Chemical sympathetic denervation, suppression of myocardial transient outward potassium current, and ventricular fibrillation in the rat

2008 ◽  
Vol 86 (10) ◽  
pp. 700-709 ◽  
Author(s):  
Juan Bai ◽  
Chongyu Ren ◽  
Wei Hao ◽  
Rui Wang ◽  
Ji-Min Cao
Keyword(s):  
Ventricular Fibrillation ◽  
Sympathetic Nerve ◽  
Sympathetic Innervation ◽  
Outward Current ◽  
Sympathetic Denervation ◽  
Transient Outward Current ◽  
Chemical Sympathectomy ◽  
Cardiac Sympathetic Nerve ◽  
Patch Clamp Technique ◽  
Kv Channel

Sympathetic denervation is frequently observed in heart disease. To investigate the linkage of sympathetic denervation and cardiac arrhythmia, we developed a rat model of chemical sympathectomy by subcutaneous injections of 6-hydroxydopamine (6-OHDA). Cardiac sympathetic innervation was visualized by means of a glyoxylic catecholaminergic histofluorescence method. Transient outward current (Ito) of ventricular myocytes was recorded with the whole-cell configuration of the patch clamp technique. We observed that sympathectomy (i) decreased cardiac sympathetic nerve density and norepinephrine level, (ii) reduced the protein expression of Kv4.2, Kv1.4, and Kv channel-interacting protein 2 (KChIP2), (iii) decreased current densities and delayed activation of Ito channels, (iv) reduced the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP response element-binding protein (CREB), and (v) increased the severity of ventricular fibrillation induced by rapid pacing. Three weeks after 6-OHDA injections, which allowed time for sympathetic regeneration, we found cardiac sympathetic nerve density, norepinephrine levels, expression levels of Kv4.2 and KChIP2 proteins, and Ito densities were partially normalized and ventricular fibrillation severity was decreased. We conclude that chemical sympathectomy downregulates the expression of selective Kv channel subunits and decreases myocardial Ito channel activities, contributing to the elevated susceptibility to ventricular fibrillation.

Chronic exposure to neuropeptide Y determines cardiac alpha 1-adrenergic responsiveness

1991 ◽  
Vol 261 (3) ◽  
pp. H969-H973 ◽  
Author(s):  
L. S. Sun ◽  
P. C. Ursell ◽  
R. B. Robinson
Keyword(s):  
Neuropeptide Y ◽  
Sympathetic Nerve ◽  
Chronic Exposure ◽  
Developmental Change ◽  
Sympathetic Innervation ◽  
Nerve Terminals ◽  
Cardiac Sympathetic Nerve ◽  
Cardiac Sympathetic Innervation ◽  
Chronotropic Response ◽  
Npy Antagonist

The onset of sympathetic innervation induces a developmental change in the cardiac alpha 1-adrenergic chronotropic response from an increase to a decrease in rate. The mechanism by which innervation induces this alteration is unknown. Neuropeptide Y (NPY), which is found abundantly in cardiac sympathetic nerve terminals, was considered as a possible mediator for this effect. Chronic conditioning by NPY in noninnervated myocyte cultures stimulated the effect of sympathetic innervation in inducing the alpha 1-inhibitory chronotropic response. Chronic conditioning by the NPY antagonist PYX-2 blocked the effect of innervation. Thus endogenous NPY may modulate alpha 1-adrenergic responsiveness during the ontogeny of cardiac sympathetic innervation.

Transient potassium currents in avian sensory neurons

1990 ◽  
Vol 63 (4) ◽  
pp. 725-737 ◽  
Author(s):  
S. K. Florio ◽  
C. D. Westbrook ◽  
M. R. Vasko ◽  
R. J. Bauer ◽  
J. L. Kenyon
Keyword(s):  
Single Channel ◽  
Outward Current ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Single Channels ◽  
Patch Clamp Technique ◽  
Small Component ◽  
Whole Cell ◽  
Outward Currents

