Slope Of Diastolic Depolarization Research Articles

Ivabradine in Septic Shock: A Narrative Review.

In patients with septic shock, compensatory tachycardia initially serves to maintain adequate cardiac output and tissue oxygenation but may persist despite appropriate fluid and vasopressor resuscitation. This sustained elevation in heart rate and altered heart rate variability, indicative of autonomic dysfunction, is a well-established independent predictor of adverse outcomes in critical illness. Elevated heart rate exacerbates myocardial oxygen demand, reduces ventricular filling time, compromises coronary perfusion during diastole, and impairs the isovolumetric relaxation phase of the cardiac cycle, contributing to ventricular-arterial decoupling. This also leads to increased ventricular and atrial filling pressures, with a heightened risk of arrhythmias. Ivabradine, a highly selective inhibitor of the sinoatrial node's pacemaker current (If or "funny" current), mitigates heart rate by modulating diastolic depolarization slope without affecting contractility. By exerting a selective chronotropic effect devoid of negative inotropic properties, ivabradine shows potential for improving hemodynamics in septic shock patients with cardiac dysfunction. This review evaluates the plausible mechanisms and existing evidence regarding the utility of ivabradine in managing patients with septic shock.

B-PO02-020 PDE4D MEDIATES DESENSITIZATION OF Β-ADRENERGIC RECEPTORS IN THE SINOATRIAL NODE IN HYPERTENSIVE HEART DISEASE

Chronotropic incompetence is common in hypertensive heart disease due to impaired β-adrenergic receptor (β-AR) responsiveness of the sinoatrial node (SAN). To determine the mechanism for impaired β-AR signaling in the SAN of angiotensin II (AngII) induced hypertensive heart disease. C57BL/6 mice were infused with saline or AngII (2.5mg/kg/day) for 21 days to induce hypertensive heart disease. Heart rate (HR) and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied by in vivo electrocardiography, in isolated atrial preparations by optical mapping, in isolated SAN myocytes by patch-clamping, and by molecular techniques. AngII infused mice had impaired HR increases in response to ISO (100mg/kg) in vivo (171.1±7.1 vs. 134±9.8 bpm; n=5-6 mice; P<0.05) and in isolated atrial preparations (10μM ISO; 160.4±9.7 vs. 96.6±7.8, n=5-6 hearts; P<0.05). ISO (10μM) induced increases in SAN conduction velocity were also smaller in AngII infused hearts (1.6±0.1 vs. 1.1±0.1 cm/s, n=5-6 hearts; P<0.05). The effects of ISO (10μM) in isolated SAN myocytes after AngII infusion were impaired as indicated by smaller increases in spontaneous action potential (AP) firing (54.5±4.6 vs. 28.3±2.7 AP/min; P<0.001), diastolic depolarization (DD) slope (33.2±3.8 vs. 19.0±3.5 mV/s; P<0.05), peak “funny” current (-3.7±0.2 vs. -1.8±0.1 pA/pF; P<0.05), and peak L-type Ca2+ current (-6.9±1.3 vs. -3.5±0.7 pA/pF; P<0.05; n=7-15 cells). SAN myocytes from AngII infused mice had diminished cAMP generation in response to ISO (126.5±4.7 vs. 103.7±5.3 nM/1000 cells; P<0.05). No differences were seen in the protein expression of β1- or β2-ARs (both n=6; P>0.05); however, AngII infused mice had increased SAN PDE4 activity (1.4±0.3 vs. 3.9±0.9 pmol/mg/min, n=5; P<0.05). Total PDE4 expression was unaltered in the SAN of AngII infused mice but localization of PDE4D surrounding both β1- and β2-ARs was increased (n=6; P<0.05). Acute application of the PDE4 inhibitor rolipram (10μM) normalized ISO (10nM) induced increases in AP firing and DD slope in SAN myocytes (n=8-10) from AngII infused mice. AngII infusion results in blunted HR responses to β-AR stimulation due to upregulation of PDE4D specifically around β-ARs in the SAN.

Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy

AimAn adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methodsExperiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findingsLG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. SignificanceLG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.

Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.

TRPV1 channels regulate the automaticity of embryonic stem cell-derived cardiomyocytes through stimulating the Na+ /Ca2+ exchanger current.

