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

    【2hr】Expression of a Gi-coupled receptor in the heart causes impaired Ca2+ handling, myofilament injury, and dilated cardiomyopathy

    包量

    机译 心脏中的Gi偶联受体表达会导致Ca2 +处理受损，肌丝损伤和扩张型心肌病
    摘要：Increased signaling by Gi-coupled receptors has been implicated in dilated cardiomyopathy. To investigate the mechanisms, we used transgenic mice that develop dilated cardiomyopathy after conditional expression of a cardiac-targeted Gi-coupled receptor (Ro1). Activation of Gi signaling by the Ro1 agonist spiradoline caused decreased cellular cAMP levels and bradycardia in Langendorff-perfused hearts. However, acute termination of Ro1 signaling with the antagonist nor-binaltorphimine did not reverse the Ro1-induced contractile dysfunction, indicating that Ro1 cardiomyopathy was not due to acute effects of receptor signaling. Early after initiation of Ro1 expression, there was a 40% reduction in the abundance of the sarcoplasmic reticulum Ca2+-ATPase (P < 0.05); thereafter, there was progressive impairment of both Ca2+ handling and force development assessed with ventricular trabeculae. Six weeks after initiation of Ro1 expression, systolic Ca2+ concentration was reduced to 0.61 ± 0.08 vs. 0.91 ± 0.07 μM for control (n = 6–8; P < 0.05), diastolic Ca2+ concentration was elevated to 0.41 ± 0.07 vs. 0.23 ± 0.06 μM for control (n = 6–8; P < 0.01), and the decline phase of the Ca2+ transient (time from peak to 50% decline) was slowed to 0.25 ± 0.02 s vs. 0.13 ± 0.02 s for control (n = 6–8; P < 0.01). Early after initiation of Ro1 expression, there was a ninefold elevation of matrix metalloprotein-ase-2 (P < 0.01), which is known to cause myofilament injury. Consistent with this, 6 wk after initiation of Ro1 expression, Ca2+-saturated myofilament force in skinned trabeculae was reduced to 21 ± 2 vs. 38 ± 0.1 mN/mm2 for controls (n = 3; P < 0.01). Furthermore, electron micrographs revealed extensive myofilament damage. These findings may have implications for some forms of human heart failure in which increased activity of Gi-coupled receptors leads to impaired Ca2+ handling and myofilament injury, contributing to impaired ventricular pump function and heart failure.
  • 2.

    【2hr】Interaction of Angiogenic Microvessels with the Extracellular Matrix

    包量

    机译 血管生成微血管与细胞外基质的相互作用
    摘要：The extracellular matrix (ECM) plays a critical role in angiogenesis by providing biochemical and positional cues as well as by mechanically influencing microvessel cell behavior. Considerable information is known concerning the biochemical cues relevant to angiogenesis, but less is known about the mechanical dynamics during active angiogenesis. The objective of this study was to characterize changes in the material properties of a simple angiogenic tissue before and during angiogenesis. During sprouting, there was an overall decrease in tissue stiffness followed by an increase during neovessel elongation. The fall in matrix stiffness coincided with peak MMP mRNA expression and elevated proteolytic activity. An elevated expression of genes for ECM componenets and cell-ECM interaction molecules and a subsequent drop in proteolytic activity (although enzyme levels remained elevated) coincided with the subsequent stiffening.. The results of this study show that the mechanical properties of a scaffold tissue may be actively modified during angiogenesis by the growing microvasculature.
  • 3.