1. We used the patch-clamp technique to study voltage-activated transient potassium currents in freshly dispersed and cultured chick dorsal root ganglion (DRG) cells. Whole-cell and cell-attached patch currents were recorded under conditions appropriate for recording potassium currents. 2. In whole-cell experiments, 100-ms depolarizations from normal resting potentials (-50 to -70 mV) elicited sustained outward currents that inactivated over a time scale of seconds. We attribute this behavior to a component of delayed rectifier current. After conditioning hyperpolarizations to potentials negative to -80 mV, depolarizations elicited transient outward current components that inactivated with time constants in the range of 8-26 ms. We attribute this behavior to a transient outward current component. 3. Conditioning hyperpolarizations increased the rate of activation of the net outward current implying that the removal of inactivation of the transient outward current allows it to contribute to early outward current during depolarizations from negative potentials. 4. Transient current was more prominent on the day the cells were dispersed and decreased with time in culture. 5. In cell-attached patches, single channels mediating outward currents were observed that were inactive at resting potentials but were active transiently during depolarizations to potentials positive to -30 mV. The probability of channels being open increased rapidly (peaking within approximately 6 ms) and then declined with a time constant in the range of 13-30 ms. With sodium as the main extracellular cation, single-channel conductances ranged from 18 to 32 pS. With potassium as the main extracellular cation, the single-channel conductance was approximately 43 pS, and the channel current reversed near 0 mV, as expected for a potassium current. 6. We conclude that the transient potassium channels mediate the component of transient outward current seen in the whole-cell experiments. This current is a relatively small component of the net current during depolarizations from normal resting potentials, but it can contribute significant outward current early in depolarizations from hyperpolarized potentials.

Divalent cations modulate the transient outward current in rat ventricular myocytes

1991 ◽  
Vol 261 (2) ◽  
pp. C310-C318 ◽  
Author(s):  
Z. S. Agus ◽  
I. D. Dukes ◽  
M. Morad
Keyword(s):  
Hippocampal Neurons ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Divalent Cations ◽  
Outward Current ◽  
Transient Outward Current ◽  
Patch Clamp Technique ◽  
Rat Ventricular Myocytes ◽  
Specific Effects ◽  
Whole Cell Patch Clamp

The modulation of the transient outward K+ current (Ito) by divalent cations was studied in enzymatically isolated rat ventricular myocytes with the whole cell patch-clamp technique. At holding potentials negative to -70 mV, 1 mM Cd2+ suppressed Ito, whereas, at potentials positive to -50 mV, the current was augmented. These effects were caused by shifts in the voltage dependence of both activation and inactivation of Ito toward more positive potentials. Cd2+ also slowed the activation kinetics of Ito by shifting the voltage dependence of its rate of activation, but the rate of inactivation was unaffected. Other divalent cations produced similar shifts but at markedly different concentrations. Thus, in the millimolar range, a rightward shift of approximately 20 mV was produced by 3 Co2+, 5 Ni2+, and 10 Ca2+, whereas 10 microM concentrations of Cu2+ and Zn2+ produced equivalent shifts. Similar effects were seen in hippocampal neurons with micromolar concentrations of Zn2+. Thus divalent cations have marked and specific effects on the kinetics and voltage dependence of Ito and may serve as a regulatory mechanism in its activation, particularly in cells with resting potentials positive to -60 mV.

Ca2+-activated Cl− current can be triggered by Na+ current-induced SR Ca2+ release in rabbit ventricle

1999 ◽  
Vol 277 (4) ◽  
pp. H1467-H1477 ◽  
Author(s):  
Hui Sun ◽  
Denis Chartier ◽  
Stanley Nattel ◽  
Normand Leblanc
Keyword(s):  
Ventricular Myocytes ◽  
Physiological Role ◽  
Reversal Potential ◽  
Outward Current ◽  
External Solution ◽  
Rabbit Heart ◽  
Transient Outward Current ◽  
Release Mechanism ◽  
Patch Clamp Technique ◽  
Reverse Mode