Calcium controls the excitation-contraction coupling in cardiomyocytes. Embryonic stem cell-derived cardiomyocytes (ESC-CMs) are an important cardiomyocyte source for regenerative medicine and drug screening. Transient receptor potential vanilloid 1 (TRPV1) channels are nonselective cation channels that permeate sodium and calcium. This study aimed to investigate whether TRPV1 channels regulate the electrophysiological characteristics of ESC-CMs. If yes, what is the mechanism behind? By immunostaining and subcellular fractionation, followed by western blotting, TRPV1 was found to locate intracellularly. The staining pattern of TRPV1 was found to largely overlap with that of the sarco/endoplasmic reticulum Ca2+ -ATPase, the sarcoplasmic reticulum (SR) marker. By electrophysiology and calcium imaging, pharmacological blocker of TRPV1 and the molecular tool TRPV1β (which could functionally knockdown TRPV1) were found to decrease the rate and diastolic depolarization slope of spontaneous action potentials, and the amplitude and frequency of global calcium transients. By calcium imaging, in the absence of external calcium, TRPV1-specific opener increased intracellular calcium; this increase was abolished by preincubation with caffeine, which could deplete SR calcium store. The results suggest that TRPV1 controls calcium release from the SR. By electrophysiology, TRPV1 blockade and functional knockdown of TRPV1 decreased the Na+ /Ca2+ exchanger (NCX) currents from both the forward and reverse modes, suggesting that sodium and calcium through TRPV1 stimulate the NCX activity. Our novel findings suggest that TRPV1 activity is important for regulating the spontaneous activity of ESC-CMs and reveal a novel interplay between TRPV1 and NCX in regulating the physiological functions of ESC-CMs.

Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling.

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, I F, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of I F are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.

Angiotensin II Induces Automatic Activity of the Isolated Guinea Pig Pulmonary Vein Myocardium through Activation of the IP₃ Receptor and the Na⁺-Ca2+ Exchanger.

The automaticity of the pulmonary vein myocardium is known to be the major cause of atrial fibrillation. We examined the involvement of angiotensin II in the automatic activity of isolated guinea pig pulmonary vein preparations. In tissue preparations, application of angiotensin II induced an automatic contractile activity; this effect was mimicked by angiotensin I and blocked by losartan, but not by PD123,319 or carvedilol. In cardiomyocytes, application of angiotensin II induced an increase in the frequency of spontaneous Ca2+ sparks and the generation of Ca2+ transients; these effects were inhibited by losartan or xestospongin C. In tissue preparations, angiotensin II caused membrane potential oscillations, which lead to repetitive generation of action potentials. Angiotensin II increased the diastolic depolarization slope of the spontaneous or evoked action potentials. These effects of angiotensin II were inhibited by SEA0400. In tissue preparations showing spontaneous firing of action potentials, losartan, xestospongin C or SEA0400 decreased the slope of the diastolic depolarization and inhibited the firing of action potentials. In conclusion, in the guinea pig pulmonary vein myocardium, angiotensin II induces the generation of automatic activity through activation of the IP3 receptor and the Na+-Ca2+ exchanger.

A Traditional Chinese Medicine Drug (TMYX) Controls Heart Rate by Modulation of the Pacemaker (F) Channels

TMYX is a traditional Chinese Medicine drug used to control cardiac rate in arrhythmic patients. The efficacy and safety of this substance is proved by its clinical use, but the molecular mechanism of action is unknown. TMYX (2 mg/ml) reduces spontaneous rate (−21.9±0.8%, n=11) of pacemaker cardiomyocytes due to a selective reduction of the diastolic depolarization slope (−49.3±3.6%, n=11) caused by a leftward shift of the activation curve of If (−7.1±0.6, n=3) and associated current inhibition.

Reduced expression of HCN channels in the sinoatrial node of streptozotocin-induced diabetic rats.

Diabetes mellitus (DM) is associated with an electrical remodeling of the heart, increasing the risk of arrhythmias. However, knowledge of electrical remodeling in the sinoatrial node (SAN) by DM is limited. We investigated the expression of HCN channel isoforms, HCN1-HCN4, in SAN from streptozotocin (STZ)-induced diabetic rats and the age-matched controls. We found that the STZ-induced diabetic rats have a lower intrinsic heart rate, a lengthened sinoatrial conduction time, and rate-corrected maximal sinoatrial node recovery time in vivo as well as a longer cycle length (CL) in vitro, as compared with the control. Optical mapping of the SAN demonstrated an inferior leading pacemaker site, reduced SAN conduction velocity and diastolic depolarization slope, and a longer action potential duration in the STZ-induced diabetic rats than in the control. The transcripts and proteins of HCN2 and HCN4 in diabetic SAN were reduced. Specific blockade of HCN channels by 3 μmol/L ivabradine significantly prolonged the CL of a Langendorff heart by 18% in the diabetic rats and 26% in the control. The reduced expression of HCN channel isoforms in the SAN of the STZ-induced diabetic rat may be an important contributor to the reduced SAN function in DM.

