Spontaneous Diastolic Depolarization Research Articles

Hyperpolarization activated cation current (<I>I</I><SUB>f</SUB>) in cardiac myocytes from pulmonary vein sleeves in the canine with atrial fibrillation

ObjectiveTo investigate the characteristics of ectopic automaticity and cation current (If) of cardiac myocytes from pulmonary vein sleeves (PVs) in canines with atrial fibrillation.MethodsThe canines (8–10 years old) were subjected to long-term, rapid atrial pacing (RAP) for 10 weeks, which induced the atrial fibrillation model. Disassociation of PVs of canines yielded single cardiac myocytes from a Landengorff column. Action potential, If and hyperpolarisation activated cyclic nucleotide-gated (HCN) currents were measured with the patch-clamp technique.ResultsCompared with the control group, cardiac myocytes from the RAP canine PVs had spontaneous diastolic depolarization, shorter action potential duration, and larger If densities. In the group of RAP cells, the half maximal activation potential (V1/2) was found to be less negative (−105.5 ± 5.2 mV) compared to control cells (−87.3 ± 4.9 mV). Current densities of If were increased significantly by β-adrenergic receptor stimulation with isoproterenol and caused an acceleration of current activation. In contrast, If currents in the RAP were reduced by carvedilol, a selective beta-adrenergic receptor. Another important finding is that HCN4-based channels may make a significant contribution to If in PVs cells, but not HCN2. Meanwhile, HCN4 current significantly increases in canine PVs cardiac myocytes with RAP.ConclusionsThe spontaneous action potential and larger If current were observed in the PVs cardiac myocytes using RAP, which may contribute to more ectopic activity events to trigger and maintain atrial fibrillation.

New pharmacological approaches to ischemic heart disease

Major steps have been made in the treatment of ischemic heart disease from the discovery of nitrates as antianginal medication to the techniques of percutaneous angioplasty. This incredible therapeutic progress has resulted in a reduced incidence of ischemic heart disease and related mortality and morbidity. However, statistical and epidemiological data indicate that in ischemic heart disease, despite the achievement of great success, there is a necessity for a further step toward treatment, considering the fact that the characteristics of this population are changing (increased prevalence of subendocardial infarction compared with classic transmural infarction, especially in the elderly population). Furthermore, the need for alternative therapeutic approaches to traditional ones is recognized. Ranolazine is a selective inhibitor of Na channels that prevents pathological extension of late Na current developing in the ischemic myocardial cell. This current is responsible for calcium overload, with consequent impairment of diastolic relaxation. Ranolazine reduces Na overload induced by calcium and improves diastolic relaxation and coronary subendocardial flow, without affecting hemodynamic parameters such as blood pressure, heart rate, or inotropic state of the heart, avoiding undesirable side effects. Efficacy of ranolazine has been evaluated in several trials, using clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). Ivabradine acts through the inhibition of late Na current (also known as If), which controls the spontaneous diastolic depolarization of sinus node cells. The partial inhibition of these channels reduces the frequency of sinus node action potential initiation, resulting in decreased heart rate without effects on contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL trial has tested whether the effect of ivabradine in lowering heart rate is able to reduce mortality and cardiovascular morbidity in patients with coronary artery disease and left ventricular systolic dysfunction. The most significant results were obtained in the subgroup of patients with life-limiting exertional angina. In this group, ivabradine significantly reduced the primary endpoint, a composite of cardiovascular death, hospitalization for fatal and nonfatal acute myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm, hospitalizations for AMI and revascularization were reduced by 73% and 59%, respectively.

Ivabradine for chronic heart failure?

In the UK, over 900,000 patients have chronic heart failure and more than 60,000 develop the condition each year.1,2 Patients with heart failure suffer significantly reduced quality of life and...