The Ca2+-activated Cl− current [ I Cl(Ca)] contributes to the repolarization of the cardiac action potential under physiological conditions. I Cl(Ca) is known to be primarily activated by Ca2+release from the sarcoplasmic reticulum (SR). L-type Ca2+ current [ I Ca(L)] represents the major trigger for Ca2+ release in the heart. Recent evidence, however, suggests that Ca2+ entry via reverse-mode Na+/Ca2+exchange promoted by voltage and/or Na+ current ( I Na) may also play a role. The purpose of this study was to test the hypothesis that I Cl(Ca) can be induced by I Na in the absence of I Ca(L). Macroscopic currents and Ca2+transients were measured using the whole cell patch-clamp technique in rabbit ventricular myocytes loaded with Indo-1. Nicardipine (10 μM) abolished I Ca(L)at a holding potential of −75 mV as tested in Na+-free external solution. In the presence of 131 mM external Na+and in the absence of I Ca(L), a 4-aminopyridine-resistant transient outward current was recorded in 64 of 81 cells accompanying a phasic Ca2+ transient. The current reversed at −42.0 ± 1.3 mV ( n = 6) and at +0.3 ± 1.4 mV ( n = 6) with 21 and 141 mM of internal Cl−, respectively, similar to the predicted reversal potential with low intracellular Cl− concentration ([Cl−]i) (−47.8 mV) and high [Cl−]i(−1.2 mV). Niflumic acid (100 μM) inhibited the current without affecting the Ca2+ signal ( n = 8). Both the current and Ca2+ transient were abolished by 10 mM caffeine ( n = 6), 10 μM ryanodine ( n = 3), 30 μM tetrodotoxin ( n = 9), or removal of extracellular Ca2+( n = 6). These properties are consistent with those of I Cl(Ca)previously described in mammalian cardiac myocytes. We conclude that 1) I Cl(Ca) can be recorded in the absence of I Ca(L), and 2) I Na-induced SR Ca2+ release mechanism is also present in the rabbit heart and may play a physiological role in activating the Ca2+-sensitive membrane Cl− conductance.

scholarly journals Hibernating myocardium results in partial sympathetic denervation and nerve sprouting

2013 ◽  
Vol 304 (2) ◽  
pp. H318-H327 ◽  
Author(s):  
Stanley F. Fernandez ◽  
Vladislav Ovchinnikov ◽  
John M. Canty ◽  
James A. Fallavollita
Keyword(s):  
Sudden Death ◽  
Sympathetic Nerve ◽  
Sympathetic Innervation ◽  
Sympathetic Denervation ◽  
Hibernating Myocardium ◽  
Arrhythmic Death ◽  
Electrical Instability ◽  
Nerve Sprouting ◽  
Nerve Dysfunction ◽  
Tissue Norepinephrine

Hibernating myocardium due to chronic repetitive ischemia is associated with regional sympathetic nerve dysfunction and spontaneous arrhythmic death in the absence of infarction. Although inhomogeneity in regional sympathetic innervation is an acknowledged substrate for sudden death, the mechanism(s) responsible for these abnormalities in viable, dysfunctional myocardium (i.e., neural stunning vs. sympathetic denervation) and their association with nerve sprouting are unknown. Accordingly, markers of sympathetic nerve function and nerve sprouting were assessed in subendocardial tissue collected from chronically instrumented pigs with hibernating myocardium ( n = 18) as well as sham-instrumented controls ( n = 7). Hibernating myocardium exhibited evidence of partial sympathetic denervation compared with the normally perfused region and sham controls, with corresponding regional reductions in tyrosine hydroxylase protein (−32%, P < 0.001), norepinephrine uptake transport protein (−25%, P = 0.01), and tissue norepinephrine content (−45%, P < 0.001). Partial denervation induced nerve sprouting with regional increases in nerve growth factor precursor protein (31%, P = 0.01) and growth associated protein-43 (38%, P < 0.05). All of the changes in sympathetic nerve markers were similar in animals that developed sudden death ( n = 9) compared with electively terminated pigs with hibernating myocardium ( n = 9). In conclusion, sympathetic nerve dysfunction in hibernating myocardium is most consistent with partial sympathetic denervation and is associated with regional nerve sprouting. The extent of sympathetic remodeling is similar in animals that develop sudden death compared with survivors; this suggests that sympathetic remodeling in hibernating myocardium is not an independent trigger for sudden death. Nevertheless, sympathetic remodeling likely contributes to electrical instability in combination with other factors.

scholarly journals Voltage-Activated Ionic Currents in Myoepithelial Cells Isolated from the Sea Anemone Calliactis Tricolor

1991 ◽  
Vol 161 (1) ◽  
pp. 333-346 ◽  
Author(s):  
MOLLY A. HOLMAN ◽  
PETER A. V. ANDERSON
Keyword(s):  
Action Potentials ◽  
Outward Current ◽  
Ionic Currents ◽  
Myoepithelial Cells ◽  
Sea Anemone ◽  
Calcium Currents ◽  
Transient Outward Current ◽  
Ionic Selectivity ◽  
Patch Clamp Technique ◽  
Steady State Current

