart, is not known. In response to adenosine (Ado), permeability (Ps)to protein of coronary arterioles of female pigs decreases acutely. Whether Ado induces similar Ps changes in arterioles from males or whether equivalent responses occur in coronary venules of either sex has not been determined. Hypotheses that 1) basal Ps properties and 2) Ps responses to vasoactive stimuli are sex independent were evaluated from measures of Ps to two hydrophilic proteins, α-lactalbumin and porcine serum albumin (PSA), in arterioles and venules isolated from hearts of adult male and female pigs. Consistent with hypothesis 1, basal Ps values of both microvessel types were independent of sex. Contrary to hypothesis 2, Ps responses to Ado varied with sex, protein, and vessel type. Confirming earlier studies, Ado induced a ~20% decrease in Ps to both proteins in coronary arterioles from females. In arterioles from males, Ado did not change Ps for α-lactalbumin (Psα-lactalb, 3 ± 13%) whereas Ps for PSA (PsPSA) decreased by 27 ± 8% (P < 0.005). In venules from females, Ado elevated PsPSA by 44 ± 20% (P < 0.05), whereas in those from males, Ado reduced PsPSA by 24 ± 5% (P < 0.05). The variety of outcomes is consistent with transvascular protein and protein-carried solute flux being regulated by multiple sex-dependent mechanisms in the heart and provides evidence of differences in exchange homeostasis of males and females in health and, likely, disease.
  • 12.

    【2hr】Direct measurement of transmural laminar architecture in the anterolateral wall of the ovine left ventricle: new implications for wall thickening mechanics

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    机译 直接测量绵羊左心室前外侧壁的透壁层流结构：对壁增厚力学的新影响
    摘要：Laminar, or sheet, architecture of the left ventricle (LV) is a structural basis for normal systolic and diastolic LV dynamics, but transmural sheet orientations remain incompletely characterized. We directly measured the transmural distribution of sheet angles in the ovine anterolateral LV wall. Ten Dorsett-hybrid sheep hearts were perfusion fixed in situ with 5% buffered glutaraldehyde at end diastole and stored in 10% formalin. Transmural blocks of myocardial tissue were excised, with the edges cut parallel to local circumferential, longitudinal, and radial axes, and sliced into 1-mm-thick sections parallel to the epicardial tangent plane from epicardium to endocardium. Mean fiber directions were determined in each section from five measurements of fiber angles. Each section was then cut transverse to the fiber direction, and five sheet angles (β) were measured and averaged. Mean fiber angles progressed nearly linearly from −41° (SD 11) at the epicardium to +42° (SD 16) at the endocardium. Two families of sheets were identified at approximately +45° (β+) and −45° (β−). In the lateral region (n = 5), near the epicardium, sheets belonged to the β+ family; in the midwall, to the β− family; and near the endocardium, to the β+ family. This pattern was reversed in the basal anterior region (n = 4). Sheets were uniformly β− over the anterior papillary muscle (n = 2). These direct measurements of sheet angles reveal, for the first time, alternating transmural families of predominant sheet angles. This may have important implications in understanding wall mechanics in the normal and the failing heart.
  • 13.

    【2hr】Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine

    包量

    机译 血清胆固醇对血管成形术后动脉粥样硬化和内膜增生的影响：氨氯地平抑制
    摘要：The objectives of the present study were to determine whether serum hypercholesterolemia (HC) promotes the development of spontaneous and angioplasty-induced lesions and whether amlodipine inhibits these lesions and cellular processes underlying their genesis. Rabbits were fed normal, 0.5%, or 2% cholesterol diets for 9 wk, which resulted in the development of increasing HC. After week one, balloon dilation of the abdominal aorta was performed while the thoracic aorta was not disturbed and monitored for the development of spontaneous lesions. Lesion size increased with the degree of HC and was accompanied by increased collagen synthesis and smooth muscle cell (SMC) proliferation at each site. Amlodipine (5 mg/kg po) inhibited lesion size by 50% (P < 0.01) at both sites in cholesterol-fed animals but not at angioplasty sites in animals on a normal diet. Local collagen synthesis was inhibited at both sites by amlodipine in the diet animals. The increase in HC was accompanied by a 1.7-fold increase in basal Ca2+ uptake in SMCs in the thoracic aorta, which was not altered by amlodipine, nifedipine, Ni2+, or La3+, revealing an uninhibitable calcium leak during atherogenesis. In culture, cholesterol enrichment increased SMC proliferation, collagen synthesis, and the secretion of a soluble SMC mitogen, which were inhibited by amlodipine (10−9 M). Finally, in SMC membranes, amlodipine uniquely restored the cholesterol-expanded membrane bilayer width without any effect on membrane fluidity. This study establishes a causal role between serum HC and the development of spontaneous and angioplasty-induced lesions and the ability of amlodipine to disrupt this action by a novel remodelling action on the SMC membrane.
  • 14.

