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1.
Pediatr Cardiol ; 27(3): 329-35, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16565908

RESUMO

In adults, pulmonary value replacement (PVR) shows improvement in right ventricular (RV) volume and function and reduces QRS duration. In addition, RV volume correlates with QRS duration and QRS change. This has not been shown in pediatric patients. The purpose of this study was to evaluate serial magnetic resonance imaging (MRI) and electrocardiogram measurements before and after early PVR in a pediatric population with repaired Tetralogy of Fallot and whether QRS duration and QRS change correlated with RV volume. A retrospective review of MRIs and electrocardiograms was conducted on 10 patients. Median age at repair was 2.1 +/- 0.7 years, and median age at PVR was 11.5 +/- 2.0 years. There were significant decreases in RV end diastolic volume (EDV)/body surface area (BSA) (p < 0.0004), end systolic volume (ESV)/BSA (p = 0.02), RVEDV/left ventricular (LV) EDV (p < 0.001), RV ejection fraction (p < 0.04), RV stroke volume (SV)/BSA (p < 0.0002), and (RVSV - LVSV)/BSA (p = 0.0007). No significant change in QRS duration occurred (p = 0.08). QRS duration (pre-r = 0.44, p = 0.20; post-r = 0.34, p = 0.33) and QRS change (r = -0.08, p = 0.83) did not correlate with RVEDV. We propose early consideration of PVR in pediatric patients. PVR improves RV volumes and function and may provide beneficial electromechanical effects by slowing the progression of QRS duration.


Assuntos
Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Implante de Prótese de Valva Cardíaca , Valva Pulmonar/cirurgia , Tetralogia de Fallot/cirurgia , Função Ventricular Direita , Criança , Pré-Escolar , Hemodinâmica , Humanos , Lactente , Imageamento por Ressonância Magnética , Período Pós-Operatório , Estudos Retrospectivos , Tetralogia de Fallot/fisiopatologia
2.
J Mol Cell Cardiol ; 33(8): 1467-76, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11448135

RESUMO

We have shown that cGMP-dependent protein kinase (PKG) mediates stimulation of L-type calcium current by cGMP in rabbit atrial myocytes. The human atrium may have similar PKG-dependent regulation of calcium current. To elucidate the significance of PKG in cardiac function, we have isolated human PKG type I alpha cDNA (+1 to 2016), determined the nucleotide sequence and analyzed specific expression of PKG in human atrium. We obtained full-length cDNA of PKG type I alpha from human atrial RNA using reverse transcriptase-polymerase chain reaction (RT-PCR). The coding region of human cardiac PKG I alpha showed 99.9% homology to previously published human PKG I alpha except for base No. 1983. At this position G was substituted for T and this resulted in an amino acid substitution from Leu649 to Phe649. The cloned PKG I alpha cDNA was expressed in COS cells and the expressed PKG showed cGMP-stimulated PKG enzyme activity and immunoreactivity. Ribonuclease protection assay, Western blot analysis, and PKG enzyme activity assays in homogenates from human atrial tissue demonstrated the presence of PKG mRNA and protein in human atrial tissue. Immunofluorescence staining confirmed that PKG is highly expressed in human atrial myocytes. These findings suggest that PKG is highly expressed in human atrium and that PKG-dependent phosphorylation may be important in regulation of calcium channel activity in human atrial myocytes.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Átrios do Coração/enzimologia , Adulto , Idoso , Substituição de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Células COS , Feminino , Imunofluorescência , Humanos , Isoenzimas/metabolismo , Cinética , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico
3.
Am J Physiol Heart Circ Physiol ; 279(5): H2095-103, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11045942

RESUMO

We examined the critical coupling conductance (G(C)) for propagation at different pacing cycle lengths (CLs) (1,000 and 400 ms). As G(C) was progressively reduced, propagation failed at a CL of 1,000 ms, whereas propagation succeeded at a CL of 400 ms over a range of G(C) values before failing at a CL of 400 ms at a lower G(C), showing facilitation of propagation at the shorter CL. Critical G(C) was (means +/- SE) 0.8 +/- 0.1 nS for a CL of 400 ms and 1.3 +/- 0.1 nS for a CL of 1,000 ms (a 63% increase, P < 0.002, n = 9 cell pairs). In 14 uncoupled cells, action potential duration at 30% repolarization (APD(30)) increased from 19.9 +/- 2.5 to 41.8 +/- 2.6 ms (P < 0.001) as CL decreased from 1,000 to 400 ms. In five cell pairs, critical G(C) with 4-aminopyridine (4-AP) was reduced to 0.4 +/- 0.1 nS at a CL of 1,000 ms (P < 0.05 compared with control solution), and critical G(C) in 4-AP was unchanged by decreasing CL to 400 ms. It is possible that the "remodeling" of atrial cells due to atrial fibrillation or tachycardia, which has been shown to produce a decrease in the transient outward current, may result in an enhanced ability to propagate, possibly facilitating further development of fibrillation under conditions of decreased cellular coupling.


Assuntos
Potenciais de Ação/fisiologia , Função Atrial , Estimulação Cardíaca Artificial , Miocárdio/metabolismo , Tempo de Reação/fisiologia , Animais , Células Cultivadas , Átrios do Coração/citologia , Sistema de Condução Cardíaco/fisiologia , Miocárdio/citologia , Coelhos
4.
Cardiovasc Res ; 48(2): 310-22, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11054477

RESUMO

OBJECTIVES: cGMP has been shown to exert both stimulatory and inhibitory effects on cardiac L-type calcium current (I(Ca)). The physiological role of cGMP in regulation of cardiac activity is still controversial. cGMP may be of importance in regulation of I(Ca) in atrial cells. The present study was focused on the role of cGMP in the modulation of I(Ca) in rabbit atrial cells. METHODS: Enzymatically isolated adult rabbit atrial cells were used to measure I(Ca) using whole cell voltage clamp. Expressed levels of cGMP-dependent protein kinase (PKG) were determined by Western blotting using PKG specific antibody in homogenates from atrial and ventricular cells. RESULTS: Nitrosoglutathione (GSNO), a nitric oxide donor that stimulates soluble guanylyl-cyclase to elevate cGMP levels increased I(Ca) while soluble G-cyclase inhibitors, ODQ or methylene blue inhibited I(Ca). Intracellular application of 8BrcGMP increased I(Ca) and blocked the inhibitory effect of methylene blue. KT-5823, an inhibitor of PKG inhibited I(Ca) and the stimulatory effect of GSNO was completely blocked ODQ or KT-5823. Inhibition of cAMP dependent protein kinase (PKA) by the 6-22 peptide completely blocked the stimulation of I(Ca) by the beta-agonist isoproterenol but not by GSNO. The potency of isoproterenol to stimulate I(Ca) was very high for atrial cells (EC(50) 2.4+/-0.6 nM) and only 100 nM isoproterenol was required to stimulate I(Ca) maximally (21.4+/-0.7 pA/pF) to a level (23.8+/-1.6 pA/pF) achieved with the inclusion of 100 microM cAMP in the pipette solution. GSNO produced an additive effect on I(Ca) already stimulated by either 10 microM isobutylmethylxanthine (phosphodiesterase inhibitor) or a low concentration (1 nM) isoproterenol but failed to produce any effect on I(Ca) maximally stimulated by 100 nM isoproterenol. Inhibition of PKG by KT-5823 significantly decreased the efficacy of isoproterenol and the maximal I(Ca) achieved with 100 nM isoproterenol was decreased to 8.2+/-0.6 pA/pF in the presence of KT-5823. Western blot analysis showed much higher expression of PKG in atrial cells compared to ventricular cells. CONCLUSIONS: These findings suggest that stimulatory effects of cGMP on I(Ca) in rabbit atrial cells are likely to be mediated via PKG dependent phosphorylation of calcium channels or associated proteins and that the effects of cGMP are not antagonistic to cAMP. PKG is highly expressed in atrial cells and PKG dependent phosphorylation may be necessary for maintaining basal I(Ca) and fully stimulating I(Ca) by beta-adrenergic activation in atrial cells.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Carbazóis , Proteínas Quinases Dependentes de GMP Cíclico/farmacologia , GMP Cíclico/farmacologia , Indóis , Miocárdio/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Alcaloides/farmacologia , Animais , Western Blotting/métodos , GMP Cíclico/análogos & derivados , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Átrios do Coração , Isoproterenol/farmacologia , Doadores de Óxido Nítrico/farmacologia , Técnicas de Patch-Clamp , Inibidores de Fosfodiesterase/farmacologia , Coelhos , Estimulação Química , Fatores de Tempo
5.
Am J Physiol Heart Circ Physiol ; 279(2): H752-63, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10924075

RESUMO

Tachycardias can be produced when focal activity at ectopic locations in either the atria or the ventricles propagates into the surrounding quiescent myocardium. Isolated rabbit atrioventricular nodal cells were coupled by an electronic circuit to a real-time simulation of an array of cell models. We investigated the critical size of an automatic focus for the activation of two-dimensional arrays made up of either ventricular or atrial model cells. Over a range of coupling conductances for the arrays, the critical size of the focus cell group for successful propagation was smaller for activation of an atrial versus a ventricular array. Failure of activation of the arrays at smaller focus sizes was due to the inhibition of pacing of the nodal cells. At low levels of coupling conductance, the ventricular arrays required larger sizes of the focus due to failure of propagation even when the focus was spontaneously active. The major differences between activation of the atrial and ventricular arrays is due to the higher membrane resistance (lower inward rectifier current) of the atrial cells.