    【2hr】Inducible and myocyte-specific inhibition of PKCα enhances cardiac contractility and protects against infarction-induced heart failure

    包量

    机译 PKCα的诱导性和心肌细胞特异性抑制作用可增强心脏收缩力，并防止梗塞引起的心力衰竭
    摘要：Mice null for the gene encoding protein kinase Cα (Prkca), or mice treated with pharmacologic inhibitors of the PKCα/β/γ isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKCα itself functions in a myocyte autonomous manner to effect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative (dn) PKCα in the heart. Consistent with the proposed function of PKCα, induction of dnPKCα expression in the adult heart enhanced baseline cardiac contractility. This increase in cardiac contractility was associated with a partial protection from long-term decompensation and secondary dilated cardiomyopathy following myocardial infarction (MI) injury. Similarly, Prkca null mice were also partially protected from infarction-induced heart failure, although the area of infarction injury was identical to controls. Thus, myocyte autonomous inhibition of PKCα protects the adult heart from decompensation and dilated cardiomyopathy following infarction injury, in association with a primary enhancement in contractility.
  • 4.

    【2hr】Cellular and subcellular alternans in the canine left ventricle

    包量

    机译 犬左心室中的细胞和亚细胞交替素
    摘要：Previous studies indicate that action potential duration (APD) alternans is initiated in the endocardial (END) and midmyocardial (MID) regions rather than the epicardium (EPI) in the canine left ventricle (LV). This study examines regional differences in the rate dependence of Ca2+ transient characteristics under conditions that give rise to APD and associated T wave alternans. The role of the sarcoplasmic reticulum (SR) was further evaluated by studying Ca2+ transient characteristics in myocytes isolated from neonates, where an organized SR is poorly developed. All studies were performed in cells and tissues isolated from the canine LV. Isolated canine ENDO, MID, and EPI LV myocytes were either field stimulated or voltage clamped, and Ca2+ transients were measured by confocal microscopy. In LV wedge preparations, increasing the basic cycle length (BCL) from 800 to 250 ms caused alternans to appear mainly in the ENDO and MID region; alternans were not observed in EPI under these conditions. Ca2+ transient alternans developed in response to rapid pacing, appearing in EPI cells at shorter BCL compared with MID and ENDO cells (BCL = 428 ± 17 vs. 517 ± 29 and 514 ± 21, respectively, P < 0.05). Further increases in pacing rate resulted in the appearance of subcellular alternans of Ca2+ transient amplitude, which also appeared in EPI at shorter BCL than in ENDO and MID cells. Ca2+ transient alternans was not observed in neonate myocytes. We conclude that 1) there are distinct regional differences in the vulnerability to rate-dependent Ca2+ alternans in dog LV that may be related to regional differences in SR function and Ca2+ cycling; 2) the development of subcellular Ca2+ alternans suggests the presence of intracellular heterogeneities in Ca2+ cycling; and 3) the failure of neonatal cells to develop Ca2+ alternans provides further support that SR Ca2+ cycling is a major component in the development of these phenomena.
  • 5.

    【2hr】Chronic high blood flow potentiates shear stress-induced release of NO in arteries of aged rats

    包量

    机译 慢性高血流增强老年大鼠动脉中剪应力诱导的NO释放
    摘要：Aging impairs shear-stress-dependent dilation of arteries via increased superoxide production, decreased SOD activity, and decreased activation of endothelial nitric oxide (NO) synthase (eNOS). In the present study, we investigated whether chronic increases in shear stress, elicited by increases in blood flow, would improve vascular endothelial function of aged rats. To this end, second-order mesenteric arteries of young (6 mo) and aged (24 mo) male Fischer-344 rats were selectively ligated for 3 wk to elevate blood flow in a first-order artery [high blood flow (HF)]. An in vitro study was then conducted on first-order arteries with HF and normal blood flow (NF) to assess shear stress (1, 10, and 20 dyn/cm2)-induced release of NO into the perfusate. In HF arteries of both age groups, shear stress-induced NO production increased significantly. In 24-mo-old rats, the reduced shear stress-induced NO production in NF arteries was normalized by HF to a level similar to that in NF arteries of 6-mo-old rats. The increased NO production in HF arteries of 24-mo-old rats was associated with increased shear stress-induced dilation, expression of eNOS protein, and shear stress-induced eNOS phosphorylation. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, reduced shear stress-induced eNOS phosphorylation and vasodilation. Superoxide production decreased significantly in HF compared with NF arteries in 24-mo-old rats. The decreased superoxide production was associated with significant increases in CuZn-SOD and extracellular SOD protein expressions and total SOD activity. These results suggest that stimulation with chronic HF restores shear-stress-induced activation of eNOS and antioxidant ability in aged arteries.
  • 6.

