Daurisoline Suppressed Early Afterdepolarizations and Inhibited L-Type Calcium Current

2010 ◽  
Vol 38 (01) ◽  
pp. 37-49 ◽  
Author(s):  
Qiang-Ni Liu ◽  
Li Zhang ◽  
Pei-Li Gong ◽  
Xiao-Yan Yang ◽  
Fan-Dian Zeng
Keyword(s):  
Steady State ◽  
Calcium Current ◽  
Left Ventricular ◽  
Papillary Muscles ◽  
Early Afterdepolarizations ◽  
Whole Cell Patch Clamp ◽  
Ventricular Cells ◽  
Steady State Inactivation ◽  
The Right ◽  
Low K

Our previous studies have shown that daurisoline (DS) exerted antiarrhythmic effects on various experimental arrhythmias. In this study, the effects of DS on early afterdepolarizations (EADs) and its possible mechanisms have been investigated. Cardiac hypertrophy was induced in rabbits by coarctating the abdominal aorta. The effects of DS on action potential duration (APD) and the incidences of EADs were studied in hypertrophied papillary muscles of rabbits in the conditions of low external K + concentration ([ K +] o ) and dofetilide (dof) by using standard microelectrode technique. The whole-cell patch clamp was used to record the L-type calcium current ( ICa-L ) in isolated left ventricular cells of rabbits. The results showed that in hypertrophied papillary muscles of rabbits with low [ K +] o ([ K +]o = 2.7 mM ), 1 µM dof prolonged APD50 and APD90 markedly and the incidence of EADs was 66.7% (4/6, p < 0.01); when 15 µM DS was applied, the incidence of EADs was 0% (0/4, p < 0.01) and the prolonged APD was shortened (p < 0.01). In a single myocyte, DS could also inhibit EADs induced by dof, low [ K +] o and low external Mg 2+ concentration ([ Mg 2+] o ) ([ Mg 2+] o = 0.5 mM ). DS could decrease the triangulation. In a single myocyte, DS could make the I-V curve upward, shift the steady-state activation curves to the right and the steady-state inactivation curves to the left and prolong the τ value of recovery curve obviously. These results suggested that DS could inhibit EADs which may be associated with its blockade effects on ICa-L .

Inhibitory effects of dauricine on early afterdepolarizations and L-type calcium current

2009 ◽  
Vol 87 (11) ◽  
pp. 954-962 ◽  
Author(s):  
Qiang-Ni Liu ◽  
Li Zhang ◽  
Pei-Li Gong ◽  
Xiao-Yan Yang ◽  
Fan-Dian Zeng
Keyword(s):  
Steady State ◽  
Calcium Current ◽  
Enzymatic Digestion ◽  
Papillary Muscles ◽  
Inhibitory Effects ◽  
Early Afterdepolarizations ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
The Right ◽  
Microelectrode Techniques

We have previously reported that dauricine exerted antiarrhythmic effects on various experimental arrhythmias. To further clarify its mechanism, the effects of dauricine on action potential duration (APD), early afterdepolarizations (EADs), triangulation, which is defined as the repolarization time from APD at 30% level (APD30) to APD at 90% level (APD90), and L-type calcium current (ICa-L) were studied using standard microelectrode techniques on rabbit papillary muscles and whole-cell patch clamp techniques on single myocytes isolated from rabbits by enzymatic digestion, respectively. Cardiac hypertrophy was induced by coarctating the abdominal aorta of rabbits. The results showed that in papillary muscles of hypertrophied rabbits, 1 µmol/L dofetilide, a selective IKr blocker, prolonged APD50 and APD90 and induced EADs (4/6, p < 0.01) with hypokalemia ([K+]o = 2.7 mmol/L). Dauricine inhibited EADs (p < 0.01) and shortened the prolonged APD (p < 0.01). In single myocytes, dauricine also inhibited EADs induced by dofetilide, hypokalemia, and hypomagnesaemia. Dauricine decreased the triangulation and reduced the peak amplitude of ICa-L at all potentials tested. Dauricine shifted the steady-state activation curves to the right and steady-state inactivation curves to the left and prolonged the τ value of the recovery curve. These results suggest that dauricine inhibits EADs and this effect may be associated with its blockade of ICa-L.