Assuntos
Função Atrial , Nó Atrioventricular/fisiologia , Sistema de Condução Cardíaco/fisiologia , Modelos Cardiovasculares , Miocárdio/citologia , Função Ventricular , Animais , Nó Atrioventricular/citologia , Células Cultivadas , Técnicas In Vitro , Coelhos
6.
Am J Physiol Heart Circ Physiol ; 278(2): H444-51, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10666074

RESUMO

The L-type calcium current (I(Ca)) is important in sustaining propagation during discontinuous conduction. In addition, I(Ca) is altered during discontinuous conduction, which may result in changes in the intracellular calcium transient. To study this, we have combined the ability to monitor intracellular calcium concentration ([Ca(2+)](i)) in an isolated cardiac cell using confocal scanning laser fluorescence microscopy with our "coupling clamp" technique, which allows action potential propagation from the real cell to a real-time simulation of a model cell. Coupling a real cell to a model cell with a value of coupling conductance (G(C) = 8 nS) just above the critical value for action potential propagation results in both an increased amplitude and an increased rate of rise of the calcium transient. Similar but smaller changes in the calcium transient are caused by increasing G(C) to 20 nS. The increase of [Ca(2+)](i) by discontinuous conduction is less than the increase of I(Ca), which may indicate that much of [Ca(2+)](i) is the result of calcium released from the sarcoplasmic reticulum rather than the integration of I(Ca).


Assuntos
Cálcio/metabolismo , Miocárdio/metabolismo , Função Ventricular/fisiologia , Potenciais de Ação/fisiologia , Animais , Separação Celular , Simulação por Computador , Sistemas Computacionais , Condutividade Elétrica , Cobaias , Microscopia Confocal , Microscopia de Fluorescência , Modelos Cardiovasculares , Miocárdio/citologia
7.
Am J Physiol Heart Circ Physiol ; 278(2): H452-60, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10666075

RESUMO

We have extended our "coupling clamp" technique, in which we couple a real cell to a real-time simulation of a model cell, to now incorporate a real cardiac cell as the central element of a two-dimensional sheet of model cells, in which the coupling conductances may be different in the x and y directions and a specific region of lack of coupling conductance may serve as a resistive barrier. We stimulated the real cell in the central location and determined the critical size of the real cell for successful activation of the entire sheet. We found that this critical size was decreased when anisotropy was present compared with the isotropic case and was further decreased when the central site of stimulation was close to the resistive barrier. The heart normally has some degree of anisotropy, and it has been shown that the remodeling that occurs in peri-infarction zones produces a particular loss of lateral connections compared with end-to-end connections among heart cells. We propose that the normal existence of anisotropy and enhancement of the degree of anisotropy both by loss of lateral gap junctions and the development of resistive barriers may play a facilitating role in the development of ectopic foci that may lead to cardiac arrhythmias.


Assuntos
Modelos Cardiovasculares , Função Ventricular/fisiologia , Animais , Anisotropia , Separação Celular , Simulação por Computador , Sistemas Computacionais , Eletrofisiologia , Cobaias , Miocárdio/citologia
8.
Pflugers Arch ; 441(2-3): 301-12, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11211117

RESUMO

The anisotropy that normally exists in the myocardium may be either enhanced in peri-infarction zones by loss of lateral cell connections or reduced by redistribution of gap junctions. To test how the degree of anisotropy affects the development of ectopic focal activity, we carried out computer simulations in which a model of an ectopic focus is incorporated as the central element of a two-dimensional sheet of ventricular cells. At low values of intercellular coupling conductance (Gc), the focus region is spontaneously active, but the limited intercellular current flow inhibits propagation. At high Gc, automaticity is suppressed by the loading effects of the surrounding cells. At intermediate Gc, the ectopic activity may propagate into the sheet. In the case of isotropic coupling, the minimum size of the focus region for propagation to occur (in terms of number of collaborating cells within the focus) is as small as approximately ten cells, and this number decreases with increasing anisotropy. Thus, the presence of anisotropy facilitates the development of ectopic focal activity. We conclude that the remodeling that occurs in peri-infarction zones may create a substrate that either facilitates (enhanced anisotropy) or inhibits (reduced anisotropy) the development of cardiac arrhythmias associated with ectopic focal activity.