Myoepithelial cells were isolated from the apical ends of mesenteries of the sea anemone Calliactis tricolor and examined using the whole-cell configuration of the patch-clamp technique. The isolation procedure produced cell fragments that were contractile and produced action potentials when depolarized. These action potentials are formed by a complex array of ionic currents consisting of at least one, and possibly two, inward calcium currents and four outward potassium currents. The ionic selectivity of the calcium currents was Ca2+&gt;Sr2+&gt;Ba2+. Outward currents consisted of a calcium-dependent outward current and three voltage-activated currents, including a 4-aminopyridine-sensitive current, a transient outward current and a steady-state current.

Ionic currents in identified swimmeret motor neurones of the crayfish Pacifastacus leniusculus

1995 ◽  
Vol 198 (7) ◽  
pp. 1483-1492 ◽  
Author(s):  
A Chrachri
Keyword(s):  
Time Course ◽  
Outward Current ◽  
Rhythmic Activity ◽  
Ionic Currents ◽  
Power Stroke ◽  
Transient Outward Current ◽  
Patch Clamp Technique ◽  
Outward Currents ◽  
Inward Currents ◽  
Motor Neurones

Ionic currents from freshly isolated and identified swimmeret motor neurones were characterized using a whole-cell patch-clamp technique. Two outward currents could be distinguished. A transient outward current was elicited by delivering depolarizing voltage steps from a holding potential of -80 mV. This current was inactivated by holding the cells at a potential of -40 mV and was also blocked completely by 4-aminopyridine. A second current had a sustained time course and continued to be activated at a holding potential of -40 mV. This current was partially blocked by tetraethylammonium. These outward currents resembled two previously described potassium currents: the K+ A-current and the delayed K+ rectifier current respectively. Two inward currents were also detected. A fast transient current was blocked by tetrodotoxin and inactivated at holding potential of -40 mV, suggesting that this is an inward Na+ current. A second inward current had a sustained time course and was affected neither by tetrodotoxin nor by holding the cell at a potential of -40 mV. This current was substantially enhanced by the addition of Ba2+ to the bath or when equimolar Ba2+ replaced Ca2+ as the charge carrier. Furthermore, this current was significantly suppressed by nifedipine. All these points suggest that this is an L-type Ca2+ current. Bath application of nifedipine into an isolated swimmeret preparation affected both the frequency of the swimmeret rhythm and the duration of power-stroke activity, suggesting an important role for the inward Ca2+ current in maintaining a regular swimmeret rhythmic activity in crayfish.

Ca2+ inhibits outward current through single K+ channels in canine atrial myocyte sarcolemma

1988 ◽  
Vol 254 (3) ◽  
pp. C397-C403 ◽  
Author(s):  
J. K. Bubien ◽  
H. Van Der Heyde ◽  
W. T. Woods
Keyword(s):  
Single Channel ◽  
Outward Current ◽  
K Channel ◽  
Transient Outward Current ◽  
Single Channels ◽  
Bathing Solution ◽  
Voltage Sensitivity ◽  
Patch Clamp Technique ◽  
K Channels ◽  
Single Channel Currents

Single-channel currents in canine atrial cells were recorded by the patch-clamp technique in a bathing solution containing 150 mM [K+] and pipette solutions containing 5 mM [K+]. One kind of current was observed in 56% of 178 cell-free patches and in 3% of 60 patches in the cell-attached configuration. Single-channel amplitude varied in direct proportion to the bath [K+]. Openings of these single channels were prevented when bath [Ca2+] exceeded 1 microM. Below this concentration single-channel percent open time was inversely proportional to log [Ca2+]. Inward current was observed at hyperpolarized membrane potentials in some patches. There was no apparent steady-state voltage sensitivity. These properties suggest that the K+ channel described in this study (gK+LF), a low transition frequency K+ conductor, may be distinct from single K+ channels previously studied in cardiac myocyte sarcolemmae. The single-channel response to "intracellular" free [Ca2+] and the single-channel kinetic characteristics described in this study are similar to the macroscopic "long-lasting transient outward current" (IIO) described by Escande et al. [Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H142-H148, 1987] in human atrial myocytes (tau open = 29.6 ms, tau inactivation = 35.7 ms, respectively). This suggests that gK+LF channels may carry IIO.

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