Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels.

Ogawa, Satoshi; Barnett, Joey V.; Sen, Luyi; Galper, Jonas B.; Smith, Thomas W.; Marsh, James D.

doi:10.1172/jci115688

Cited by 72 publications

(45 citation statements)

References 28 publications

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“…Changes in calcium current have been described in neonatal rat cells cultured with or without sympathetic ganglia or neurons. Innervated myocytes show an increase in calcium current of ϳ50% (29,35). Similar studies (44) have reported an increase in sodium current in innervated neonatal rat ventricular cells.…”

Section: Discussionsupporting

confidence: 68%

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Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes

Bru–Mercier

Deroubaix

Rousseau³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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2001.-The effect of catecholamine depletion (induced by prior treatment with reserpine) was studied in Wistar rat ventricular myocytes using whole cell voltage-clamp methods. Two calcium-independent outward currents, the transient outward potassium current (I to) and the sustained outward potassium current (I sus), were measured. Reserpine treatment decreased tissue norepinephrine content by 97%. Action potential duration in the isolated perfused heart was significantly increased in reserpine-treated hearts. In isolated ventricular myocytes, Ito density was decreased by 49% in reserpine-treated rats. This treatment had no effect on Isus. The Ito steady-state inactivation-voltage relationship and recovery from inactivation remained unchanged, whereas the conductance-voltage activation curve for reserpine-treated rats was significantly shifted (6.7 mV) toward negative potentials. The incubation of myocytes with 10 M norepinephrine for 7-10 h restored Ito, an effect that was abolished by the presence of actinomycin D. Norepinephrine (0.5 M) had no effect on I to. However, in the presence of both 0.5 M norepinephrine and neuropeptide Y (0.1 M), I to density was restored to its control value. These results suggest that the sympathetic nervous system is involved in Ito regulation. Sympathetic norepinephrine depletion decreased the number of functional channels via an effect on the ␣-adrenergic cascade and norepinephrine is able to restore expression of Ito channels.heart; denervation; adrenergic system; neuropeptide Y TRANSIENT OUTWARD POTASSIUM CURRENT (I to ) and sustained outward potassium current (I sus ) play an important role in the regulation of action potential plateau amplitude and duration. Downregulation of these repolarizing currents increases the duration of the action potential (26) and may be involved in the genesis of arrhythmia by increasing the heterogeneity of action potential duration. I to amplitude is regulated by ␣ 1 -agonists in rat ventricular myocytes (2, 4) and by ␤-adrenergic agonists in canine Purkinje fibers (27). Both effects inducing a decrease in I to are modulated by phosphorylation. A marked decrease in I to density has been reported in various cardiac diseases including subacute myocardial infarction (22), myocardial hypertrophy (3, 5), hypertrophic cardiomyopathy (25), Xlinked muscular dystrophy (32), diabetes (16), and the acute phase of Chagas' disease (31).The mechanisms underlying the reduction of I to are not fully understood. Some lines of evidence suggest that the expression of I to is modulated by a trophic effect of the sympathetic nervous system. Three different models associating a decrease in I to with a decrease in sympathetic innervation have been studied. In Chagas' disease, the sympathetic nerve terminals are destroyed (23). This destruction occurs at the same time as a marked decrease in I to density during the acute phase of the disease (14, 31). In this model, a 24-h application of norepinephrine restored I to to normal values via adrenergic stimulation of protei...

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Section: Discussionsupporting

confidence: 68%

“…In myocardial infarction (17,36) and heart failure (25), a decrease in I to was reported, whereas a stimulation of the sympathetic nervous system was also reported. These observations raise the question as to whether reductions of I to were linked to chronic stimulatory effects of catecholamine (29). Until now, this point received no answer.…”

Section: Discussionmentioning

confidence: 99%

Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes

Bru–Mercier

Deroubaix

Rousseau³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…Cell suspensions underwent two preplating steps to minimize contamination with nonmyocyte cells; in some experiments, cardiac myocytes were isolated from neonatal rats exactly as described (21). Dissociated cells were placed in culture medium consisting of Dulbecco's modified essential medium, 7.5% fetal calf serum, and 0.1% penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Modulation of the Endothelial Nitric-oxide Synthase-Caveolin Interaction in Cardiac Myocytes