Clinical perspective: the importance of heart rate reduction in heart failure

Clinical perspective: the importance of heart rate reduction in heart failure

The “Funny” Current (If) Inhibition by Ivabradine at Membrane Potentials Encompassing Spontaneous Depolarization in Pacemaker Cells

Recent clinical trials have shown that ivabradine (IVA), a drug that inhibits the funny current (If) in isolated sinoatrial nodal cells (SANC), decreases heart rate and reduces morbidity and mortality in patients with cardiovascular diseases. While IVA inhibits If, this effect has been reported at essentially unphysiological voltages, i.e., those more negative than the spontaneous diastolic depolarization (DD) between action potentials (APs). We tested the relative potency of IVA to block If over a wide range of membrane potentials, including those that encompass DD governing to the SANC spontaneous firing rate. A clinically relevant IVA concentration of 3 μM to single, isolated rabbit SANC slowed the spontaneous AP firing rate by 15%. During voltage clamp the maximal If was 18 ± 3 pA/pF (at −120 mV) and the maximal If reduction by IVA was 60 ± 8% observed at −92 ± 4 mV. At the maximal diastolic depolarization (~−60 mV) If amplitude was only −2.9 ± 0.4 pA/pF, and was reduced by only 41 ± 6% by IVA. Thus, If amplitude and its inhibition by IVA at physiologically relevant membrane potentials are substantially less than that at unphysiological (hyperpolarized) membrane potentials. This novel finding more accurately describes how IVA affects SANC function and is of direct relevance to numerical modeling of SANC automaticity.

Understanding the Atrioventricular Dissociation

A 56-year old male patient was addressed to our intensive cardiac care unit with a diagnosis of “complete atrioventricular (AV) block”, 4 days following surgical treatment of symptomatic obstructive hypertrophic cardiomyopathy including large septal resection and mitral valve replacement. We noted no relevant medical history. On physical examination, at admission, the patient presented normal hemodynamic, regular heart rate about 60 bpm, no signs of right heart failure. An abnormal transient jugular vein pulse was noted. The EKG on admission is presented in Fig. 1. Do you agree with the diagnosis of complete AV block? Diagnosisof considered “complex”EKG features appears tobe reserved for cardiologists or even to electrophysiologists, although good sense and simple logical approach allowmaking the diagnosis yourself in a number of cases. Let‘s go for a typical case of a suspected AV conduction disorder following cardiac surgery. First, let’s review some elementary considerations on the cardiac conduction physiology. Sinoatrial node is a part of a specialized type of myocardial network which has the particularity of being also pacemaker myocyte cells. This specialized network is represented by sinoatrial node, AV node, His and bundle branch as well as distal Purkinje fibers. Unlike the rest of themyocytes, these pacemaker cells may initiate action potential through spontaneous diastolic depolarization. Because of a higher depolarization slope, the impulse initiated from sinoatrial node depresses the activity of subsidiary pacemaker sites, and also automatically generates electrical pulses that spread as waves of electrical excitation over the atria and then to ventricles via AV node. Interruption of the conduction at any level enables subsidiary pacemakers to emerge usually at a slower rate (the lower andmore distal is the block, the slower is the rate). On the opposite, enhanced automaticity in any part of this specialized myocardial network may overdrive normal sinus node activity, particularly when the latest is slower.

Novel blockers of hyperpolarization‐activated current with isoform selectivity in recombinant cells and native tissue

BACKGROUND AND PURPOSE Selective hyperpolarization activated, cyclic nucleotide-gated channel (HCN) blockers represent an important therapeutic goal due to the wide distribution and multiple functions of these proteins, representing the molecular correlate of f- and h-current (I(f) or I(h) ). Recently, new compounds able to block differentially the homomeric HCN isoforms expressed in HEK293 have been synthesized. In the present work, the electrophysiological and pharmacological properties of these new HCN blockers were characterized and their activities evaluated on native channels. EXPERIMENTAL APPROACH HEK293 cells expressing mHCN1, mHCN2 and hHCN4 isoforms were used to verify channel blockade. Selected compounds were tested on native guinea pig sinoatrial node cells and neurons from mouse dorsal root ganglion (DRG) by patch-clamp recordings and on dog Purkinje fibres by intracellular recordings. KEY RESULTS In HEK293 cells, EC18 was found to be significantly selective for HCN4 and MEL57A for HCN1 at physiological membrane potential. When tested on guinea pig sinoatrial node cells, EC18 (10 µM) maintained its activity, reducing I(f) by 67% at -120 mV, while MEL57A (3 µM) reduced I(f) by 18%. In contrast, in mouse DRG neurons, only MEL57A (30 and 100 µM) significantly reduced I(h) by 60% at -80 mV. In dog cardiac Purkinje fibres, EC18, but not MEL57A, reduced the amplitude and slowed the slope of the spontaneous diastolic depolarization. CONCLUSIONS Our results have identified novel and highly selective HCN isoform blockers, EC18 and MEL57A; the selectivity found in recombinant system was maintained in various tissues expressing different HCN isoforms.