    【2hr】Carbon monoxide and Ca2+-activated K+ channels in cerebral arteriolar responses to glutamate and hypoxia in newborn pigs

    包量

    机译 一氧化碳和Ca2 +激活的K +通道在新生小猪对谷氨酸和缺氧的脑小动脉反应中
    摘要：Large conductance calcium activated (KCa) channels regulate the physiological functions of many tissues, including cerebrovascular smooth muscle. L-glutamic acid (glutamate) is the principal excitatory neurotransmitter in the central nervous system and oxygen tension is a dominant local regulator of vascular tone. In vivo, glutamate and hypoxia dilate newborn pig cerebral arterioles and both dilations are blocked by inhibition of CO production. CO dilates cerebral arterioles by activating KCa channels. Therefore, the present study was designed to investigate effects of glutamate and hypoxia on cerebral CO production and the role of KCa channels in the cerebral arteriolar dilations to glutamate and hypoxia. In the presence of iberiotoxin or paxilline that block dilation to the KCa channel opener, NS1619, neither CO nor glutamate dilated pial arterioles. Conversely, neither paxilline nor iberiotoxin inhibited dilation to acute severe or moderate prolonged hypoxia. Both glutamate and hypoxia increased CSF CO concentration. Iberiotoxin that blocked dilation to glutamate did not attenuate the increase in CSF CO. The guanylyl cyclase inhibitor, 1H–(,,) oxadiazolo (4,3-a) quinoxalin-1-one (ODQ), that blocked dilation to sodium nitroprusside did not inhibit dilation to hypoxia. These data suggest that dilation of newborn pig pial arterioles to glutamate is mediated by activation of KCa channels consistent with the intermediary signal being CO. Surprisingly, although heme oxygenase (HO) inhibition attenuates dilation to hypoxia, hypoxia increases CSF CO concentration, and KCa channel antagonists block dilation to CO, neither KCa channel blockers nor ODQ altered dilation to hypoxia suggesting the contribution of the HO/CO system to hypoxia-induced dilation is not by stimulating vascular smooth muscle KCa channels or guanylyl cyclase.
  • 7.

    【2hr】The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats

    包量

    机译 通过自觉大鼠的COX-2介导的后调节，可增强缺血预处理的晚期心脏保护作用
    摘要：The present study sought to determine whether the combination of late preconditioning (PC) with postconditioning enhances the reduction in infarct size. Chronically instrumented rats were assigned to a 45-min (subset 1) or 60-min (subset 2) coronary occlusion followed by 24 h of reperfusion. In each subset, rats received no further intervention (control) or were preconditioned 24 h before occlusion (PC), post-conditioned at the onset of reperfusion following occlusion, or pre-conditioned and postconditioned without (PC + postconditioning) or with the COX-2 inhibitor celecoxib (3 mg/kg ip; PC + postconditioning + celecoxib) 10 min before postconditioning. Myocardial cyclooxygenase-2 (COX-2) protein expression and COX-2 activity (assessed as myocardial levels of PGE2) were measured 6 min after reperfusion in an additional five groups (control, PC, postconditioning, PC + postconditioning, and PC + postconditioning + celecoxib) subjected to a 45-min occlusion. PC alone reduced infarct size after a 45-min occlusion but not after a 60-min occlusion. Postconditioning alone did not reduce infarct size in either setting. However, the combination of late PC and postconditioning resulted in a robust infarct-sparing effect in both settings, suggesting additive cardioprotection. Celecoxib completely abrogated the infarct-sparing effect of the combined interventions in both settings. Late PC increased COX-2 protein expression and PGE2 content. PGE2 content (but not COX-2 protein) was further increased by the combination of both interventions, suggesting that postconditioning increases the activity of COX-2 induced by late PC. In conclusion, the combination of late PC and postconditioning produces additive protection, likely due to a postconditioning-induced enhancement of COX-2 activity.
  • 8.