The impacts of age and frailty on heart rate and sinoatrial node function.

Sinoatrial node (SAN) function declines with age; however, not all individuals age at the same rate and health status can vary from fit to frail. Frailty was quantified in young and aged mice using a non-invasive frailty index so that the impacts of age and frailty on heart rate and SAN function could be assessed. SAN function was impaired in aged mice due to alterations in electrical conduction, changes in SAN action potential morphology and fibrosis in the SAN. Changes in SAN function, electrical conduction, action potential morphology and fibrosis were correlated with, and graded by, frailty. This study shows that mice of the same chronological age have quantifiable differences in health status that impact heart rate and SAN function and that these differences in health status can be identified using our frailty index. Sinoatrial node (SAN) dysfunction increases with age, although not all older adults are affected in the same way. This is because people age at different rates and individuals of the same chronological age vary in health status from very fit to very frail. Our objective was to determine the impacts of age and frailty on heart rate (HR) and SAN function using a new model of frailty in ageing mice. Frailty, which was quantified in young and aged mice using a frailty index (FI), was greater in aged vs. young mice. Intracardiac electrophysiology demonstrated that HR was reduced whereas SAN recovery time (SNRT) was prolonged in aged mice; however, both parameters showed heteroscedasticity suggesting differences in health status among mice of similar chronological age. Consistent with this, HR and corrected SNRT were correlated with, and graded by, FI score. Optical mapping of the SAN demonstrated that conduction velocity (CV) was reduced in aged hearts in association with reductions in diastolic depolarization (DD) slope and action potential (AP) duration. In agreement with in vivo results, SAN CV, DD slope and AP durations all correlated with FI score. Finally, SAN dysfunction in aged mice was associated with increased interstitial fibrosis and alterations in expression of matrix metalloproteinases, which also correlated with frailty. These findings demonstrate that age-related SAN dysfunction occurs in association with electrical and structural remodelling and that frailty is a critical determinant of health status of similarly aged animals that correlates with changes in HR and SAN function.

Clinical utility of ivabradine in cardiovascular disease management: current status

Clinical utility of ivabradine in cardiovascular disease management: current status Giuseppe MC Rosano,1,2 Cristiana Vitale,1,2 Ilaria Spoletini,1 Maurizio Volterrani11Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; 2Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK Abstract: Ivabradine is a selective antagonist of the funny channels with anti-anginal and anti-ischemic properties, approved for the treatment of coronary artery disease (CAD) and heart failure (HF). It provides pure heart rate reduction, reducing the diastolic depolarization slope, without altering hemodynamic parameters. This review summarizes the current knowledge on the efficacy of ivabradine in patients with cardiovascular diseases, with a particular focus on its role in the clinical management of patients with CAD and HF. There is consistent evidence that ivabradine is effective in reducing angina pectoris symptoms and myocardial ischemia. At approved doses ivabradine is safe, improves exercise tolerance, and reduces heart rate. Available data from clinical trials support its use in the management of patients with stable CAD and chronic HF. Recent studies have cast doubt on the safety of non-approved high doses of ivabradine for the treatment of patients with CAD and without clinical HF, but have shown no concerns on the doses approved for clinical use. Keywords: ivabradine, coronary artery disease, heart failure, angina pectoris, exercise performance

0222: The TRPM4 channel modulates mammalian sinus rhythm

The transient receptor potential melastatin 4 (TRPM4) channel produces a Ca2+-activated non-selective monovalent cationic current that was detected in several cardiac preparations, including mouse sino atrial node isolated cells. TRPM4 is known to participate in spontaneous electrical activities such as in neurons or in cardiac ventricular preparations submitted to hypoxia/reoxygenation. Here, we evaluated whether it is involved in sinus rhythm. We used mouse, rat and rabbit isolated right atria that exhibited spontaneous beating since they contained the sinus node. Intracellular microelectrodes were used to record the spontaneous action potentials under superfusion of oxygenated physiological solution. In mouse, superfusion of the non-selective cation channel inhibitor flufenamic acid significantly reduced spontaneous beating rate to 89±2% (n=8) and 38±9% (n=4) of control for 10-5 and 10-4 mol.L-1 respectively. Moreover, superfusion of the TRPM4 specific inhibitor 9-phenanthrol produced a concentration-dependant reduction in AP rate (maximal reduction = 62±3% that of control; EC50=8x10-6 mol.L-1 for 9-phenanthrol; n=13) in wild type mice, but not in Trpm4-/- mice. Interestingly, the effect of 9-phenanthrol was higher when then initial beating rate was low. Similar results were obtained in rat and rabbit. Recording the activity of specific sinoatrial node cells in rabbit revealed that 10-5 mol.L-1 9-phenanthrol reduced diastolic depolarization slope by 22±4% (n=4). It is know that the diastolic depolarization slope is due to the funny current If, the Na/Ca exchanger, the T-type Ca2+ current, and modestly, a Ca2+-activated non-selective cationic current. TRPM4 most likely participates in this last current, exerting an effect against bradycardia.

Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm

The transient receptor potential melastatin 4 (TRPM4) channel is expressed in the sinoatrial node, but its physiologic roles in this tissue with cardiac pacemaker properties remain unknown. This Ca(2+)-activated nonselective cation channel (NSCCa) induces cell depolarization at negative potentials. It is implicated in burst generation in neurons and participates in induction of ectopic beating in cardiac ventricular preparations submitted to hypoxia/reoxygenation. Accordingly, TRPM4 may participate in action potential (AP) triggering in the sinoatrial node. The purpose of this study was to investigate the influence of TRPM4 on spontaneous heart beating. Spontaneous APs were recorded using intracellular microelectrodes in mouse, rat, and rabbit isolated right atria. In the spontaneously beating mouse atrium, superfusion of the TRPM4-specific inhibitor 9-phenanthrol produced a concentration-dependent reduction in AP rate (maximal reduction = 62% that of control; EC50 = 8 × 10(-6) mol●L(-1)) without affecting other AP parameters. These effects were absent in TRPM4(-/-) mice. 9-Phenanthrol exerted a rate-dependent reduction with a higher effect at low rates. Similar results were obtained in rat. Moreover, application of 9-phenanthrol produced a reduction in diastolic depolarization slope in rabbit sinus node pacemaker cells. These data showed that TRPM4 modulates beating rate. Pacemaker activity in the sinoatrial node results from the slow diastolic depolarization slope due to the "funny" current, Na/Ca exchange, and a Ca(2+)-activated nonselective cation current, which can be attributable in part to TRPM4 that may act against bradycardia.

Hyperpolarization‐Activated Cyclic Nucleotide‐Gated Channels and Ventricular Arrhythmias in Heart Failure: A Novel Target for Therapy?

Arrhythmias are a common and often fatal complication of heart failure accounting for 50% to 70% of cardiac deaths due to tachyarrhythmic mechanisms.[1][1] In the failing heart, disturbances in cardiac rhythm are the likely result of cardiac remodeling consisting of structural and/or

Ivabradine: an intelligent drug for the treatment of ischemic heart disease.

Heart rate (HR) is a precisely regulated variable, which plays a critical role in health and disease. Elevated resting HR is a significant predictor of all-cause and cardiovascular mortality in the general population and patients with cardiovascular disease (CVD). β-blocking drugs exert negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing; calcium channel antagonists (CCAs) functionally antagonize coronary vasoconstriction mediated through α-adreno-receptors and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotropes. From these observations derives the necessity to find alternative, more selective drugs to reduce HR through inhibition of specific electrical current (If). Ivabradine (IVA) is a novel specific HR-lowering agent that acts in sinus atrial node (SAN) cells by selectively inhibiting the pacemaker If current in a dose-dependent manner by slowing the diastolic depolarization slope of SAN cells, and by reducing HR at rest during exercise in humans. Coronary artery diseases (CAD) represent the most common cause of death in middle–aged and older adults in European Countries. Most ischemic episodes are triggered by an increase in HR, that induces an imbalance between myocardial oxygen delivery and consumption. IVA, a selective and specific inhibitor of the If current which reduced HR without adverse hemodynamic effects, has clearly and unequivocally demonstrated its efficacy in the treatment of chronic stable angina pectoris (CSAP) and myocardial ischemia with optimal tolerability profile due to selective interaction with If channels. The aim of this review is to point out the usefulness of IVA in the treatment of ischemic heart disease.

Ivabradine: potential clinical applications in critically ill patients

It has been extensively demonstrated that an elevated heart rate is a modifiable, independent risk factor for cardiovascular events. A high heart rate increases myocardial oxygen consumption and reduces diastolic perfusion time. It can also increase ventricular diastolic pressures and induce ventricular arrhythmias. Critical care patients are prone to develop a stress induced cardiac impairment and consequently an increase in sympathetic tone. This in turn increases heart rate. In this setting, however, heart rate lowering might be difficult because the effects of inotropic drugs could be hindered by heart rate reducing drugs like beta-blockers. Ivabradine is a new selective antagonist of funny channels. It lowers heart rate, reducing the diastolic depolarization slope. Moreover, ivabradine is not active on sympathetic pathways, thus avoiding any interference with inotropic amines. We reviewed the literature available regarding heart rate control in critical care patients, focusing our interest on the use of ivabradine to assess the potential benefits of the drug in this particular setting.

