Sinoatrial Node Of Heart Research Articles

Ca2+-Driven Selectivity of the Effect of the Cardiotonic Steroid Marinobufagenin on Rabbit Sinoatrial Node Function.

The synergy between Na+-K+ pumps, Na+-Ca2+ exchangers, membrane currents and the sarcoplasmic reticulum (SR) generates the coupled-clock system, which governs the spontaneous electrical activity of heart sinoatrial node cells (SANCs). Ca2+ mediates the degree of clock coupling via local Ca2+ release (LCR) from the SR and activation of cAMP/PKA signaling. Marinobufagenin (MBG) is a natural Na+-K+ pump inhibitor whose effect on SANCs has not been measured before. The following two hypotheses were tested to determine if and how MBG mediates between the Na+-K+ pump and spontaneous SAN activity: (i) MBG has a distinct effect on beat interval (BI) due to variable effects on LCR characteristics, and (ii) Ca2+ is an important mediator between MBG and SANC activity. Ca2+ transients were measured by confocal microscopy during application of increasing concentrations of MBG. To further support the hypothesis that Ca2+ mediates between MBG and SANC activity, Ca2+ was chelated by the addition of BAPTA. Dose response tests found that 100 nM MBG led to no change in BI in 6 SANCs (no BI change group), and to BI prolongation in 10 SANCs (BI change group). At the same concentration, the LCR period was prolonged in both groups, but more significantly in the BI change group. BAPTA-AM prolonged the BI in 12 SANCs. In the presence of BAPTA, 100 nM MBG had no effect on SANC BI or on the LCR period. In conclusion, the MBG effects on SANC function are mediated by the coupled clock system, and Ca2+ is an important regulator of these effects.

Whole genome sequencing identifies a deletion mutation in the unknown-functional KCNG2 from familial sick sinus syndrome

Sick sinus syndrome (SSS) is a term used for a variety of disorders defined by abnormal cardiac impulse formation and by abnormal propagation from the heart's sinoatrial node. In this study, we present a case from a Chinese family in which two closely related individuals had the symptoms and electrocardiographic evidence of SSS. We hypothesized that multiple individuals affected by the disease in the family was an indication of its genetic predisposition, and thus performed high-throughput sequencing for the participants from the family to detect potential disease-associated variants. One of the potential variants that was identified was a KCNG2 gene variant (NC_000018.9: g.77624068_77624079del). Further bioinformatic analysis showed that the observed variant may be a pathogenic mutation. The results of protein-protein docking and whole cell patch-clamp measurements implied that the deletion variant in KCNG2 could affect its binding the KV2.1 protein, and finally affect the function of Kv channel, which is an important determinant in regulation of heartbeat. Therefore, we inferred that the variable KCNG2 gene may affect the function of Kv channel by changing the binding conformation of KCNG2 and KV2.1 proteins and then adversely affect propagation from the sinoatrial node and cardiac impulse formation by changing the action potential repolarization of heart cells. In summary, our findings suggested that the dominant KCNG2 deletion variant in the examined Chinese family with SSS may be a potential disease-associated variant.

Similitude Methods and Three-Dimensional Simulation of the Electrical Activity of the Rabbit Sinoatrial Node and Adjacent Atrial Myocardium

This study focuses on possible applications of similitude design methods for three-dimensional simulation of the electrical activity of the sinoatrial node of the rabbit heart and the adjacent atrial myocardium. The proposed mathematical model has a hierarchical shape, where the relationship between the sinoatrial node and adjacent atrial myocardium is at the top and the dynamics of ion processes on the cardiomyocyte membranes is at the lower level of the model. Examples of using this three-dimensional model are given for the description of: (a) rhythm generation in the sinoatrial node of the heart; (b) the effect of doubling of the action potential duration in the site of the atrial myocardium with reduced electrical intercellular conductivity; and (c) the modulation effect of the electrical fibroblast–cardiomyocyte relationship on the peacemaker activity.

In utero exposure to nicotine abolishes the postnatal response of the cardiac sodium current to isoproterenol in newborn rabbit atrium

In utero exposure to tobacco smoke is associated with sudden infant death syndrome (SIDS) and cardiac arrhythmias in newborns. The arrhythmogenic mechanisms seem linked to alterations of the cardiac sodium current (INa). We previously reported that in utero exposure to nicotine delays the postnatal development of the heart sinoatrial node in rabbits and altered expression of the sodium channels NaV1.5 and NaV1.1 in the atrium surrounding it. These channels react differently to sympathetic stimulation. The purpose of this study was to test whether nicotine altered the response of INa to stimulation by the β-adrenoreceptor agonist isoproterenol in atrial myocytes. Our hypothesis is that changes in the sympathetic response of sinoatrial node peripheral cells may create a substrate for arrhythmia. Using the patch-clamp technique we measured the effect of nicotine on the response of INa to adrenergic stimulation in isolated cardiomyocytes. Isoproterenol increased INa by 50% in newborn sham rabbits but had no effect in newborn rabbits exposed to nicotine in utero. Our data also show that nicotine increases the late sodium current, an effect that may promote QT prolongation. We provide the first evidence linking fetal exposure to nicotine to long-term alterations of INa response to isoproterenol. These changes may impair INa adaptation to sympathetic tone and prevent awakening from sleep apnea, thus leading to arrhythmias that could potentially be involved in SIDS. Our data also raise concerns about the use of nicotine replacement therapies for pregnant women.