    【2hr】Reduced central blood volume and cardiac output and increased vascular resistance during static handgrip exercise in postural tachycardia syndrome

    包量

    机译 姿势性心动过速综合征的静态手柄锻炼过程中中心血容量和心输出量减少，血管阻力增加
    摘要：Postural tachycardia syndrome (POTS) is characterized by exercise intolerance and sympathoactivation. To examine whether abnormal cardiac output and central blood volume changes occur during exercise in POTS, we studied 29 patients with POTS (17–29 yr) and 12 healthy subjects (18–27 yr) using impedance and venous occlusion plethysmography to assess regional blood volumes and flows during supine static handgrip to evoke the exercise pressor reflex. POTS was subgrouped into normal and low-flow groups based on calf blood flow. We examined autonomic effects with variability techniques. During handgrip, systolic blood pressure increased from 112 ± 4 to 139 ± 9 mmHg in control, from 119 ± 6 to 143 ± 9 in normal-flow POTS, but only from 117 ± 4 to 128 ± 6 in low-flow POTS. Heart rate increased from 63 ± 6 to 82 ± 4 beats/min in control, 76 ± 3 to 92 ± 6 beats/min in normal-flow POTS, and 88 ± 4 to 100 ± 6 beats/min in low-flow POTS. Heart rate variability and coherence markedly decreased in low-flow POTS, indicating uncoupling of baroreflex heart rate regulation. The increase in central blood volume with handgrip was absent in low-flow POTS and blunted in normal-flow POTS associated with abnormal splanchnic emptying. Cardiac output increased in control, was unchanged in low-flow POTS, and was attenuated in normal-flow POTS. Total peripheral resistance was increased compared with control in all POTS. The exercise pressor reflex was attenuated in low-flow POTS. While increased cardiac output and central blood volume characterizes controls, increased peripheral resistance with blunted or eliminated in central blood volume increments characterizes POTS and may contribute to exercise intolerance.
  • 9.

    【2hr】The Role of the Cyclooxygenase Products in Evoking Sympathetic Activation in Exercise

    包量

    机译 环氧合酶产物在运动中引起交感神经激活的作用
    摘要：Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied; in part because of systemic effects of pharmacologic agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and post exercise muscle ischemia (PEMI) before and after local infusion of 6 mg ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n=10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to ~33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Δ502±111; post ketorolac: Δ348±62%, P=0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P=0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip, and suggest that prostaglandins contribute to the exercise pressor reflex.
  • 10.

    【2hr】The Role of Spatial Dispersion of Repolarization in Inherited and Acquired Sudden Cardiac Death Syndromes

    包量

    机译 复极化的空间分散在遗传性和获得性心脏猝死综合征中的作用
    • 作者：Charles Antzelevitch
    • 刊名：American Journal of Physiology - Heart and Circulatory Physiology
    • 2007年第4期
    摘要：This review examines the role of spatial electrical heterogeneity within ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia (CPVT) are critically examined. In the long QT Syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada Syndrome, it is thought to be due to selective abbreviation of the APD of right ventricular (RV) epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death.
  • 11.

    【2hr】Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly, by reducing oxidative stress

    包量

    机译 尿皮质激素通过减少氧化应激而间接响应再灌注损伤，从而阻止线粒体通透性转变
    摘要：Urocortin (Ucn) protects hearts against ischemia and reperfusion injury whether given prior to ischemia or at reperfusion. Here we investigate the roles of protein kinase C, reactive oxygen species, and the mitochondrial permeability transition pore (MPTP) in mediating these effects. In Langendorff-perfused rat hearts, acute Ucn treatment improved hemodynamic recovery during reperfusion after 30 min global ischemia; this was accompanied by less necrosis (lactate dehydrogenase release) and MPTP opening (mitochondrial entrapment of [3H]-2-deoxyglucose). Ucn pre-treatment protected mitochondria against calcium-induced MPTP opening, but only if the mitochondria had been isolated from hearts after reperfusion. These mitochondria also exhibited less protein carbonylation, suggesting that Ucn decreases levels of oxidative stress. In isolated adult and neonatal rat cardiac myocytes, both acute (60 min) and chronic (16 hr) treatment with Ucn reduced cell death following simulated ischemia and re-oxygenation. This was accompanied by less MPTP opening as measured using tetramethylrhodamine methyl ester. The level of oxidative stress during reperfusion was reduced in cells which had been pre-treated with Ucn suggesting that this is the mechanism by which Ucn desensitizes the MPTP to reperfusion injury. Despite the fact that we could find no evidence that either PKCε or PKCα translocate to the mitochondria following acute Ucn treatment, inhibition of PKC with chelerythrine eliminated the effect of Ucn on oxidative stress. Our data suggests that acute Ucn treatment protects the heart by inhibiting MPTP opening. However, the mechanism appears to be indirect, involving a PKC-mediated reduction in oxidative stress.
  • 12.

    【2hr】Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway

    包量

    机译 硝基亚油酸通过Keap1 / Nrf2信号通路抑制血管平滑肌细胞增殖
    摘要：Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells (VSMCs). The present study examined the role of nitro-linoleic acid (LNO2) in the regulation of VSMC proliferation. We observed that LNO2 inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO2 induced growth arrest of VSMCs in the G1/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27kip1. Furthermore, LNO2 triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs. LNO2 upregulated the expression of Nrf2 protein levels, but not mRNA levels, in VSMCs. A forced activation of Nrf2 led to an upregulation of p27kip1 and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO2-induced upregulation of p27kip1 and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO2 inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.
  • 13.

    【2hr】Asynchrony of ventricular activation affects magnitude and timing of fiber stretch in late-activated regions of the canine heart

    包量

    机译 心室激活的异步性影响犬心脏晚期激活区域中纤维舒张的幅度和时间
    摘要：Abnormal electrical activation of the left ventricle results in mechanical dyssynchrony, which is in part characterized by early stretch of late-activated myofibers. To describe the pattern of deformation during “prestretch” and gain insight into its causes and sequelae, we implanted midwall and transmural arrays of radiopaque markers into the left ventricular anterolateral wall of open-chest, isoflurane-anesthetized, adult mongrel dogs. Biplane cineradiography (125 Hz) was used to determine the time course of two- and three-dimensional strains while pacing from a remote, posterior wall site. Strain maps were generated as a function of time. Electrical activation was assessed with bipolar electrodes. Posterior wall pacing generated prestretch at the measurement site, which peaked 44 ms after local electrical activation. Overall magnitudes and transmural gradients of strain were reduced when compared with passive inflation. Fiber stretch was larger at aortic valve opening compared with end diastole (P < 0.05). Fiber stretch at aortic valve opening was weakly but significantly correlated with local activation time (r2 = 0.319, P < 0.001). With a short atrioventricular delay, fiber lengths were not significantly different at the time of aortic valve opening during ventricular pacing compared with atrial pacing. However, ejection strain did significantly increase (P < 0.05). We conclude that the majority of fiber stretch occurs after local electrical activation and mitral valve closure and is different from passive inflation. The increased shortening of these regions appears to be because of a reduced afterload rather than an effect of length-dependent activation in this preparation.
  • 14.

    【2hr】Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase

    包量

    机译 缺乏脂肪酸酰胺水解酶的小鼠与年龄有关的心脏功能障碍，心肌硝化应激，炎症基因表达和细胞凋亡减少
    摘要：Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (FAAH−/−) mice and their wild-type (FAAH+/+) littermates. Additionally, we have explored the effects of anandamide on TNF-α-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2- to 3-mo-old (young) FAAH−/− and FAAH+/+ mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-α, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose)polymerase cleavage and caspase-3/9 activity, observed in 28- to 31-mo-old (aging) FAAH+/+ mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB1 and CB2 receptor gene expression between young and aging FAAH−/− and FAAH+/+ mice. Anandamide dose dependently attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression, NF-κB activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB1-and CB2-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis.
  • 15.