T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells

Treatment of disorders of the sinus node or the atrioventricular node requires insights into the molecular mechanisms of development and homoeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogramme terminally differentiated working cardiomyocytes into pacemaker cells. TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice using tamoxifen. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na(+) channel (Na(V)1.5; I(Na)), and inwardly rectifying K(+) ion channels (K(ir) genes; I(K1)). Concordantly, we observed conduction slowing in these hearts and reductions in I(Na) and I(K1) in cardiomyocytes isolated from these hearts. The reduction in I(K1) resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current I(f) was observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. TBX3 reprogrammes terminally differentiated working cardiomyocytes and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce I(K1) density to enable diastolic depolarization are promising TBX3 characteristics that may facilitate biological pacemaker formation strategies.

Critical evaluation of ivabradine for the management of chronic stable angina

Critical evaluation of ivabradine for the management of chronic stable angina Waqas Khan, Jeffrey S BorerDivision of Cardiovascular Medicine and the Department of Medicine, State University of New York Downstate Medical Center and College of Medicine, Brooklyn and New York, NY, USAAbstract: Angina pectoris is the most common symptom of coronary artery disease (CAD). Angina results from an imbalance between myocardial oxygen supply and demand. Heart rate (HR) reduction can beneficially alter both elements of this imbalance by increasing diastolic filling time and reducing myocardial oxygen demand. Therefore, HR reduction is an accepted approach to angina prevention. ß-blockers, calcium-channel blockers, and long-acting nitrates are currently the cornerstones in prevention and management of stable angina. However, use of these treatments may be limited by adverse effects or development of tolerance. Thus, additional approaches to angina prevention may be useful for many patients with CAD. The discovery of the f-channel and the resulting current, If, that modulates the rate of spontaneous diastolic depolarization of sinoatrial nodal (SAN) myocytes led to the study of these channels as targets for lowering HR. This resulted in the development of a novel agent, ivabradine, a selective and specific If inhibitor. Ivabradine slows the slope of diastolic depolarization of the action potential in the SAN cells, decreasing HR at rest and during exercise, but has no other cardiovascular effects. In different subpopulations with chronic stable angina, ivabradine markedly improves exercise capacity and significantly decreases the number of ambient angina attacks. In a post-hoc analysis of the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction), ivabradine also reduced mortality, myocardial infarctions, and heart failure hospitalizations among patients with angina. To date, the drug has been well tolerated; transient visual disturbances and bradycardia are the only potentially important, though relatively infrequent, concerns and are readily reversible with drug cessation. This article will review and critically evaluate the data supporting use of ivabradine in patients with CAD and angina, both in preventing the symptom and, potentially, in altering the natural history of CAD.Keywords: coronary artery disease, cardiovascular pharmacology, clinical trials

Electrophysiological effects of ivabradine in dog and human cardiac preparations: Potential antiarrhythmic actions

Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V max), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1–10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V max block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V max block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat −1 in dog ventricular muscle. In addition to a fast recovery of V max from inactivation (τ = 41–46 ms) observed in control, a second slow component for recovery of V max was expressed (offset kinetics of V max block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.

