Increased Availability and Open Probability of Single L-Type Calcium Channels From Failing Compared With Nonfailing Human Ventricle

Schröder, F; Handrock, Renate; Beuckelmann, Dirk J.; Hirt, Stephan; Hullin, Roger; Priebe, Leo; Schwinger, Robert H. G.; Weil, Joachim; Herzig, Stefan

doi:10.1161/01.cir.98.10.969

Cited by 245 publications

(212 citation statements)

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“…In hypertrophied guinea pig hearts, inhomogeneous changes in I Ca,L were considered to contribute to a transmurally heterogeneous prolongation of ventricular APD (4). Schroder et al (39) found that single Ca 2ϩ channels exhibited increased availability and opening probability in cells isolated from failing human hearts, but whole cell I Ca,L did not show significant differences, when compared with nonfailing cells, in agreement with a previous report in humans (27). Recently, it has been found that the L-type Ca 2ϩ channel number is reduced and channel open times are increased in ventricular cells from pacing-induced canine failing hearts, so that overall I Ca,L density is unchanged (10).…”

Section: Discussionmentioning

confidence: 99%

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Lau

Ducharme

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

222

187

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action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283: H1031-H1041, 2002. First published May 30, 2002 10.1152/ ajpheart.00105.2002.-Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K ϩ current (IK1) was homogeneously reduced by ϳ41% (at Ϫ60 mV) in the three cell types. Transient outward K ϩ current (Ito1) was decreased by 43-45% at ϩ30 mV, and the slow component of the delayed rectifier K ϩ current (IKs) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K ϩ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of IK1, Ito1, and IKs increases APD and favors occurrence of EADs. heterogeneity; early afterdepolarizations; congestive heart failure; arrhythmias

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Section: Discussionmentioning

confidence: 99%

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Lau

Ducharme

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

222

187

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“…Single-channel recordings were performed by using the cell-attached configuration of the patchclamp method as described (35). Cells were placed in disposable Petri dishes containing 3 ml of a high-potassium depolarizing solution [25 mM KCl͞120 mM potassium glutamate͞2 mM MgCl 2 ⅐6H 2 O͞10 mM Hepes͞2 mM EGTA͞10 mM dextrose͞1 mM CaCl 2 ͞1 mM Na 2 -ATP (pH 7.3) with KOH].…”

Section: Methodsmentioning

confidence: 99%

“…Openings and closures were identified by the half-height criterion. The fraction of active sweeps within a channel-containing patch (availability), the open probability within active sweeps (open probability), and the peak value of single-channel ensemble average currents (I peak ) were determined as described (35). In double-channel patches, these parameters were corrected for the number of channels as described (36).…”

Section: Methodsmentioning

confidence: 99%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Two subtypes of ␤-adrenoceptors, ␤1 and ␤2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human ␤2-adrenoceptors survive high-expression levels, unlike mice overexpressing ␤1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by ␤2-but not ␤1-adrenoceptors, on the chronic effects of human ␤2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where G␣i2, a functionally important cardiac Gi ␣-subunit, was inactivated by targeted gene deletion. Survival of ␤2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G␣i2. Homozygous knockout͞␤2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout͞␤2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with ␤2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout͞␤2-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous G␣i2 knockout animals. Cardiac G␣i3 protein was increased in all G␣i2 knockout mouse strains. Our results demonstrate that G␣i2 takes an essential protective part in chronic signaling of overexpressed ␤2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by ␤2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by G␣i3. This result indicates that subtype-specific signaling of ␤2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G␣ isoform.L-type calcium channel ͉ single channel recording ͉ mouse genetics ͉ survival curve ͉ pertussis toxin C ardiac stimulatory catecholamine effects are mediated by both ␤ 1 -and ␤ 2 -adrenergic receptors (␤-adrenoceptors), mainly through cAMP-dependent protein kinase A-catalyzed phosphorylation of cardiac proteins involved in calcium homeostasis, such as phospholamban and the L-type calcium channel. Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1, 2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4-6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7-9).Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10, 11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimu...

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“…Similar reduction of I to and I K1 has been observed in ventricular cells isolated from failing human hearts. 3,17 In terms of I Ca,L , various changes such as an increase, 18 no change, 19 and a decrease 20 in the density of I Ca,L have been reported in myocytes of failing human hearts. In BIO 14.6 hamsters, the density of I Ca,L was significantly depressed at the late heart failure stage, although it was unaltered at 20 weeks (unpublished observations).…”

Section: Matsumoto Et Al Et a Receptor Blockade On Electrical Remodelingmentioning

confidence: 99%

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Matsumoto

Aihara²,

Yamauchi-Kohno³

et al. 2002

Circulation

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Background-The endothelin (ET) system is activated in failing hearts. Congestive heart failure frequently is associated with ventricular arrhythmias, which may result from electrical remodeling such as changes of ionic current density and heterogeneous action potential prolongation. We examined the effects of long-term ET A receptor blockade on the electrophysiological properties of ventricular cells, the surface ECG, and the survival in BIO 14.6 cardiomyopathic hamsters. Methods and Results-Membrane currents and action potentials were recorded from left ventricular cells isolated from normal F1␤ hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ET A receptor antagonist. In ventricular cells of untreated BIO 14.6 hamsters, the action potential duration was prolonged and the densities of the L-type Ca 2ϩ current (I Ca,L ), the transient outward current (I to ), the delayed rectifier K ϩ current (I K ), and the inward rectifier K ϩ current (I K1 ) were decreased compared with those of F1␤ hamsters. Long-term treatment with the ET A receptor antagonist significantly attenuated action potential duration prolongation and reduction of I to , I K , and I Ca,L in BIO 14.6 ventricular cells. Long-term ET A receptor blockade prevented the QT prolongation and ventricular arrhythmias and improved the survival rate in the cardiomyopathic hamsters. Conclusions-Long-term treatment with an ET

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Increased Availability and Open Probability of Single L-Type Calcium Channels From Failing Compared With Nonfailing Human Ventricle

Abstract: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.

Cited by 245 publications

References 44 publications

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

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Increased Availability and Open Probability of Single L-Type Calcium Channels From Failing Compared With Nonfailing Human Ventricle

Abstract: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.

Cited by 245 publications

References 44 publications

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Contact Info

Product

Resources

About

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors