Changes in Ca
            <sup>2+</sup>
            Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure

Ahmmed, Gias U.; Dong, Paul R; Song, Guoji; Ball, Nancy; Xu, Yancheng; Walsh, Richard A.; Chiamvimonvat, Nipavan

doi:10.1161/01.res.86.5.558

Cited by 82 publications

(68 citation statements)

References 44 publications

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“…On the other hand, phase I of mechanical restitution was nearly flat in the failing SHHF hearts, and there was no further prolongation of the already prolonged action potentials with the introduction of early extrasystoles. Action potential prolongation is common in heart failure (1,11,33) and has been attributed to decreases in K ϩ currents [i.e., inward rectifier current (I K1 ) and transient outward current (I to )] (11) and to changes in Ca 2ϩ cycling that delay the Ca 2ϩ -dependent inactivation of L-type Ca 2ϩ currents (1,33). The lack of change in action potential duration with early extrasystoles in the failing SHHF hearts raises the possibility that voltage-or Ca 2ϩ -dependent facilitation of L-type Ca 2ϩ channels may be reduced in heart failure.…”

Section: Discussionmentioning

confidence: 99%

Mechanical alternans and restitution in failing SHHF rat left ventricles

Dumitrescu

Narayan

Efimov

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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We examined mechanical alternans and electromechanical restitution in normal and failing rat hearts. Alternans occurred at 5 Hz in failing versus 9 Hz in control hearts and was reversed by 300 nM isoproterenol, 6 mM extracellular Ca2+, 300 nM −BAY K 8644, or 50 nM ryanodine. Restitution curves comprised phase I, which was completed before relaxation of the steady-state beat, and phase II, which occurred later. Phase I action potential area and developed pressure ratios were significantly reduced in the failing versus control hearts. Phase II was a monoexponential increase in relative developed pressure as the extrasystolic interval was increased. The plateau of phase II was significantly elevated in failing hearts. Thapsigargin (3 μM) plus ryanodine (200 nM) potentiated phase I to a significantly greater extent in control versus failing hearts and abolished phase II in both groups. The results suggest that both regulation of Ca2+ influx across the sarcolemma and Ca2+ release by the sarcoplasmic reticulum may contribute to altered excitation-contraction coupling in the failing spontaneously hypertensive heart failure prone rat heart.

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Section: Discussionmentioning

confidence: 99%

Mechanical alternans and restitution in failing SHHF rat left ventricles

Dumitrescu

Narayan

Efimov

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…Western Blot Analysis-Immunoblots were performed as described previously (12). Protein samples were prepared from atria and ventricles of mice, cats and rats.…”

Section: Methodsmentioning

confidence: 99%

Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts

Tuteja

Zhang

et al. 2003

Journal of Biological Chemistry

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243

289

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The repolarization phase of cardiac action potential is prone to aberrant excitation that is common in cardiac patients. Here, we demonstrate that this phase is markedly sensitive to Ca 2؉ because of the surprising existence of a Ca 2؉ -activated K ؉ currents in cardiac cells. The current was revealed using recording conditions that preserved endogenous Ca 2؉ buffers. The Ca 2؉ -activated K ؉ current is expressed differentially in atria compared with ventricles. Because of the significant contribution of the current toward membrane repolarization in cardiac myocytes, alterations of the current magnitude precipitate abnormal action potential profiles. We confirmed the presence of a small conductance Ca 2؉ -activated K ؉ channel subtype (SK2) in human and mouse cardiac myocytes using Western blot analysis and reverse transcription-polymerase chain reaction and have cloned SK2 channels from human atria, mouse atria, and ventricles. Because of the marked differential expression of SK2 channels in the heart, specific ligands for Ca 2؉ -activated K ؉ currents may offer a unique therapeutic opportunity to modify atrial cells without interfering with ventricular myocytes.Cardiac action potentials (APs) 1 are shaped predominantly by the interplay between transient inward Na ϩ , Ca 2ϩ , and outward K ϩ currents (1). While the repolarization phase of the AP can be wrought by the kinetics of the principal currents, small and sustained outward currents also define this phase, rendering this region prone to irregular membrane excitation.In humans, delineation of the outward currents that confer the late repolarization phase of the cardiac AP is crucial for our understanding of the etiology of arrhythmias. We provide a novel report that demonstrates that the repolarization phase of cardiac AP shows marked sensitivity toward apamin, an exclusive ligand for a small conductance Ca 2ϩ -activated K ϩ channel (2).Ca 2ϩ -activated K ϩ channels (K Ca ) are present in most neurons and mediate the afterhyperpolarizations following AP (3, 4). However, functional significance of K Ca in the heart has not previously been documented. K Ca channels can be divided into three main subfamilies (3, 5-7). These include the large-conductance Ca 2ϩ -and voltage-activated K ϩ channels (BK), the intermediate-conductance K Ca channels (IK), and the smallconductance K Ca channels (SK), which are sensitive to apamin and scyllatoxin. Among the SK channels, they are encoded by at least three genes, SK1, SK2, SK3 (4, 6), with differential sensitivity toward apamin. SK2 is highly sensitive to apamin, with a half-blocking concentration (IC 50 ) of 60 pmol/liter, whereas SK1 channels are not affected by 100 nmol/liter apamin (2). SK3 channels are intermediate.Here, we report for the first time, the presence of I K,Ca (Ca 2ϩ -activated K ϩ current) in cardiac myocytes that plays a crucial role in cardiac AP profile. Using a combination of electrophysiological recordings and biochemical and molecular biological techniques, we have identified the presence of SK2...