Abstract 89: The Ventriculo-Ventricular Coupling Index: A Novel Approach to Assessing Biventricular Function

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Navin K Kapur ◽  
Mark J Aronovitz ◽  
Robert Blanton ◽  
Emily Mackey ◽  
Vikram Paruchuri ◽  
...  
Keyword(s):  
Heart Failure ◽  
Steady State ◽  
Left Ventricular ◽  
External Jugular Vein ◽  
Arterial Elastance ◽  
Left Heart Failure ◽  
Novel Approach ◽  
Coupling Index ◽  
Ventricular Efficiency ◽  
The Right

Bi-ventricular (Bi-V) function in primary pulmonary hypertension (PPH) or PH secondary to left heart failure (SPH) remains difficult to characterize. As a measure of ventricular efficiency, ventriculo-arterial coupling (VAC) is calculated as the ratio of effective arterial elastance (Ea) to end-systolic elastance (Ees). No measure currently assesses ventriculo-ventricular coupling (VVC). Therefore, we developed a novel catheter-based approach to quantify Bi-V function using pressure-volume loop (PVL) analysis and hypothesized that Bi-V VAC ratios, defined as the VVC index (VVCI), may discriminate PPH and SPH. Methods: Adult male mice (n=6/group) underwent constriction of the pulmonary artery (PAC) or thoracic aorta (TAC) to model PPH and SPH respectively. Sham-operated animals underwent a left thoracotomy. Closed chest simultaneous Bi-V catheterization was performed after 7 days in PPH and 10 weeks in SPH. Conductance catheters were used for right and left ventricular PVL analysis via the right external jugular vein and right common carotid artery under steady-state conditions and with variable preload. Results: Steady-state Bi-V PVL and changes in VAC ratios and the VVCI are shown below. In sham mice VAC ratios and the VVCI reflect optimal ventricular efficiency. In PPH, the VVCI is significantly increased, while in SPH, the VVCI is significantly decreased compared to controls. Conclusion: These results identify a novel method to quantify Bi-V function in mice and further show that the VVCI can distinguish PPH and SPH. These findings have important implications for examining cardiac function in preclinical and clinical studies of left- and right-sided heart failure.

scholarly journals Heart anatomy of Giraffa camelopardalis rothschildi: a case report

2008 ◽  
Vol 53 (No. 3) ◽  
pp. 165-168 ◽  
Author(s):  
W. Perez ◽  
M. Lima ◽  
G. Pedrana ◽  
F. Cirillo
Keyword(s):  
Case Report ◽  
Coronary Artery ◽  
Left Ventricle ◽  
Left Coronary Artery ◽  
Left Ventricular ◽  
Left Auricle ◽  
Papillary Muscles ◽  
Atrioventricular Valve ◽  
Heart Anatomy ◽  
The Right

In the present study the most outstanding anatomical findings of the heart of a giraffe are described. Two papillary muscles were found in the right ventricle, namely magnus and subarterial. There were no papillary parvi muscles. The supraventricular crest gave insertion to various tendinous chords. These chords fixed the angular cusp of the right atrioventricular valve. The pectinate muscles were better developed in the left auricle than in the right one. Within the left ventricle two big papillary muscles were found as well as a notorious septomarginal trabecula. The left coronary artery irrigated the majority of the heart’s territory. It gave origin to the interventricular paraconal branch and to the circumflex branch. The latter gave off the branch of the left ventricular border and the interventricular subsinosal branch.

scholarly journals The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. II. Closed state reverse use-dependent block by 4-aminopyridine.