Correlation of heart rate with heart rate variability in sedentary young Indian women

Background: Autonomic nervous system (ANS) provides physiological balance in our body by regulating many bodily functions through its sympathetic and parasympathetic branches. Heart rate variability (HRV) is noninvasive method to assess ANS control at sinoatrial node of heart. HRV is derived from variations in heart rate (HR) over time through RR intervals. Aim: This study aims to investigate the correlation between HR and time and frequency domain indices of HRV. Materials and Methods: The study included 32 sedentary young women (20–24 years) from Jamia Millia Islamia, India. Twenty minutes electrocardiograph (ECG) recording was done for HRV analysis and 6 seconds ECG was recorded for HR measurement. Time domain indices of HRV such as SDNN, RMSSD, PNN50, and frequency domain indices of HRV such as total power, low-frequency (LF) power, high-frequency (HF) power, and LF/HF ratio were obtained. Results: There was significant inverse correlation between HR and RMSSD (P = 0.03, r = −0.37) and PNN50 (P = 0.003, r = −0.49) and total power (P = 0.02, r = −0.39). SDNN (P = 0.82, r = −0.03), HF power (P = 0.55, r = −0.10) showed nonsignificant inverse correlation trends with HR. LF power (P = 0.62, r = 0.09) and LF/HF ratio (P = 0.81, r = 0.04) demonstrated nonsignificant linear correlation trend with HR. Conclusion: The findings of this study demonstrated that there is an inverse correlation between HRV and HR of sedentary young women. Lower HR is associated with higher HRV and vice versa. Therefore, HR should be taken into consideration when recording HRV. HR may act as a method to quickly assess the function of ANS.

Main Regularities of Mutual Location of Different Pacemaker Cells in the Rat Heart Sinoatrial Node

The distribution of pacemaker cells and atrial working cardiomyocytes in the anterior right atrial wall was studied using intracellular glass microelectrodes under conditions of short-term culturing. It was shown that the dominant pacemaker region and the functional tail are located in the lateral area of the central part of the sinoatrial node, while the medial area is occupied by latent pacemaker cells.

To the formation of a unified rhythm in the heart sinoatrial node

The dynamics of establishing a unified sinoatrial node rhythm are considered. Mutual synchronization is shown to result in phase shifts and excitation delays. Rhythmogenesis in systems of two or many interacting pacemaker cells is examined in several point models and distributed models (Noble, Bonhoeffer-van der Pol, FitzHugh, Hodgkin-Huxley, Morris-Lecar).

Rhythmogenesis in the heart sinoatrial node

The most significant experimental data on the formation of the common rhythm of the heart sinoatrial node are presented for both the intact heart sinoatrial node and cardiomyocytes in cell structures. The basic mathematical models for studying the synchronization processes in the sinoatrial node, including the Noble equation, Bonhoffer-van der Pol model, and modified axiomatic models, are described. The basic results obtained with the mathematical models are presented. The most important causes affecting the formation of the common rhythm—the pacemaker potential shape in the slow diastolic depolarization phase, its porosity, the coupling force between pacemakers, and the electrical power of pacemakers—are revealed. Rhythmogenesis is studied using the modified axiomatic model. The method allows the calculation of the common rhythm of the sinoatrial node, with allowance for the mutual effect of the pacemaker cells, including the coupling force, electric power of cells, and possibility of the cells clustering. It has been shown that the common rhythm of the sinoatrial node is generally formed at the intermediate level of the rhythms of all pacemaker cells.

Therapeutic effects of If blockade: Evidence and perspective

Heart rate slowing has been accepted for decades as a primary therapeutic approach to prevention (and even to treatment) of angina pectoris. Pure heart rate slowing has not been achieved with previously available rate-slowing pharmacological agents (beta adrenergic blockers, certain calcium channel blockers), all of which have other pharmacological effects that may be beneficial but also may underlie adverse drug effects. Modulation of heart rate is a function of variation in the I f current, a sodium–potassium mediated membrane phenomenon that is active physiologically only in the heart's sinoatrial node. Though the current first was described more than 25 years ago, a practical pharmacological method for its inhibition only recently has been developed, tested and approved for use in Europe. The effective drug, ivabradine, has demonstrated anti-anginal, anti-ischemic efficacy and now is being tested for its effect on survival in patients with coronary artery disease and impaired left ventricular function, as well as for heart failure. The data supporting the use of the drug for angina prevention, and the potential for additional applications, are reviewed in this article.