Spironolactone diminishes spontaneous ventricular premature beats by reducing HCN4 protein expression in rats with myocardial infarction

Hyperpolarization-activated current (If) is the major ionic current contributing to the spontaneous diastolic depolarization of cardiac sinus node pacemaker cells. It is mediated by hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. However, several observations support a potential role of HCN channels in the arrhythmogenesis of working myocardium under pathological conditions. Spironolactone, a classic aldosterone blocker, has been proved to prevent spontaneous ventricular arrhythmias after myocardial infarction (MI). Here, we examined the effect of spironolactone on the expression of HCN channels and ventricular premature beats (VPBs) using a rat MI model. Sprague-Dawley rats were divided into a sham-operated group and MI groups treated with intragastric administration of saline or spironolactone (80 µg/kg/day) for 7 days immediately after ligation of the left coronary artery. Compared to the sham group, HCN2 and HCN4 protein levels were increased in MI rats. Treatment with spironolactone prevented the MI-induced increase of HCN4 protein levels (1.47 ± 0.16 vs. 1.81 ± 0.21, P<0.05). MI rats exhibited a marked increase of VPBs compared to the sham group (104 ± 17 vs. 3 ± 1 VPBs/h, P < 0.05). This the increase was reduced by spironolactone (55 ± 14 vs. 104 ± 17 VPBs/h, P < 0.05). Moreover, If current inhibitor (ivabradine, 0.5 mg/kg) further decreased the occurrence of VPBs in the control and spironolactone groups to the same level (54 ± 13 vs. 49 ± 8 VPBs/h, P > 0.05). In conclusion, spironolactone may prevent ischemia-induced VPBs by reducing HCN4 protein expression to basal levels.

The Cardiac Conduction System

The human heart beats 2.5 billion times during a normal lifespan, a feat accomplished by cells of the cardiac conduction system (CCS). The functional components of the CCS can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. Human diseases of the conduction system have been identified that alter impulse generation, impulse propagation, or both. CCS dysfunction is primarily due to acquired conditions such as myocardial ischemia/infarct, age-related degeneration, procedural complications, and drug toxicity. Inherited forms of CCS disease are rare, but each new mutation provides invaluable insight into the molecular mechanisms governing CCS development and function. Applying a multidisciplinary approach, which includes human genetic screening, biophysical analysis, and transgenic mouse technology, has yielded a broad array of gene families involved in maintaining normal CCS physiology (Figure 1). In this review, we discuss gene families that have been implicated in human CCS diseases of rhythm, conduction block, accessory conduction, and development (Table). We also investigate evolving therapeutic strategies that may serve as adjuvant or replacement therapy to current implantable pacemakers. Figure 1. Cardiac conduction system cell. Genes identified in human cardiac conduction system disease are highlighted. View this table: Table. Genetic Basis of Conduction System Disease The human sinoatrial node (SAN) is a crescent-shaped, intramural structure with its head located subepicardially at the junction of the right atrium and the superior vena cava and its tail extending 10 to 20 mm along the crista terminalis.26 The SAN has complex 3-dimensional tissue architecture with central and peripheral components made up of distinct ion channel and gap junction expression profiles.27 Central and peripheral cells have different action potential characteristics and conduction properties (Figure 2).27 Experimental and computational models have demonstrated that SAN heterogeneity is necessary to maintain normal automaticity and impulse conduction.28,–,30 Figure 2. Electrophysiological heterogeneity of the …

CSPE Young Investigator Award Session

CSPE Young Investigator Award Session

Expression and distribution of voltage-gated ion channels in ferret sinoatrial node