Assuntos
Arritmias Cardíacas/fisiopatologia , Simulação por Computador , Modelos Biológicos , Potenciais de Ação , Anisotropia , Comunicação Celular , Condutividade Elétrica , Junções Comunicantes , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/citologia , Ventrículos do Coração/fisiopatologia , Humanos , Potenciais da Membrana , Isquemia Miocárdica/fisiopatologia
9.
J Pharmacol Exp Ther ; 291(3): 967-75, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10565812

RESUMO

We previously showed that stimulation of cGMP-dependent protein kinase (PKG) stimulates L-type calcium current in newborn but not in adult rabbit ventricular myocytes. We have now isolated rabbit PKG type Ialpha cDNA (+1 to 2095), determined the sequence, and analyzed specific expression of PKG in adult and newborn rabbit heart by Western and Northern analyses to elucidate the developmental decline in the significance of PKG in cardiac function. We obtained full-length cDNA of PKG Ialpha from newborn rabbit heart mRNA with reverse transcription-polymerase chain reaction. The coding region of rabbit PKG Ialpha showed 94% homology to sequences of human and bovine PKG Ialpha. The deduced amino acid sequence of 671 amino acids showed seven substitutions between rabbit and either human or bovine PKG Ialpha. The major substitutions were found in the cGMP-binding domain. The cloned PKG 1alpha cDNA was expressed in COS cells. Expressed PKG showed cGMP stimulated PKG activity and immunoreactivity. Northern blot analysis of cardiac tissue demonstrated PKG Ialpha mRNA of 6.8 kb, with much higher levels in newborn than in adult cells. Western analysis in homogenates from ventricular tissues and isolated ventricular myocytes of rabbit heart showed much higher expression of PKG type I protein in newborn compared with adult cells. These findings suggest that PKG is developmentally regulated in rabbit heart and is expressed at a much higher level in newborn than in adult cells. The greater expression of PKG in newborn cells could be responsible for differences in the significance of cGMP in adult and newborn rabbit cells.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/biossíntese , Miocárdio/enzimologia , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Northern Blotting , Western Blotting , Canais de Cálcio/metabolismo , DNA Complementar/análise , DNA Complementar/biossíntese , Feminino , Coração/crescimento & desenvolvimento , Técnicas In Vitro , Isoenzimas/biossíntese , Cinética , Masculino , Dados de Sequência Molecular , Miocárdio/citologia , RNA Mensageiro/biossíntese , Coelhos
10.
Circulation ; 99(12): 1623-9, 1999 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-10096941

RESUMO

BACKGROUND: Acute ischemia often occurs in cardiac tissue that has prior injury, resulting in spatially inhomogeneous distributions of membrane properties and intercellular coupling. Changes in action potential conduction with ischemia, which can be associated with release of catecholamines, may be particularly important in tissue that has discontinuous conduction resulting from prior infarction, hypertrophy, or myopathy. METHODS AND RESULTS: Isolated guinea pig ventricular myocytes were electrically coupled by a coupling-clamp circuit to a comprehensive computer model of a guinea pig ventricular myocyte to assess alterations in the critical value of coupling conductance required for action potential conduction from the real cell to the model cell when the real cell was exposed to a solution that included hypoxia, acidosis, and an elevated extracellular potassium concentration to simulate acute ischemia. The "ischemic" solution increased critical coupling conductance from 6.2+/-0.1 to 7.4+/-0.2 nS and decreased the associated maximum conduction delay from 31+/-1 to 23+/-1 ms (mean+/-SEM, n=11). The ischemic solution plus 1 micromol/L norepinephrine decreased critical coupling conductance from 5.9+/-0.2 to 5.0+/-0.1 nS and increased maximum conduction delay from 31+/-2 to 54+/-4 ms (mean+/-SEM, n=8). CONCLUSIONS: The release of catecholamines with ischemia, in a setting of partially uncoupled cells, may play a major role in producing long conduction delays, which may allow reentrant pathways.


Assuntos
Potenciais de Ação , Ventrículos do Coração/citologia , Isquemia/fisiopatologia , Animais , Hipóxia Celular/fisiologia , Células Cultivadas , Cobaias , Células Híbridas , Norepinefrina/farmacologia
11.
Am J Physiol ; 276(2): H391-400, 1999 02.
Artigo em Inglês | MEDLINE | ID: mdl-9950838

RESUMO

Previous work with model systems for action potential conduction have been restricted to conduction between two real cells or conduction between a model cell and a real cell. The inclusion of additional elements to make a linear strand has allowed us to investigate the interactions between cells at a higher level of complexity. When, in the simplest case of a linear strand of three elements, the conductance between elements 2 and 3 (GC2) is varied, this affects the success or failure of propagation between elements 1 and 2 (coupled by GC1) as well as the success or failure of propagation between elements 2 and 3. Several major features were illustrated. 1) When GC1 was only slightly greater than the coupling conductance required for successful propagation between a model cell and a real cell, addition of a third element of the strand either prevented conduction from element 1 to element 2 (when GC2 was high) or allowed conduction from element 1 to element 2 but not conduction from element 2 to element 3 (when GC2 was low). 2) For higher levels of GC1, there was an allowable "window" of values of GC2 for successful conduction from element 1 through to element 3. The size of this allowable window of GC2 values increased with increasing values of GC1, and this increase was produced by increases in the upper bound of GC2 values. 3) When the size of the central element of the strand was reduced, this facilitated conduction through the strand, increasing the range of the allowable window of GC2 values. The overall success or failure of conduction through a structure of cells that has a spatially inhomogeneous distribution of coupling conductances cannot be predicted simply by the average or the minimum value of coupling conductance but may depend on the actual spatial distribution of these conductances.


Assuntos
Comunicação Celular/fisiologia , Coração/fisiologia , Modelos Cardiovasculares , Animais , Cardiologia/métodos , Eletrofisiologia , Cobaias , Miocárdio/citologia
12.
Am J Physiol ; 274(6): H2152-62, 1998 06.
Artigo em Inglês | MEDLINE | ID: mdl-9841483

RESUMO

Atrial activation involves interactions between cells with automaticity and slow-response action potentials with cells that are intrinsically quiescent with fast-response action potentials. Understanding normal and abnormal atrial activity requires an understanding of this process. We studied interactions of a cell with spontaneous activity, represented by a "real-time" simulation of a model of the rabbit sinoatrial (SA) node cell, simultaneously being electrically coupled via our "coupling clamp" circuit to a real, isolated atrial myocyte with variations in coupling conductance (Gc) or stimulus frequency. The atrial cells were able to be driven at a regular rate by a single SA node model (SAN model) cell. Critical Gc for entrainment of the SAN model cell to a nonstimulated atrial cell was 0.55 +/- 0.05 nS (n = 7), and the critical Gc that allowed entrainment when the atrial cell was directly paced at a basic cycle length of 300 ms was 0.32 +/- 0.01 nS (n = 7). For each atrial cell we found periodic phenomena of synchronization other than 1:1 entrainment when Gc was between 0.1 and 0.3 nS, below the value required for frequency entrainment, when the atrial cell was directly driven at a basic cycle length of either 300 or 600 ms. In conclusion, the high input resistance of the atrial cells allows successful entrainment of nodal and atrial cells at low values of Gc, but further uncoupling produces arrhythmic interactions.


Assuntos
Potenciais de Ação/fisiologia , Função Atrial/fisiologia , Nó Atrioventricular/fisiologia , Comunicação Celular/fisiologia , Animais , Arritmias Cardíacas/fisiopatologia , Condutividade Elétrica , Modelos Cardiovasculares , Coelhos
13.
Am J Physiol ; 274(6): H1902-13, 1998 06.
Artigo em Inglês | MEDLINE | ID: mdl-9841518

RESUMO

Action potential conduction through the atrium and the ventricle of the heart depends on the membrane properties of the atrial and ventricular cells, particularly with respect to the determinants of the initiation of action potentials in each cell type. We have utilized both current- and voltage-clamp techniques on isolated cells to examine biophysical properties of the two cell types at physiological temperature. The resting membrane potential, action potential amplitude, current threshold, voltage threshold, and maximum rate of rise measured from atrial cells (-80 +/- 1 mV, 109 +/- 3 mV, 0.69 +/- 0.05 nA, -59 +/- 1 mV, and 206 +/- 17 V/s, respectively; means +/- SE) differed significantly (P < 0.05) from those values measured from ventricular cells (-82.7 +/- 0.4 mV, 127 +/- 1 mV, 2.45 +/- 0.13 nA, -46 +/- 2 mV, and 395 +/- 21 V/s, respectively). Input impedance, capacitance, time constant, and critical depolarization for activation also were significantly different between atrial (341 +/- 41 M omega, 70 +/- 4 pF, 23.8 +/- 2. 3 ms, and 19 +/- 1 mV, respectively) and ventricular (16.5 +/- 5.4 M omega, 99 +/- 4.3 pF, 1.56 +/- 0.32 ms, and 36 +/- 1 mV, respectively) cells. The major mechanism of these differences is the much greater magnitude of the inward rectifying potassium current in ventricular cells compared with that in atrial cells, with an additional difference of an apparently lower availability of inward Na current in atrial cells. These differences in the two cell types may be important in allowing the atrial cells to be driven successfully by normal regions of automaticity (e.g., the sinoatrial node), whereas ventricular cells would suppress action potential initiation from a region of automaticity (e.g., an ectopic focus).