Topography of 3H-DHA, 3H-QNB, 3H-Dopamine, and 3H-DAGO Binding Sites Distribution in the Central Part of the Sinoatrial Node in Rat Heart

The topography of distribution of 3H-dihydroalprenolol, 3H-quinucledinyl benzilate, 3H-dopamine, and 3H-DAGO binding sites in the central part of the sinoatrial node in rat heart was studied by autoradiography after electrophysiological identification of the dominant pacemaker region location. Receptor asymmetry between the lateral and median regions of the central part of the sinoatrial node was shown. The dominant pacemaker region lay in the lateral area of the sinoatrial node; the number of binding sites for all four ligands was minimum in it. The number of binding sites gradually increased in the cranial and caudal directions from the dominant pacemaker region along the sinoatrial node artery (more smoothly in the caudal direction). The relative densities of bindings sites for 3H-dihydroalprenolol and 3H-dopamine were higher in the lateral region compared to the perinodal working myocardium, while the densities for 3H-quinucledinyl benzilate and 3H-DAGO were virtually the same. The distribution of binding sites along the artery in the median region of the sinoatrial node was even for 3H-quinucledinyl benzilate and 3H-DAGO. For 3H-DAGO these parameters were close to those in the perinodal atrial myocardium, for 3H-quinucledinyl benzilate somewhat lower. Curves presenting the distribution of binding site densities for 3H-dihydroalprenolol and 3H-dopamine in the median region of the sinoatrial node were similar, with a pronounced peak in the region contralateral to the dominant pacemaker region, and significantly higher binding parameters compared to those for the perinodal atrial myocardium. The difference consisted in higher density of 3H-dopamine binding sites in the median region of the sinoatrial node in comparison with the lateral region. Binding activity was maximum in the wall of the sinoatrial node artery. The distribution of binding sites for ligands to the main autonomic nervous system neurotransmitters in the rat heart sinoatrial node is heterogeneous.

Vagal control of heart rate is modulated by extracellular potassium

Heart rate (HR) recovery from heavy exercise is associated with a shift in cardiac sympatho-vagal balance and a transient hypokalaemia. Since changes in extracellular potassium ([K +] 0) affect membrane currents in the sino-atrial node, in particular the acetylcholine-activated potassium current ( I K,ACh), the hyperpolarization-activated current ( I f) and the L-type calcium current ( I Ca,L), we investigated whether mimicking [K +] 0 concentrations seen during and immediately after exercise could directly modulate the HR response to vagal nerve stimulation (VNS) in the isolated guinea-pig atria preparation pre-stimulated with noradrenaline (NA, 1 μM). Lowering [K +] 0 from 4 to 3 mM significantly enhanced the HR response to VNS (5 Hz, 5 V, 30 s, ΔHR 84.5±14.1 bpm and 119.3±18.2 bpm, respectively). Increasing [K +] 0 to 8 or 10 mM significantly decreased the drop in HR with VNS in comparison to the response to 3 mM K + Tyrode (ΔHR 56.4±9.1 bpm and 52.1±8.7 bpm, respectively). These results could be simulated using the OXSOFT heart sino-atrial node computer model by activating I K,ACh during changes in [K +] 0. However, changing [K +] 0 in the model had no significant effect on the decrease in beating frequency brought about by decreasing I f or I Ca,L. We conclude that the magnitude of the decrease in HR with VNS is enhanced in low [K +] 0 and reduced in high [K +] 0. The increased efficacy of cardiac vagal activation in low [K +] 0 might therefore facilitate the drop in HR after heavy exercise where there is a transient hypokalaemia. Modelling suggests this result may be explained by the effects of changes in [K +] 0 on the current–voltage relationship for I K,ACh.

Molecular Characterization of the Hyperpolarization-activated Cation Channel in Rabbit Heart Sinoatrial Node

We cloned a cDNA (HAC4) that encodes the hyperpolarization-activated cation channel (If or Ih) by screening a rabbit sinoatrial (SA) node cDNA library using a fragment of rat brain If cDNA. HAC4 is composed of 1150 amino acid residues, and its cytoplasmic N- and C-terminal regions are longer than those of HAC1-3. The transmembrane region of HAC4 was most homologous to partially cloned mouse If BCNG-3 (96%), whereas the C-terminal region of HAC4 showed low homology to all HAC family members so far cloned. Northern blotting revealed that HAC4 mRNA was the most highly expressed in the SA node among the rabbit cardiac tissues examined. The electrophysiological properties of HAC4 were examined using the whole cell patch-clamp technique. In COS-7 cells transfected with HAC4 cDNA, hyperpolarizing voltage steps activated slowly developing inward currents. The half-maximal activation was obtained at -87.2 +/- 2.8 mV under control conditions and at -64.4 +/- 2.6 mV in the presence of intracellular 0.3 mM cAMP. The reversal potential was -34.2 +/- 0.9 mV in 140 mM Na+o and 5 mM K+o versus 10 mM Na+i and 145 mM K+i. These results indicate that HAC4 forms If in rabbit heart SA node.