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“…9 See further details in the expanded Materials and Methods section that can be found in the online data supplement available at http://www.circresaha.org.…”

Section: Methodsmentioning

confidence: 99%

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

Ahmmed

Dong

et al. 2001

Circulation Research

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Abstract-We directly tested the effects of nitric oxide (NO) on Na ϩ channels in guinea pig and mouse ventricular myocytes using patch-clamp recordings. We have previously shown that NO donors have no observed effects on expressed Na ϩ channels. In contrast, NO (half-blocking concentration of 523 nmol/L) significantly reduces peak whole-cell Na ϩ current (I Na ) in isolated ventricular myocytes. The inhibitory effect of NO on I Na was not associated with changes in activation, inactivation, or reactivation kinetics. At the single-channel level, the reduction in macroscopic current was mediated by a decrease in open probability and/or a decrease in the number of functional channels with no change in single-channel conductance. Application of cell permeable analogs of cGMP or cAMP mimics the inhibitory effects of NO. Furthermore, the effects of NO on I Na can only be blocked by inhibition of both cGMP and cAMP pathways. Sulfhydryl-reducing agent does not reverse the effect of NO. In summary, although NO exerts its action via the known guanylyl cyclase (GC)/cGMP pathway, our findings provide evidence that NO can mediate its function via a GC/cGMP-independent mechanism involving the activation of adynylyl cyclase (AC) and cAMP-dependent protein kinase. Key Words: nitric oxide Ⅲ cardiac Na ϩ current Ⅲ protein kinase A Ⅲ protein kinase G N itric oxide (NO) is a uniquely diffusible and reactive molecular messenger, which is found in abundance and plays important regulatory roles in different systems throughout the body. 1 In the cardiovascular system, NO is the major endothelium-derived relaxing factor (EDRF) and causes vasodilation and reduces blood pressure. 2 In addition, NO functions as an important endogenous inhibitor of vascular lesion formation. 3 The coronary endothelium is responsible for the bulk of the endogenous, physiological production of NO. 4 However, NO can also be produced within the cardiac myocytes themselves by the constitutive NO synthase. 5 NO modulates cardiac contractility both in vitro and in vivo. 6 More recently, it was shown that NO can regulate both adenylyl cyclase (AC) and guanylyl cyclase (GC) in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect, whereas low levels of NO increase cAMP and induce a positive contractile response. 7 We have previously shown using heterologous expression systems that although Ca 2ϩ channel can be directly modulated by NO, Na ϩ channels are unaffected by direct NO modulation. 8 Here, we show that NO modulates Na ϩ channels in native cardiac myocytes. In addition, we provide evidence to demonstrate that NO modulates Na ϩ channels via second messenger pathways through activation of protein kinase G (PKG) and protein kinase A (PKA). Materials and MethodsSingle left ventricular myocytes were isolated from guinea pigs and mice (Charles River Laboratories, Wilmington, Mass) as previously described. 9 See further details in the expanded Materials and Methods section that can be found in the online data supplement av...

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Changes in Ca ²⁺ Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure

Cited by 82 publications

References 44 publications

Mechanical alternans and restitution in failing SHHF rat left ventricles

Mechanical alternans and restitution in failing SHHF rat left ventricles

Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

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Changes in Ca 2+ Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure

Cited by 82 publications

References 44 publications

Mechanical alternans and restitution in failing SHHF rat left ventricles

Mechanical alternans and restitution in failing SHHF rat left ventricles

Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts

Nitric Oxide Modulates Cardiac Na + Channel via Protein Kinase A and Protein Kinase G

Contact Info

Product

Resources

About

Changes in Ca ²⁺ Cycling Proteins Underlie Cardiac Action Potential Prolongation in a Pressure-Overloaded Guinea Pig Model With Cardiac Hypertrophy and Failure

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G