Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity

Ono, Koichi; Ito, Hiroyuki

doi:10.1152/ajpheart.1995.269.2.h453

Cited by 78 publications

(114 citation statements)

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“…The rapid and slow delayed rectifier potassium current (I Kr and I Ks ) has a prominent role in the SAN. I Kr is the major factor determining the maximum diastolic potential and ensures the firing of the subsequent AP in the SAN (30). In the SAN of HF rabbits, I f and I Ks were reduced by 40 and 20%, respectively (31).…”

Section: Discussionmentioning

confidence: 99%

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Chang

Chuang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca 2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.

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Section: Discussionmentioning

confidence: 99%

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Chang

Chuang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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“…The results of the study showed that three major ion channels that contribute to the DD, activation of I f and deactivation of I Kr which both initiate the DD [12,13] and I CaL , which becomes activated at the termination of the DD and produces the rapid upstroke of the AP [15] (Fig.1A), are not involved in the ischemia-induced rate reduction. I CaL , in fact, increased, whereas I Kr remained unchanged and I f was either also unchanged or increased in 5.4 or 10 mM KCl, respectively.…”

Section: Three Major Currents I F I Cal and I Kr Do Not Fail Whementioning

confidence: 95%

“…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]. Thus, all studied currents are critically involved in either membrane-electrophysiology or intracellular Ca 2+ dynamics during the DD.…”

Section: Study Design and Hypothesismentioning

confidence: 99%

“…In other words, whereas both I f and I Kr determine the maximum diastolic potential and initiate the early linear part of the DD [12,13], this later critical I NCX prompt is required to steadily and timely bring the membrane potential to the AP threshold. Indeed, while the increase in I CaL found under ischemic-like conditions results in a lower take-off potential, as seen in Fig.1B, this does not compensate for the absence of an exponentially rising, late DD phase resulted from the deficiency of NCX function.…”

Section: Ca 2+ Cycling Within Cardiac Pacemaker Cells Is a "Clock"mentioning

confidence: 99%

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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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“…Thus, very little I Kr exists during the plateau phase of the action potential. During repolarization, there is recovery from inactivation causing an outward current responsible for late repolarization, followed by slow deactivation (Ono & Ito, 1995). In rabbit SA node cells, I Kr activation starts around -50 mV with a voltage of half maximal activation of -17.4 mV (Lei & Brown, 1996).…”

Section: Rapid Component Of the Delayed Rectifier Kmentioning

confidence: 99%

Creation of a Biopacemaker: Lessons from the Sinoatrial Node

Haan¹,

Verkerk

Tan³

2011

Modern Pacemakers - Present and Future

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Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity

Cited by 78 publications

References 0 publications

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

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

Creation of a Biopacemaker: Lessons from the Sinoatrial Node

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