Féron

Dessy²,

Opel

et al. 1998

Journal of Biological Chemistry

172

104

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The endothelial isoform of nitric oxide synthase (eNOS) is dually acylated and thereby targeted to signaltransducing microdomains termed caveolae. In endothelial cells, eNOS interacts with caveolin-1, which represses eNOS enzyme activity. In cardiac myocytes, eNOS associates with the muscle-specific caveolin-3 isoform, but whether this interaction affects NO production and regulates myocyte function is unknown. We isolated neonatal cardiac myocytes from mutant mice with targeted disruption of the eNOS gene and transfected them with wild-type (WT) eNOS or myristoylation-deficient (myr ؊ ) eNOS mutant cDNA. In myocytes expressing WT eNOS, the muscarinic cholinergic agonist carbachol completely abrogated the spontaneous beating rate and induced a 4-fold elevation of the cGMP level. By contrast, in the myr ؊ eNOS myocytes, carbachol failed to exert its negative chronotropic effect and to increase cGMP levels. We then used a reversible permeabilization protocol to load intact neonatal rat myocytes with an oligopeptide corresponding to the caveolin-3 scaffolding domain. This peptide completely and specifically inhibited the carbachol-induced negative chronotropic effect and the accompanying cGMP elevation. Thus, our results suggest that acylated eNOS may couple muscarinic receptor activation to heart rate control and indicate a key role for eNOS/caveolin interactions in the cholinergic modulation of cardiac myocyte function.The endothelial isoform of nitric-oxide synthase (eNOS) 1 , originally identified in large vessel endothelium, is now known to be expressed in numerous cell types, including cardiac myocytes. The eNOS enzyme is dually acylated (for review, see Refs. 1 and 2) and is thereby specifically targeted to plasmalemmal signal-transducing microdomains termed caveolae (3, 4). In endothelial cells and cardiac myocytes, eNOS is quantitatively associated with caveolin (4), the structural protein of caveolae, and a stable protein-protein interaction takes place at consensus sequences present within both proteins and leads to the inhibition of the eNOS activity (5-8). More recently, we have also documented that, in endothelial cells, when intracellular Ca 2ϩ concentration is increased by an agonist, a regulatory cycle is initiated (2, 9), wherein (i) Ca 2ϩ /calmodulin activates eNOS by disrupting the heteromeric complex formed between eNOS and caveolin; (ii) activated, caveolin-free eNOS is translocated from caveolae, probably associated with enzyme desensitization; (iii) when Ca 2ϩ returns to basal levels, eNOS reassociates with caveolin; and (iv) the inhibitory complex is restored to caveolae, a process facilitated by eNOS palmitoylation. The role (if any) of this eNOS-caveolin regulatory cycle in cardiac myocytes, however, remains to be established.The location of eNOS in plasmalemmal caveolae and its interaction with caveolin may find several biological justifications. First, the compartmentation of eNOS with other signaling proteins may facilitate, or improve the efficacy of, the coupling between agonist stim...

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“…Dihydropyridine-DHP binding studies were carried out as described previously (Chapados et al 1992;Davidoff et al 1997;Gruver et al 1993;Ogawa et al 1992;Scatchard 1949). A crude ventricular homogenate was placed into ice-cold buffer containing (mM); 50 HEPES, 1 MgCl 2 , 1 EDTA, pH 7.4.…”

Section: Radioligand Bindingmentioning

confidence: 99%

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Kim

Davidoff

Mäki

et al. 2000

Journal of Comparative Physiology B: Biochemical, Systemic, and

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Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm).Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current-and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates. Keywords

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Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels.

Cited by 72 publications

References 28 publications

Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes

Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes

Modulation of the Endothelial Nitric-oxide Synthase-Caveolin Interaction in Cardiac Myocytes

Intracellular calcium and the relationship to contractility in an avian model of heart failure

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