1993 ◽  
Vol 101 (4) ◽  
pp. 603-626 ◽  
Author(s):  
D L Campbell ◽  
Y Qu ◽  
R L Rasmusson ◽  
H C Strauss
Keyword(s):  
Steady State ◽  
Right Ventricular ◽  
Ventricular Myocytes ◽  
Patch Clamp Technique ◽  
Time Constants ◽  
Closed State ◽  
Whole Cell Patch Clamp ◽  
Dependent Behavior ◽  
Steady State Inactivation ◽  
K Current

Block of the calcium-independent transient outward K+ current, I(to), by 4-aminopyridine (4-AP) was studied in ferret right ventricular myocytes using the whole cell patch clamp technique. 4-AP reduces I(to) through a closed state blocking mechanism displaying "reverse use-dependent" behavior that was inferred from: (a) development of tonic block at hyperpolarized potentials; (b) inhibition of development of tonic block at depolarized potentials; (c) appearance of "crossover phenomena" in which the peak current is delayed in the presence of 4-AP at depolarized potentials; (d) relief of block at depolarized potentials which is concentration dependent and parallels steady-state inactivation for low 4-AP concentrations (V1/2 approximately -10 mV in 0.1 mM 4-AP) and steady-state activation at higher concentrations (V1/2 = +7 mV in 1 mM 4-AP, +15 mV in 10 mM 4-AP); and (e) reassociation of 4-AP at hyperpolarized potentials. No evidence for interaction of 4-AP with either the open or inactivated state of the I(to) channel was obtained from measurements of kinetics of recovery and deactivation in the presence of 0.5-1.0 mM 4-AP. At hyperpolarized potentials (-30 to -90 mV) 10 mM 4-AP associates slowly (time constants ranging from approximately 800 to 1,300 ms) with the closed states of the channel (apparent Kd approximately 0.2 mM). From -90 to -20 mV the affinity of the I(to) channel for 4-AP appears to be voltage insensitive; however, at depolarized potentials (+20 to +100 mV) 4-AP dissociates with time constants ranging from approximately 350 to 150 ms. Consequently, the properties of 4-AP binding to the I(to) channel undergo a transition in the range of potentials over which channel activation and inactivation occurs (-30 to +20 mV). We propose a closed state model of I(to) channel gating and 4-AP binding kinetics, in which 4-AP binds to three closed states. In this model 4-AP has a progressively lower affinity as the channel approaches the open state, but has no intrinsic voltage dependence of binding.

scholarly journals Extracellular proton depression of peak and late Na+ current in the canine left ventricle

2011 ◽  
Vol 301 (3) ◽  
pp. H936-H944 ◽  
Author(s):  
Lisa Murphy ◽  
Danielle Renodin ◽  
Charles Antzelevitch ◽  
José M. Di Diego ◽  
Jonathan M. Cordeiro
Keyword(s):  
Action Potential ◽  
Cell Types ◽  
Left Ventricular ◽  
Extracellular Acidosis ◽  
Epicardial Cells ◽  
Ventricular Cells ◽  
Recovery From Inactivation ◽  
Ventricular Tissue ◽  
Steady State Inactivation ◽  
Acidic Conditions

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na+ current ( INa) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record INa. Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast INa showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast INa magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast INa was observed at pH 6.6. Acidosis did not affect steady-state inactivation of INa or recovery from inactivation. Analysis of late INa during a 500-ms pulse showed that the acidosis significantly reduced late INa at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late INa compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late INa when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late INa in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.

Abstract 1523: A Novel SCN5A Gain-of-Function Mutation M1875T Associated with Familial Atrial Fibrillation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takeru Makiyama ◽  
Masaharu Akao ◽  
Satoshi Shizuta ◽  
Takahiro Doi ◽  
Kei Nishiyama ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mutational Analysis ◽  
Gain Of Function ◽  
Japanese Family ◽  
Function Type ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
Familial Atrial Fibrillation ◽  
The Right ◽  
Inherited Arrhythmias

Background: Mutations in the cardiac sodium (Na + ) channel gene, SCN5A , have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only one phenotype, long-QT syndrome type3 (LQTS3). Methods and Results: We studied a Japanese family with autosomal dominant hereditary atrial fibrillation (AF), multiple members of which showed onset of AF or frequent premature atrial contractions at a young age. The 31-year-old proband received radio-frequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A . Further investigations revealed the aggregation of this mutation in all of the affected individuals (Figure A ). Functional assays of the M1875T Na + channels using whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V 1/2 of the voltage dependence of steady-state inactivation (Figure B ), and no late Na + current which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals. Conclusions: We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na + channels, which is a novel mechanism predisposing increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

scholarly journals The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. I. Basic characterization and kinetic analysis.

1993 ◽  
Vol 101 (4) ◽  
pp. 571-601 ◽  
Author(s):  
D L Campbell ◽  
R L Rasmusson ◽  
Y Qu ◽  
H C Strauss
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Nonlinear Least Squares ◽  
Patch Clamp Technique ◽  
Time Constants ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
K Current ◽  
Necessary And Sufficient

Enzymatically isolated myocytes from ferret right ventricles (12-16 wk, male) were studied using the whole cell patch clamp technique. The macroscopic properties of a transient outward K+ current I(to) were quantified. I(to) is selective for K+, with a PNa/PK of 0.082. Activation of I(to) is a voltage-dependent process, with both activation and inactivation being independent of Na+ or Ca2+ influx. Steady-state inactivation is well described by a single Boltzmann relationship (V1/2 = -13.5 mV; k = 5.6 mV). Substantial inactivation can occur during a subthreshold depolarization without any measurable macroscopic current. Both development of and recovery from inactivation are well described by single exponential processes. Ensemble averages of single I(to) channel currents recorded in cell-attached patches reproduce macroscopic I(to) and indicate that inactivation is complete at depolarized potentials. The overall inactivation/recovery time constant curve has a bell-shaped potential dependence that peaks between -10 and -20 mV, with time constants (22 degrees C) ranging from 23 ms (-90 mV) to 304 ms (-10 mV). Steady-state activation displays a sigmoidal dependence on membrane potential, with a net aggregate half-activation potential of +22.5 mV. Activation kinetics (0 to +70 mV, 22 degrees C) are rapid, with I(to) peaking in approximately 5-15 ms at +50 mV. Experiments conducted at reduced temperatures (12 degrees C) demonstrate that activation occurs with a time delay. A nonlinear least-squares analysis indicates that three closed kinetic states are necessary and sufficient to model activation. Derived time constants of activation (22 degrees C) ranged from 10 ms (+10 mV) to 2 ms (+70 mV). Within the framework of Hodgkin-Huxley formalism, Ito gating can be described using an a3i formulation.

Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

2006 ◽  
Vol 291 (2) ◽  
pp. H570-H580 ◽  
Author(s):  
Ling Xiao ◽  
Liming Zhang ◽  
Wei Han ◽  
Zhiguo Wang ◽  
Stanley Nattel
Keyword(s):  
Sex Differences ◽  
Action Potentials ◽  
Ionic Current ◽  
Ionic Currents ◽  
Left Ventricular ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Qt Intervals ◽  
Whole Cell Patch Clamp ◽  
Ventricular Cells

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 ± 21 vs. 237 ± 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K+ current ( IK1) were observed. Transient outward K+ current ( Ito) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller Ito (e.g., at +30 mV, female vs. male: 2.5 ± 0.2 vs. 3.5 ± 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K+ current ( IKr) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K+ current ( IKs) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 ± 0.1 vs. 0.8 ± 0.1 pA/pF; P < 0.001; endocardium: 1.2 ± 0.1 vs. 0.7 ± 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial IKs. Female dogs had larger L-type Ca2+ current ( ICa,L) densities in all layers than male dogs (e.g., at −20 mV, female vs. male, epicardium: −4.2 ± 0.4 vs. −3.2 ± 0.2 pA/pF; midmyocardium: −4.5 ± 0.5 vs. −3.3 ± 0.3 pA/pF; endocarium: −4.5 ± 0.4 vs. −3.2 ± 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.