    【2hr】INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN HEART FAILURE IS NOT DUE TO DESENSITIZATION OF THE ARTERIAL BAROREFLEX

    包量

    机译 心脏衰竭中心脏交感神经活动的增加不是由于动脉压力反射变弱
    摘要：Increased sympathetic drive to the heart worsens prognosis in heart failure, but the level of cardiac sympathetic nerve activity (CSNA) has been assessed only by indirect methods, which do not permit testing whether its control by arterial baroreceptors is defective. To do this, CSNA was measured directly in 16 female sheep, 8 of which had been ventricularly paced at 200–220 beats/min for 4–6 weeks, until their ejection fraction fell to between 35 and 40%. Recording electrodes were surgically implanted in the cardiac sympathetic nerves and after 3 days’ recovery, responses to intravenous phenylephrine and nitroprusside infusions were measured in conscious sheep. Electrophysiological recordings showed that resting CSNA (bursts/100 heart beats) was significantly elevated in heart failure sheep (89±3) compared with normal animals (46±6, P<0.001). This increased CSNA was not accompanied by any increase in the low frequency power of heart rate variability. The baroreceptor- heart rate reflex was significantly depressed in heart failure (maximum gain −3.29±0.56 vs. −5.34±0.66 beats/min/mmHg in normal animals), confirming published findings. In contrast, the baroreflex control of CSNA was undiminished (maximum gain in heart failure −6.33±1.06, vs. −6.03±0.95 %/mmHg in normal sheep). Direct recordings in a sheep model of heart failure thus show that resting CSNA is strikingly increased, but this is not due to defective control by arterial baroreceptors.
  • 16.

    【2hr】Interaction between spiral and paced waves in cardiac tissue

    包量

    机译 心脏组织中的螺旋波与起搏波之间的相互作用
    摘要：For prevention of lethal arrhythmias, patients at risk receive implantable cardioverter-defibrillators, which use high-frequency antitachycardia pacing (ATP) to convert tachycardias to a normal rhythm. One of the suggested ATP mechanisms involves paced-induced drift of rotating waves followed by their collision with the boundary of excitable tissue. This study provides direct experimental evidence of this mechanism. In monolayers of neonatal rat cardiomyocytes in which rotating waves of activity were initiated by premature stimuli, we used the Ca2+-sensitive indicator fluo 4 to observe propagating wave patterns. The interaction of the spiral tip with a paced wave was then monitored at a high spatial resolution. In the course of the experiments, we observed spiral wave pinning to local heterogeneities within the myocyte layer. High-frequency pacing led, in a majority of cases, to successful termination of spiral activity. Our data show that 1) stable spiral waves in cardiac monolayers tend to be pinned to local heterogeneities or areas of altered conduction, 2) overdrive pacing can shift a rotating wave from its original site, and 3) the wave break, formed as a result of interaction between the spiral tip and a paced wave front, moves by a paced-induced drift mechanism to an area where it may become unstable or collide with a boundary. The data were complemented by numerical simulations, which was used to further analyze experimentally observed behavior.
  • 17.

    【2hr】Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

    包量

    机译 心脏受限的血管紧张素转换酶过度表达导致传导缺陷和连接蛋白失调
    摘要：Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na+ channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca2+ channel, Kv4.2 K+ channel α-subunit, and Cx45 mRNA abundances and the peak ventricular Na+ current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.
  • 18.

    【2hr】Regulation of Ca2+ and electrical alternans in cardiac myocytes: Role of CaMKII and repolarizing currents

    包量

    机译 心肌细胞中Ca2 +和电交替素的调节：CaMKII和复极化电流的作用
    摘要：Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca2+ transient (CaT). Because of experimental difficulty in independently controlling the Ca2+ and electrical subsystems, mathematical modelling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1. (I) CaT alternans results from refractoriness of the SR Ca2+ release system; alternation of the L-type calcium current (ICa(L)) has a negligible effect; (II) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger (INaCa) and underlies APD alternans; (III) Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; (IV). Increase of the rapid delayed rectifier current (IKr) also suppresses APD alternans, but without suppressing CaT alternans. Thus, CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans), while IKr enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and IKr enhancement as a possible antiar-rhythmic intervention.
  • 19.