Spontaneous diastolic depolarization in the sinoatrial (SA) node enables it to serve as pacemaker of the heart. The variable cell morphology within the SA node predicts that ion channel expression would be heterogeneous and different from that in the atrium. To evaluate ion channel heterogeneity within the SA node, we used fluorescent in situ hybridization to examine ion channel expression in the ferret SA node region and atrial appendage. SA nodal cells were distinguished from surrounding cardiac myocytes by expression of the slow (SA node) and cardiac (surrounding tissue) forms of troponin I. Nerve cells in the sections were identified by detection of GAP-43 and cytoskeletal middle neurofilament. Transcript expression was characterized for the 4 hyperpolarization-activated cation channels, 6 voltage-gated Na(+) channels, 3 voltage-gated Ca(2+) channels, 24 voltage-gated K(+) channel α-subunits, and 3 ancillary subunits. To ensure that transcript expression was representative of protein expression, immunofluorescence was used to verify localization patterns of voltage-dependent K(+) channels. Colocalizations were performed to observe any preferential patterns. Some overlapping and nonoverlapping binding patterns were observed. Measurement of different cation channel transcripts showed heterogeneous expression with many different patterns of expression, attesting to the complexity of electrical activity in the SA node. This study provides insight into the possible role ion channel heterogeneity plays in SA node pacemaker activity.

Role of Polyamines and cAMP-dependent Mechanisms on 5α-dihydrotestosterone-elicited Functional Effects in Isolated Right Atria of Rat

Androgens produce acute vasodilation of systemic, pulmonary, and coronary arteries in several mammal preparations and increase cardiomyocyte contractility. A decrease of the spontaneous beating of sinoatrial cells has also been described. The aim of this study was to characterize the direct effect of 5alpha-dihydrotestosterone on the spontaneous chronotropism and inotropism in the same preparation as an approach to establish the effect on cardiac output and their mechanism of action. The effects were studied on isolated right atria of Wistar rats placed in an organ bath in Tyrode solution at 37 degrees C and bubbled with carbogen. In male rats, the acute administration of 5alpha-dihydrotestosterone, a nonaromatizable derivate of testosterone, elicited a positive inotropism, which was associated with a negative chronotropism. As reported in the left atria, polyamines and beta-adrenoceptors played a role in 5alpha-dihydrotestosterone-elicited positive inotropism because the effect was antagonized by alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, and atenolol, a beta1-adrenoceptor blocker, but not on the negative effect on chronotropism. The androgen increased the sinoatrial node recovery time, suggesting an effect on the mechanisms of spontaneous diastolic depolarization involved in atria pacemaking. These effects of 5alpha-dihydrotestosterone are not hormonally regulated because they are similarly produced in estrogenized females and gonadectomized male and female rats. These results suggest that the androgen could acutely improve cardiac performance.

A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes

Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na(+) current (referred to as late I(Na)) may contribute to DD and initiate AP firing and that 2) blocking late I(Na) will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H(2)O(2), 50 micromol/l) caused DD and AP firing. The H(2)O(2)-induced activity was suppressed by the late I(Na) inhibitors tetrodotoxin (TTX, 1 micromol/l) and ranolazine (5 micromol/l). In cells with DD but no spontaneous APs, the late I(Na) enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 micromol/l) significantly reduced the slope of DD by 81 +/- 12% and 75 +/- 11% and the frequency of spontaneous firing by 70 +/- 15% and 74 +/- 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 micromol/l inhibited this current by 41 +/- 4%, 73 +/- 2%, and 91 +/- 1%, respectively, suggesting that a slowly inactivating I(Na) underlies the DD. ATX-II and H(2)O(2) increased the amplitude of this current, and the effects of ATX-II and H(2)O(2) were attenuated by ranolazine or TTX. In conclusion, late I(Na) can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.

What keeps us ticking: a funny current, a calcium clock, or both?

The processes underlying the initiation of the heartbeat, whether due to intracellular metabolism or surface membrane events, have always been a major focus of cardiac research. About 50 years ago, a pioneering work initiated by Silvio Weidmann and others applied the Hodgkin–Huxley formalism of membrane excitation to interpret the cardiac electrical activity, including the pacemaker depolarization (see D. Noble, 1979. The initiation of the heartbeat, Clarendon Press). The underlying idea was that voltageand time-dependent gating of various surface membrane channels not only generated the cardiac pacemaker action potential (AP), but also controlled the spontaneous depolarization between AP's and thus determinedwhen thenextAPwouldoccur. According to this description, the ensemble of surface membrane ion channels works as a clock that regulates the rate and rhythm of spontaneous AP firing, otherwise known as normal automaticity. A formidable research effort then concentrated in attempting to target which of the surface membrane ion channels had an important role in controlling the spontaneous diastolic depolarization (DD). Originally, a major role was attributed to the “IK-decay theory”. This was strongly influenced by the previous Hodgkin–Huxley model of nerve AP, which described the slow depolarization following a nerve AP as due to the decay of a K current. This model of pacemaker depolarization lasted some 20 years, until it was turned upside-down by a full re-interpretation based on the discovery of the If current. Other ionic currents gated by membrane depolarization, i.e. ICaL, ICaT, IST, non-gated and non-specific background leak currents, and also a current generated by the Na–Ca exchange (NCX) carrier, were also proposed to be involved in pacemaking. Based on a wealth of experimental evidence, If is today considered as the most important ion channel involved in the rate regulation of cardiac pacemaker cells, and is sometimes referred to as “the pacemaker channel.” Several studies, some of which recent, have also shown that in addition to voltage and time, surface membrane electrogenic molecules are strongly modulated by Ca and phosphorylation. The studies of a sub-group of pacemaker cell researchers focusing Journal of Molecular and Cellular Cardiology 47 (2009) 157–170

Heart rate control: f-channel blockers

This review is devoted to the problem of pharmacological heart rate (HR) control in patients with cardiovascular diseases. Analysis of the literature allows the conclusion that an increased HR at rest (more than 80 bpm) may be regarded as an independent risk factor for both overall and cardiovascular mortality. Naturally, HR decrease is one of the most important goals of combination therapy for cardiovascular diseases, in particular, coronary heart disease (CHD). One of the possible approaches to the solution of this task is to develop and introduce into clinical practice medications capable of inhibiting the automatism of sinoatrial node pacemaker cells by blocking specialized potential-dependent transmembrane f-channels in the pacemaker cell membrane. After the mechanism of action, this group of agents are named f channel blockers. The electrophysiological mechanisms responsible for spontaneous diastolic depolarization of sinoatrial node pacemaker cells, as well as the problems of the fundamental, clinical, and evidence-based pharmacology of f -blockers (exemplified by Ivabradine), are considered in the review.

Expression and Distribution of Voltage Gated Ion Channels in Ferret SA Node

Spontaneous diastolic depolarization in the sinoatrial (SA) node enables it to serve as pacemaker of the heart. The combination of variation of cellular morphology within the SA node and heterogeneity of ion channel expression in the atrium predict that ion channel expression would be different and more heterogeneous than in the atrium. To evaluate ion channel heterogeneity within the SA node, we used fluorescent in-situ hybridization to examine ion channel transcript expression in the ferret SA nodal region and atrial appendage. We analyzed transcripts for 24 voltage-gated K+ channel alpha subunits, 4 hyperpolarization-activated cation channels, 3 voltage-gated Ca2+ channels and 6 voltage-gated Na+ channels and 3 ancillary subunits. Immunofluorescence was used to verify localization patterns of voltage-dependent K+ channels. Co-localizations were performed to observe any preferential patterns. Neuronal antibodies were used in association with K+ channel transcripts and antibodies to segregate the associated patterns in cardiac tissue. There were some overlapping and non-overlapping binding patterns observed. As positive controls, oligonucleotide probes from Troponin I slow and Troponin I cardiac sequences were used. Measurement of different K+ channel transcripts showed heterogeneous expression with many different patterns of expression, attesting to the complexity of electrical activity in the SA node. This study enabled us for the first time to analyze the microscopic distribution of different transcripts in contiguous images and in a continuous manner over a cross-section of the SA nodal region. Such information provides a better understanding of the role that ion channel heterogeneity might play a role in SA node pacemaker activity.

Ivabradine: Novel if channel inhibitor

Pacemaker activity of the heart involves interplay between several ionic currents that ins uence spontaneous diastolic depolarization of the sinoatrial node, including I f current. The search for pure heart rate-lowering agents to prevent angina without over all adverse effects of β-blockers [1] began more than three decades ago. The discovery of I f current and I f channels offered a possible approach to the developing pure heart rate-lowering agents. [1]