    【2hr】Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle

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    机译 雌激素诱导的冠状动脉收缩由血管平滑肌中产生的超氧化物介导
    摘要：Although previous studies demonstrated beneficial effects of estrogen on cardiovascular function, the Women's Health Initiative has reported an increased incidence of coronary heart disease and stroke in postmenopausal women taking hormone replacement therapy (HRT). The objective of the present study was to identify a molecular mechanism whereby estrogen, a vasodilatory hormone, could possibly increase the risk of cardiovascular disease. Isometric contractile force recordings were performed on endothelium-denuded porcine coronary arteries, while molecular and fluorescence studies identified estrogen signaling molecules in coronary smooth muscle. Estrogen (1-1000nM) relaxed arteries in an endothelium-independent fashion; however, when arteries were pretreated with agents to uncouple NO production from nitric oxide synthase (NOS), estrogen contracted coronary arteries with an EC50 of 7.3 ± 4nM. Estrogen-induced contraction was attenuated by reducing superoxide (O2−). Estrogen-stimulated O2− production was detected in NOS-uncoupled coronary myocytes. Interestingly, only the Type 1 NOS isoform (nNOS) was detected in myocytes, making this protein a likely target mediating both estrogen-induced relaxation and contraction of endothelium-denuded coronary arteries. Estrogen-induced contraction was completely inhibited by 1μM nifedipine or 10μM indomethacin, indicating involvement of dihydropyridine-sensitive calcium channels and contractile prostaglandins. We propose that a single molecular mechanism can mediate the dual and opposite effect of estrogen on coronary arteries: by stimulating Type 1 (n)NOS in coronary arteries, estrogen produces either vasodilation via NO or vasoconstriction via superoxide.
  • 15.

    【2hr】Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and δ1-opioid receptor agonists is mediated by iNOS

    包量

    机译 NO供体，腺苷A1受体激动剂和δ1-阿片受体激动剂诱导的晚期预处理由iNOS介导
    摘要：Although ischemia-induced late preconditioning (PC) is known to be mediated by inducible nitric oxide (NO) synthase (iNOS), the role of this enzyme in pharmacologically induced late PC remains unclear. We tested whether targeted disruption of the iNOS gene abrogates late PC elicited by three structurally different NO donors [diethylenetriamine/NO (DETA/NO), nitroglycerin (NTG), and S-nitroso-N-acetyl-penicillamine (SNAP)], an adenosine A1 receptor agonist [2-chloro-N6-cyclopentyladenosine (CCPA)], and a δ1-opioid receptor agonist (TAN-670). The mice were subjected to a 30-min coronary occlusion followed by 24 h of reperfusion. In iNOS knockout (iNOS–/–) mice, infarct size was similar to wild-type (WT) controls, indicating that iNOS does not modulate infarct size in the absence of PC. Pretreatment of WT mice with DETA/NO, NTG, SNAP, TAN-670, or CCPA 24 h before coronary occlusion markedly reduced infarct size. In iNOS–/– mice, however, the late PC effect elicited by DETA/NO, NTG, SNAP, TAN-670, and CCPA was completely abrogated. Furthermore, in WT mice pretreated with TAN-670 or CCPA, the selective iNOS inhibitor 1400W also abolished the delayed PC properties of these drugs; 1400W had no effect in WT mice. These data demonstrate that iNOS plays an obligatory role in NO donor-induced, adenosine A1 receptor agonist-induced, and δ1-opioid receptor agonist-induced late PC, underscoring the critical role of this enzyme as a common mediator of cardiac adaptations to stress.
  • 16.

    【2hr】Splanchnic hyperemia and hypervolemia during Valsalva maneuver in postural tachycardia syndrome

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    机译 姿势性心动过速综合征的Valsalva动作中的内脏充血和血容量过多
    摘要：Prior work demonstrated dependence of the change in blood pressure during the Valsalva maneuver (VM) on the extent of thoracic hypovolemia and splanchnic hypervolemia. Thoracic hypovolemia and splanchnic hypervolemia characterize certain patients with postural tachycardia syndrome (POTS) during orthostatic stress. These patients also experience abnormal phase II hypotension and phase IV hypertension during VM. We hypothesize that reduced splanchnic arterial resistance explains aberrant VM results in these patients. We studied 17 POTS patients aged 15–23 yr with normal resting peripheral blood flow by strain gauge plethysmography and 10 comparably aged healthy volunteers. All had normal blood volumes by dye dilution. We assessed changes in estimated thoracic, splanchnic, pelvic-thigh, and lower leg blood volume and blood flow by impedance plethysmography throughout VM performed in the supine position. Baseline splanchnic blood flow was increased and calculated arterial resistance was decreased in POTS compared with control subjects. Splanchnic resistance decreased and flow increased in POTS subjects, whereas splanchnic resistance increased and flow decreased in control subjects during stage II of VM. This was associated with increased splanchnic blood volume, decreased thoracic blood volume, increased heart rate, and decreased blood pressure in POTS. Pelvic and leg resistances were increased above control and remained so during stage IV of VM, accounting for the increased blood pressure overshoot in POTS. Thus splanchnic hyperemia and hypervolemia are related to excessive phase II blood pressure reduction in POTS despite intense peripheral vasoconstriction. Factors other than autonomic dysfunction may play a role in POTS.
  • 17.

