Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea‐pig sino‐atrial node

Rigg, Lauren; Terrar, D A

doi:10.1113/expphysiol.1996.sp003983

Cited by 146 publications

(131 citation statements)

References 11 publications

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“…In fact, with the help of imaging techniques, Ca 2+ chelating fluorophores and electrophysiology, Ca 2+ transients were visualized during the DD slope and preceded the large entry of calcium through the calcium channels [87] . Alternative pharmacological approaches with SR blockers revealed modifications in the rate and the shape of the AP from guinea pig sinoatrial cells [88] . Evidence for a functional interaction between the ryanodine receptor-mediated Ca 2+ release and the cardiac isoform of the NCX-1 Na + -Ca 2+ exchanger [89][90][91] gave rise to an alternative theory, "the calcium clock", in which diastolic spontaneous Ca 2+ release activates the Na + -Ca 2+ NCX-1 exchanger in its forward mode.…”

Section: Calcium Clock Modelmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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Section: Calcium Clock Modelmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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“…37 Evidence indicates that release of calcium from the SR also plays an important role in pacemaking, because pharmacological interventions that deplete the SR calcium store slow the rate of the diastolic depolarization and increase cycle length in pacemaker cells. [21][22][23] The mechanism involved seems to involve highly localized SR calcium release "sparks," occurring during the final third of the diastolic depolarization. 41 Adrenergic stimulation increases SR Ca 2ϩ load, 24,42 and increases the frequency of calcium sparks, 43 although it is not known whether NO modulates calcium sparks in pacemaking cells.…”

Section: Calcium Currents and Heart Rate Responsiveness To Ne In The Shrmentioning

confidence: 99%

“…20 Data regarding the precise role of nNOS in modulating calcium currents in the sinoatrial node (SAN) remain limited. However, evidence linking SR calcium release to the generation of pacemaker rate [21][22][23] and the positive chronotropic action of ␤-agonists 24,25 suggests that nNOS-mediated regulation of I CaL could modulate the chronotropic response of the heart to ␤-adrenergic stimulation. Moreover, recent work has reported high levels of cAMPprotein kinase A (PKA)-mediated phosphorylation of calcium channels in SAN cells.…”

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confidence: 99%

Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its β-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer

Heaton

Lei

et al. 2006

Hypertension

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Abstract-Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that ␤-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the ␤-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of ␤-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling. Key Words: sinoatrial node Ⅲ norepinephrine Ⅲ nitric oxide synthase M any cardiovascular diseases (eg, heart failure, hypertension, and postmyocardial infarction) are also diseases of the autonomic nervous system. Neurohumoral activation and high levels of circulating catecholamines are negative prognostic indicators for sudden cardiac death and strong independent predictors of mortality. [1][2][3][4] In hypertension, cardiac sympathetic hyperactivity 5-7 and decreased cardiac parasympathetic tone 8,9 result in tachycardia and contribute to the pathophysiological phenotype. However, a significant component of the neural impairment may also occur postjunctionally at the level of the ␤-adrenoceptor, because the arrhythmic action of isoprenaline is enhanced in papillary muscles from the spontaneously hypertensive rat (SHR). 10 This correlates with increased basal and isoprenalinestimulated L-type calcium current (I CaL ) in ventricular myocytes from the SHR compared with the normotensive Wistar Kyoto rat (WKY). 11 Whether similar events occur in supraventricular tissue has not been established.It is now widely recognized that reduced bioavailability of NO, secondary to oxidative stress, is important in the pathophysiology of hypertension. 12,13 Moreover, downregulation of soluble guanyl...

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“…A plethora of recent data has emerged to conclusively show that intracellular Ca 2+ dynamics, in tight cooperation with surface membrane proteins, are critical for the normal spontaneous firing of SANC (reviews [6,7]). Nathan's group, in fact, was among the pioneers that discovered the major role of intracellular Ca 2+ cycling in pacemaker function, showing that ryanodine, which interferes with Ca 2+ release from the sarcoplasmic reticulum (SR), and BAPTA-AM, which chelates intracellular Ca 2+ , significantly slowed the spontaneous beating rate of cardiac pacemaker cells [8][9][10] The forth inward current measured was the "funny" current (I f ) activated by membrane hyperpolarization, often referred to as "the" pacemaker current [11,12]. Finally, the authors completed their set of tested currents with an outward current, delayed rectifier K + current, specifically, its rapid component I Kr , deactivation of which has a major contribution into the DD dynamics in rabbit SANC [13].…”

Section: Study Design and Hypothesismentioning

confidence: 99%

Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

Maltsev

Lakatta

2007

Journal of Molecular and Cellular Cardiology

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Cardiac ischemia is an important global health problem. It leads to contraction failure, arrhythmias, and cardiac cell death. Sinus bradycardia characterized by a slow heart rate (<60 bpm) is a prominent ischemia-related arrhythmia directly caused by a deficiency of heart beat initiation within the sinoatrial node (SAN), due to a failure of the heart's primary pacemaker cells (SANC). The study presented by Yi-Mei Du and Richard Nathan in this issue of Journal of Molecular and Cellular Cardiology [1] deals with the ionic basis of ischemia-induced bradycardia in isolated SANC. The results of their study not only contribute to understanding of ischemia-induced bradycardia, but also help to delineate the fundamental mechanisms of cardiac pacemaker cell function. Study design and hypothesisIn their studies, Du and Nathan simulated ischemia by superfusing SANC with a solution without glucose, at pH 6.6 that contained either 5.4 or 10 mM KCl. This lead, to a 13% or 43% reduction, respectively, in the spontaneous beating rate of freshly isolated SANC. This simulated ischemia is not true ischemia, e.g. there is no associated hypoxia or flow deficiency effects other than elevated [K + ]. Nonetheless simulated ischemia of this sort is often applied in studies like the present one. And, in their careful approach to the problem, the authors first demonstrated that their "ischemic" solutions produced bradycardia in the intact rabbit heart. Then, in isolated SANC they measured the effects of this simulated ischemia on membrane potential and ion currents under voltage clamp. Such an approach is not surprising, because it has been believed for almost half a century that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells. This dogma stems from the Nobel prize triumph of the Hodgkin-Huxley neuron membrane excitability theory [2] and subsequent modification of this theory and extrapolation to the heart cells by Noble (1960) [3]. According to this theory, generation of spontaneous action potentials (APs) by cardiac pacemaker cells is portrayed as a membrane delimited process, i.e. by a pure interplay of time-and voltage-dependent ion currents. Pacemaker field researchers have focused mainly on the identification of multiple ion current components in pacemaker cells, and their respective roles in the spontaneous diastolic depolarization of these cells (DD, Fig.1A) that brings the membrane to the excitation threshold (reviews [4,5]). Du and Nathan thus tested an hypothesis that bradycardia induced by their

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Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea‐pig sino‐atrial node

Cited by 146 publications

References 11 publications

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its β-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer

Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

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