Assuntos
Potenciais de Ação/fisiologia , Animais , Eletrofisiologia , Átrios do Coração , Sistema de Condução Cardíaco/fisiologia , Ventrículos do Coração , Técnicas de Patch-Clamp , Coelhos
14.
J Gen Physiol ; 111(1): 95-112, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9417138

RESUMO

The effects of intercellular coupling conductance on the activity of two electrically coupled isolated rabbit sinoatrial nodal cells were investigated. A computer-controlled version of the "coupling clamp" technique was used in which isolated sinoatrial nodal cells, not physically in contact with each other, were electrically coupled at various values of ohmic coupling conductance, mimicking the effects of mutual interaction by electrical coupling through gap junctional channels. We demonstrate the existence of four types of electrical behavior of coupled spontaneously active cells. As the coupling conductance is progressively increased, the cells exhibit: (a) independent pacemaking at low coupling conductances, (b) complex dynamics of activity with mutual interactions, (c) entrainment of action potential frequency at a 1:1 ratio with different action potential waveforms, and (d) entrainment of action potentials at the same frequency of activation and virtually identical action potential waveforms. The critical value of coupling conductance required for 1:1 frequency entrainment was <0.5 nS in each of the five cell pairs studied. The common interbeat interval at a relatively high coupling conductance (10 nS), which is sufficient to produce entrainment of frequency and also identical action potential waveforms, is determined most by the intrinsically faster pacemaker cell and it can be predicted from the diastolic depolarization times of both cells. Evidence is provided that, at low coupling conductances, mutual pacemaker synchronization results mainly from the phase-resetting effects of the action potential of one cell on the depolarization phase of the other. At high coupling conductances, the tonic, diastolic interactions become more important.


Assuntos
Relógios Biológicos/fisiologia , Nó Sinoatrial/fisiologia , Potenciais de Ação/fisiologia , Animais , Condutividade Elétrica , Feminino , Junções Comunicantes/fisiologia , Íons , Masculino , Fibras Musculares Esqueléticas/fisiologia , Técnicas de Patch-Clamp , Coelhos , Nó Sinoatrial/citologia
15.
Can J Cardiol ; 13(11): 1085-92, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9413242

RESUMO

The authors previously developed a technique for studying a mathematical model cell with spontaneous activity, namely, a 'real time' simulation of a rabbit sinoatrial node (SAN) model cell that is simultaneously electrically coupled via a 'coupling clamp' circuit to a real, isolated ventricular myocyte. This technique was applied to investigate the effects of coupling conductance (Gc), cell size and modulation of membrane potential by elevated extracellular potassium ion concentrations on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: spontaneous pacing of the SAN model cell but not driving of the ventricular cell; cessation of spontaneous pacing; or pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell, only the first two outcomes are possible. Above this critical size, there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium ion concentrations from 4 to 8 mM increases both the lower and upper boundaries of Gc for this range. Elevation of extracellular potassium ion concentrations, commonly observed in myocardial ischemia, may affect either inhibition or release of inhibition of an ectopic focus.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiologia , Miocárdio/citologia , Nó Sinoatrial/fisiopatologia , Animais , Modelos Animais de Doenças , Cobaias , Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Coelhos , Disfunção Ventricular Esquerda/fisiopatologia
16.
Am J Physiol ; 272(4 Pt 2): H1759-69, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9139960

RESUMO

We previously developed a technique (R. Kumar, R. Wilders, R. W. Joyner, H. J. Jongsma, E. E. Verheijck, D. A. Golod, A. C. G. van Ginneken, and W. N. Goolsby. Circulation 94: 833-841, 1996) for study of a mathematical model cell with spontaneous activity, viz. a "real-time" simulation of a rabbit sinoatrial node cell (SAN model cell; R. Wilders, H. J. Jongsma, and A. C. van Ginneken. Biophys. J. 60: 1202-1216, 1991) simultaneously being electrically coupled via our "coupling clamp" [H. Sugiura and R. W. Joyner. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1591-H1604, 1992] circuit to a real, isolated ventricular myocyte. We now apply this technique to investigate effects of coupling conductance (Gc), cell size, and the modulation of membrane potential by elevated extracellular potassium concentration on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: 1) spontaneous pacing of the SAN model cell but not driving of the ventricular cell, 2) cessation of spontaneous pacing, or 3) pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell only the first two of these outcomes is possible. Above this critical size there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium concentration from 4 to 8 mM increases both the lower bound and upper bound of Gc for this range. Elevation of extracellular potassium concentration, as commonly observed in myocardial ischemia, may have effects on either inhibiting or releasing from inhibition an ectopic focus.


Assuntos
Coração/fisiologia , Modelos Cardiovasculares , Miocárdio/citologia , Potássio/farmacologia , Animais , Arritmias Cardíacas , Células Cultivadas , Simulação por Computador , Eletrofisiologia , Coração/efeitos dos fármacos , Ventrículos do Coração , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Modelos Teóricos , Isquemia Miocárdica , Coelhos , Nó Sinoatrial/fisiologia , Fatores de Tempo
17.
Cardiovasc Res ; 33(3): 573-82, 1997 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9093527

RESUMO

OBJECTIVE: Cyclic GMP has been shown to be in some respects an inhibitory modulator of heart function. Various studies on the modulation of cardiac L-type calcium current (ICa) by cGMP in different species show inconsistency and the role of cGMP remains unclear and controversial. The present study was focused on the differences in the modulation of basal ICa by cGMP in adult and newborn rabbit ventricular cells. METHODS: Enzymatically isolated adult and newborn (1-4-day-old) rabbit ventricular myocytes were used to measure ICa under whole-cell voltage clamp conditions with internal perfusion of isolated cells. RESULTS: We have shown that in adult ventricular cells, the intracellular perfusion of 8BrcGMP did not produce any effect on basal ICa, while intracellular perfusion of 8BrcGMP or 8CPT-cGMP in newborn ventricular cells significantly and reversibly increased basal ICa without changing the voltage dependence for activation of ICa. Both methylene blue and LY-83583 (which inhibit guanylyl cyclase and thus lower cGMP levels), in adult ventricular cells, failed to produce any significant effect on basal ICa, while in newborn ventricular cells the application of methylene blue or LY-83583 produced irreversible inhibition of basal ICa. Similarly, KT-5823, an inhibitor of cGMP-dependent protein kinase, also inhibited basal ICa in newborn ventricular cells but not in adult ventricular cells. However, extracellular application of methylene blue during the intracellular perfusion of 8BrcGMP was unable to inhibit ICa. Extracellular application of nitrosoglutathione which releases nitric oxide produced a significant increase in ICa in newborn but not in adult ventricular cells. Intracellular application of a cAMP-dependent protein kinase inhibitor peptide blocked the stimulatory effect of cAMP but not of 8CPT-cGMP, while the stimulatory effect of nitrosoglutathione on ICa was not blocked by the presence of a phosphodiesterase inhibitor (isobutylmethyl-xanthine). CONCLUSIONS: We propose that, for newborn rabbit ventricular cells, cGMP plays a crucial role in maintaining basal ICa by a mechanism mediated via protein-kinase-G-dependent phosphorylation of calcium channels or some associated protein.


Assuntos
Animais Recém-Nascidos/metabolismo , Canais de Cálcio/efeitos dos fármacos , Carbazóis , GMP Cíclico/análogos & derivados , Indóis , Miocárdio/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Alcaloides/farmacologia , Aminoquinolinas/farmacologia , Animais , Cálcio/metabolismo , Células Cultivadas , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Feminino , Glutationa/análogos & derivados , Glutationa/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Masculino , Azul de Metileno/farmacologia , Compostos Nitrosos/farmacologia , Técnicas de Patch-Clamp , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Proteínas Quinases , Coelhos , S-Nitrosoglutationa , Tionucleotídeos/farmacologia , Fatores de Tempo
18.
Am J Physiol ; 271(5 Pt 2): H2168-82, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8945938