scholarly journals K(+) currents in cultured neurones from a polyclad flatworm

2000 ◽  
Vol 203 (20) ◽  
pp. 3189-3198
Author(s):  
S.D. Buckingham ◽  
A.N. Spencer
Keyword(s):  
Steady State ◽  
Patch Clamp ◽  
K Channels ◽  
Type K ◽  
Whole Cell Patch Clamp ◽  
Recovery From Inactivation ◽  
Steady State Inactivation ◽  
The Brain ◽  
K Currents ◽  
Cultured Neurones

Cells from the brain of the polyclad flatworm Notoplana atomata were dispersed and maintained in primary culture for up to 3 weeks. Whole-cell patch-clamp of presumed neurones revealed outwardly directed K(+) currents that comprised, in varying proportions, a rapidly activating (time constant tau =0.94+/−0.79 ms; N=15) and inactivating (tau =26.1+/−1.9 ms; N=22) current and a second current that also activated rapidly (tau =1.1+/−0.2 ms; N=9) (means +/− s.e.m.) but did not inactivate within 100 ms. Both current types activated over similar voltage ranges. Activation and steady-state inactivation overlap and are markedly rightward-shifted compared with most Shaker-like currents (half-activation of 16.9+/−1. 9 mV, N=7, half-inactivation of −35.4+/−3.0 mV, N=5). Recovery from inactivation was rapid (50+/−2.5 ms at −90 mV). Both currents were unaffected by tetraethylammonium (25 mmol l(−1)), whereas 4-aminopyridine (10 mmol l(−1)) selectively blocked the inactivating current. The rapidly inactivating current, like cloned K(+) channels from cnidarians and certain cloned K(+) channels from molluscs and the Kv3 family of vertebrate channels, differed from most A-type K(+) currents reported to date. These findings suggest that K(+) currents in Notoplana atomata play novel roles in shaping excitability properties.

Cyclic AMP selectively reduces the N-type calcium current component of mouse sensory neurons in culture by enhancing inactivation

1989 ◽  
Vol 61 (1) ◽  
pp. 97-105 ◽  
Author(s):  
R. A. Gross ◽  
R. L. Macdonald
Keyword(s):  
Steady State ◽  
Cyclic Amp ◽  
Cholera Toxin ◽  
Calcium Current ◽  
Calcium Currents ◽  
Resting Membrane Potential ◽  
High Threshold ◽  
Drg Neurons ◽  
Inactivation Curve ◽  
Steady State Inactivation

1. The single-electrode voltage-clamp technique was used to assess the effect of elevated intracellular cyclic AMP levels on the three calcium current components of mouse dorsal root ganglion (DRG) neurons in culture. 2. Neither forskolin, cholera toxin, nor 8-Br-cyclic AMP affected the isolated transient low-threshold (T) calcium current. 3. When calcium currents were evoked at clamp potentials (Vc) positive to -20 mV from holding potentials (Vh) near the resting membrane potential, the calcium current consisted primarily of the transient high-threshold (N) and the slowly inactivating high-threshold (L) calcium current components. Under these conditions forskolin, cholera toxin, and 8-Br-cyclic AMP reduced the peak calcium current but had little or no effect on the late (greater than or equal to 300 ms) calcium current. When calcium currents were evoked from very negative Vh, however, there was no effect of these compounds. 4. Forskolin had no effect on the voltage-dependence of the current-voltage relation, nor on the rate of recovery of the calcium current from inactivation. 5. In other experiments, current traces were fitted using a multiexponential curve-fitting program that determined the amplitudes and inactivation time constants (tau i) of the three calcium current components. Forskolin selectively reduced the magnitude of the (curve-fitted) N current, and reduced its tau i. 6. Forskolin also enhanced steady-state inactivation of the N current, producing a -7.5 mV shift in the steady-state inactivation curve. 7. Cholera toxin, forskolin, and 8-Br-cyclic AMP had similar effects on calcium currents in mouse DRG neurons in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

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