    【2hr】Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction

    包量

    机译 高血糖会改变PI3k和Akt信号传导并导致内皮细胞增殖功能障碍
    摘要：Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM d-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and ) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM d-glucose (control) exhibited log-phase growth on days 7–10. d-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM d-glucose. dGlucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM d-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM d-glucose. We conclude that d-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.
  • 18.

    【2hr】Nitric oxide increases carbon monoxide production by piglet cerebral microvessels

    包量

    机译 一氧化氮增加仔猪脑微血管的一氧化碳产量
    摘要：Carbon monoxide (CO) and nitric oxide (NO) can be involved in regulation of cerebral circulation. Inhibition of production of either one of these gaseous intercellular messengers inhibits newborn pig cerebral arteriolar dilation to the excitatory amino acid glutamate. Glutamate can increase NO production. Therefore, the present study tests the hypothesis that NO, which is increased by glutamate, stimulates the production of CO by cerebral microvessels. Experiments used freshly isolated cerebral microvessels from piglets that express only heme oxygenase-2 (HO-2). CO production was measured by gas chromatography-mass spectrometry. Although inhibition of nitric oxide synthase with L-nitro arginine (LNA) did not alter basal HO-2 catalytic activity or CO production, LNA blocked glutamate stimulation of HO-2 activity and CO production. Further, the NO donor sodium nitroprusside mimicked the actions of glutamate on HO-2 and CO production. The action of NO appears to be via cGMP because 8-br-cGMP mimics and ODQ blocks, glutamate stimulation of CO production and HO-2 catalytic activity. Inhibitors of neither casein kinase nor PI3 kinase altered HO-2 catalytic activity. Conversely, inhibition of calmodulin with calmidazolium chloride blocked glutamate stimulation of CO production and reduced HO-2 catalytic activity. These data suggest that glutamate may activate NOS producing NO that leads to CO synthesis via a cGMP dependent elevation of HO-2 catalytic activity. These results are consistent with the findings in vivo that either HO or NOS inhibition blocks cerebrovascular dilation to glutamate in piglets.
  • 19.

    【2hr】Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade

    包量

    机译 基于导管的顺行冠状动脉内病毒基因传递与冠状静脉阻塞
    摘要：Hayase, Motoya, Federica del Monte, Yoshiaki Kawase, Brian D. MacNeill, Jennifer McGregor, Ryuichi Yoneyama, Kozo Hoshino, Tsuyoshi Tsuji, Alec M. De Grand, Judith K. Gwathmey, John V. Frangioni, and Roger J. Hajjar. Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade. Am J Physiol Heart Circ Physiol 288: H2995–H3000, 2005; doi:10.1152/ajpheart.00703.2004.—The purpose of this study is to evaluate the feasibility of percutaneous antegrade myocardial gene transfer (PAMGT). A consistent and safe technique for in vivo gene transfer is required for clinical application of myocardial gene therapy. PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and after adenosine (25 μg) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of 1011 plaque-forming units in each coronary artery) carrying β-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n = 9); in another set of animals, PAMGT was performed without coronary vein blockade (n = 5). At 1 wk after gene delivery, the animals were killed. Quantitative β-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative β-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. β-Galactosidase activity increased significantly in the β-galactosidase group compared with the saline group: 1.34 ± 0.18 vs. 0.81 ± 0.1 ng (P ≤ 0.01) in the left ventricular wall and 0.91 ± 0.1 vs. 0.66 ± 0.07 ng (P ≤ 0.05) in the right ventricular wall. PAMGT with selective coronary venous blockade is feasible, reproducible, and safely achieved in a large-animal model.
  • 20.

    【2hr】Focal gap junction uncoupling and spontaneous ventricular ectopy

    包量

    机译 局灶性间隙连接解耦和自发性室性变
    摘要：Genetic studies in the mouse have demonstrated that conditional cardiac-restricted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wild-type recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising ~15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, P < 0.05) and by invasive hemodynamics (17.6% reduction in change of pressure over time, P < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (P < 0.01), including frequent runs of nonsustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resticted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias.
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