    【2hr】Effect of the Na-K-2Cl Cotransporter NKCC1 on Systemic Blood Pressure and Smooth Muscle Tone

    包量

    机译 Na-K-2Cl转运蛋白NKCC1对系统性血压和平滑肌音的影响
    摘要：Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCC1 is activated by vasoconstrictors and inhibited by nitrovasodilators, contributes to smooth muscle tone in vitro, and is upregulated in hypertension. To determine the role of NKCC1 in systemic vascular resistance and hypertension, blood pressure was measured in rats before and after inhibition of NKCC1 with bumetanide. Intravenous infusion of bumetanide sufficient to yield a free plasma concentration above the IC50 for NKCC1 produced an immediate drop in blood pressure of 5.2 % (P < 0.001). The reduction was not prevented when the renal arteries were clamped, indicating that it was not due to a renal effect of bumetanide. Bumetanide did not alter blood pressure in NKCC1 null mice, demonstrating that it was acting specifically through NKCC1. In third-order mesenteric arteries, bumetanide-inhibitable efflux of 86Rb was acutely stimulated 133 % by phenylephrine, and bumetanide reduced the contractile response to phenylephrine, indicating that NKCC1 influences tone in resistance vessels. The hypotensive effect of bumetanide was proportionately greater in rats made hypertensive by a 7-day infusion of norepinephrine (12.7 %, p < 0.001 vs. normotensive rats) but much less so when hypertension was produced by a fixed aortic coarctation (8.0 %), again consistent with an effect of bumetanide on resistance vessels rather than other determinants of blood pressure. We conclude that NKCC1 influences blood pressure through effects on smooth muscle tone in resistance vessels and that this effect is augmented in hypertension.
  • 20.

    【2hr】NADPH oxidase modulates myocardial Akt, ERK1/2 activation, and angiogenesis after hypoxia-reoxygenation

    包量

    机译 NADPH氧化酶调节缺氧-复氧后的心肌Akt，ERK1 / 2活化和血管生成
    摘要：Recent studies have demonstrated that reactive oxygen species (ROS) mediate myocardial ischemia-reperfusion (I/R) and angiogenesis via the mitogen-activated protein kinases and the serine-threonine kinase Akt/protein kinase B pathways. NADPH oxidases are major sources of ROS in endothelial cells and cardiomyocytes. In the present study, we investigated the role of NADPH oxidase-derived ROS in hypoxia-reoxygenation (H/R)-induced Akt and ERK1/2 activation and angiogenesis using porcine coronary artery endothelial cells (PCAECs) and a mouse myocardial I/R model. Our data demonstrate that exposure of PCAECs to hypoxia for 2 h followed by 1 h of reoxygenation significantly increased ROS formation. Pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI, 10 μM) and apocynin (Apo, 200 and 600 μM), significantly attenuated H/R-induced ROS formation. Furthermore, exposure of PCAECs to H/R caused a significant increase in Akt and ERK1/2 activation. Exposure of PCAEC spheroids and mouse aortic rings to H/R significantly increased endothelial spheroid sprouting and vessel outgrowth, whereas pharmacological inhibition of NADPH oxidase or genetic deletion of the NADPH oxidase subunit, p47phox (p47phox−/−), significantly suppressed these changes. With the use of a mouse I/R model, our data further show that the increases in myocardial Akt and ERK1/2 activation and vascular endothelial growth factor (VEGF) expression were markedly blunted in the p47phox−/− mouse subjected to myocardial I/R compared with the wild-type mouse. Our findings underscore the important role of NADPH oxidase and its subunit p47phox in modulating Akt and ERK1/2 activation, angiogenic growth factor expression, and angiogenesis in myocardium undergoing I/R.
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