RESUMO

A method for coupling an isolated cardiac cell to a simulated cardiac cell, i.e., the real-time solution of a mathematical model of such cell, has been developed. With this "model clamp" technique, the real cell and the model cell are coupled by any desired value of intercellular coupling conductance, producing the effect of mutual interaction by electrical coupling through gap junctional channels. We implemented the model clamp technique with our previously published model of an isolated rabbit sinoatrial node cell. We used this model clamp system to study synchronization of sinoatrial node cells with regard to the critical value of intercellular coupling conductance required for frequency entrainment and the common interbeat interval during frequency entrainment. This common interbeat interval lay between the intrinsic intervals of the real cell and the model cell, but was closer to that of the intrinsically faster beating cell. Critical coupling conductance increased with increasing difference in intrinsic interbeat interval of the real cell and the model cell and ranged between 50 and 300 pS in 11 hybrid cell pairs.


Assuntos
Modelos Cardiovasculares , Nó Sinoatrial/fisiologia , Potenciais de Ação , Animais , Simulação por Computador , Eletrofisiologia , Técnicas de Patch-Clamp , Coelhos , Nó Sinoatrial/citologia , Fatores de Tempo
19.
Am J Physiol ; 271(4 Pt 2): H1507-16, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8897946

RESUMO

Conduction through the cardiac syncytium varies from being nearly continuous, with very well coupled cells, to being clearly discontinuous, with significant conduction delays over very short distances. The Purkinje-ventricular muscle junction (PVJ) sites on the endocardial surface have characteristic delays of conduction and the presence of discrete groups of cells that suggest significant discontinuities of the conduction process at PVJ sites, as compared with the more nearly continuous conduction within either the Purkinje or the ventricular muscle layers of the papillary muscle. The purpose of the present study was to examine the relative sensitivity of conduction at PVJ sites versus conduction within the Purkinje or the ventricular muscle layer of the canine papillary muscle to agents that modulate L-type calcium current. We have used cadmium as a relatively specific blocker of L-type calcium current and isoproterenol as an agent to increase L-type calcium current to test the hypothesis that discontinuous conduction at the PVJ sites would be more sensitive to these agents than would continuous conduction within either the Purkinje layer or the ventricular muscle layer of a canine papillary muscle. Conduction delay at the PVJ sites was significantly increased by cadmium, with some PVJ sites reversibly becoming nonjunctional at 200-400 microM cadmium. Isoproterenol significantly decreased PVJ delay, and this effect was attenuated by carbachol. All of the effects on conduction delay at the PVJ sites were much greater than the effects for the same agents on conduction velocity within either the Purkinje or the ventricular muscle layer of the papillary muscle.


Assuntos
Condução Nervosa , Músculos Papilares/fisiologia , Ramos Subendocárdicos/fisiologia , Animais , Cádmio/farmacologia , Cálcio/fisiologia , Cães , Condutividade Elétrica , Feminino , Isoproterenol/farmacologia , Masculino , Condução Nervosa/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos
20.
Circulation ; 94(4): 833-41, 1996 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-8772708

RESUMO

BACKGROUND: We used a mathematical model of a sinoatrial nodal cell (SAN model) electrically coupled to real ventricular cells (VCs) to investigate action potential conduction from an automatic focus. METHODS AND RESULTS: Since input resistance of a VC is less than that of an SAN cell, coupling of the SAN model, with a size factor of 1, to a VC produced either (1) spontaneous pacing at the slower rate of the SAN model but without driving (activation) of the VC for lower values of coupling conductance (Gj) or (2) inhibition of pacing of the SAN model by electrical coupling to the VC for higher values of Gj. When the SAN model was adjusted in size to be 3 to 5 times larger than a sinoatrial nodal cell, thus making effective SAN model capacitance 3 to 5 times larger and input resistance 3 to 5 times smaller, the SAN model propagated activity to the coupled VC for Gj above a critical value. When the VC was paced at 1 Hz, the coupled cell pair demonstrated a stable rhythm of alternating cycle lengths and alternating conduction directions. By increasing pacing frequency to 2 Hz, we converted this rhythm to a regular 2-Hz frequency in which each action potential originated in the VC. More complex periodic interactions were observed at intermediate cycle lengths and lower or higher values of Gj. CONCLUSIONS: The phenomena we observed demonstrate the critical role of the size of an automatic focus as well as the coupling in the propagation of activity from the focus into surrounding myocardium.


Assuntos
Coração/fisiologia , Modelos Cardiovasculares , Nó Sinoatrial/fisiologia , Função Ventricular , Potenciais de Ação , Animais , Simulação por Computador , Condutividade Elétrica , Estimulação Elétrica , Cobaias , Técnicas In Vitro , Fatores de Tempo
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