An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation

The cellular basis of cardiac pacemaking is still debated. Reliable computational models of the sinoatrial node (SAN) action potential (AP) may help gain a deeper understanding of the phenomenon. Recently, novel models incorporating detailed Ca(2+)-handling dynamics have been proposed, but they fail to reproduce a number of experimental data, and more specifically effects of 'funny' (I(f)) current modifications. We therefore developed a SAN AP model, based on available experimental data, in an attempt to reproduce physiological and pharmacological heart rate modulation. Cell compartmentalization and intracellular Ca(2+)-handling mechanisms were formulated as in the Maltsev-Lakatta model, focusing on Ca(2+)-cycling processes. Membrane current equations were revised on the basis of published experimental data. Modifications of the formulation of currents/pumps/exchangers to simulate I(f) blockers, autonomic modulators and Ca(2+)-dependent mechanisms (ivabradine, caesium, acetylcholine, isoprenaline, BAPTA) were derived from experimental data. The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges: 352 ms cycle length, 80 mV AP amplitude, -58 mV maximum diastolic potential (MDP), 108 ms APD(50), and 7.1 Vs(-1) maximum upstroke velocity. Rate modulation by I(f) -blocking drugs agrees with experimental findings: 20% and 22% caesium-induced (5mM) and ivabradine-induced (3 μM) rate reductions, respectively, due to changes in diastolic depolarization (DD) slope, with no changes in either MDP or take-off potential (TOP). The model consistently reproduces the effects of autonomic modulation: 20% rate decrease with 10 nM acetylcholine and 28%increase with 1 μM isoprenaline, again entirely due to increase in the DD slope,with no changes in either MDP or TOP. Model testing of BAPTA effects showed slowing of rate, -26%, without cessation of beating. Our up-to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca(2+)-related system by BAPTA, making it a useful tool for further investigation. Simulation results suggest that a detailed description of the intracellular Ca(2+) fluxes is fully compatible with the observation that I(f) is a major component of pacemaking and rate modulation.

Blocking effects of acehytisine on pacemaker currents (If) in sinoatrial node cells and human HCN4 channels expressed in Xenopus laevis oocytes

Ethnopharmacological relevanceThe root of Aconitum coreanum (Levl.) Raipaics has been extensively used to treat various kinds of disorders including cardiovascular disease in China for a long time. According to recent studies, its antiarrhythmic actions are attributable to the active component, acehytisine. However, the underlying mechanism remains poorly understood. Aim of the studyThe effects of acehytisine on the spontaneous activity in sinoatrial nodes and the electropharmacological action of this drug on If in pacemaker cells and hHCN4 channels in oocytes were to be investigated. Materials and methodsSinoatrial nodes were cut from rabbit heart, and transmembrane potentials were recorded by standard microelectrode technique. A whole-cell patch clamp technique was employed to record If isolated enzymatically from rabbit sinoatrial node pacemaker cells. Human HCN4 channels were heterologously expressed in Xenopus oocytes and studied using the two-electrode voltage clamp technique. ResultsAcehytisine decreased the pacemaker rate of firing and slope of diastolic depolarization, modified the action potential configurations and blocked If in rabbit sinoatrial node cells and hHCN4 channels expressed in Xenopus oocytes in a concentration-dependent, voltage-independent and non-use-dependent manner. Its electropharmacological properties were consistent with those of a close-state blocker. ConclusionOur findings are likely to shed light on the clinical application of acehytisine in the treatment of cardiovascular disorders.

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. &szlig;-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

Angiotensin II decreases spontaneous firing rate of guinea-pig sino-atrial node cells

Angiotensin II (Ang II) plays an important role in the regulation of cardiac function, but its electrophysiological effects on sino-atrial (SA) node are not well understood. In this study, the immediate effect of Ang II on action potentials and ionic currents were investigated by using whole-cell patch-clamps in single guinea-pig SA node pacemaker cells. We demonstrated that Ang II exerted a negative effect on spontaneous firing rate, with a concomitant reduction in the slope of diastolic depolarization. The inhibitory effect of Ang II on spontaneous activity displayed a concentration-dependent manner in the range of 1–1000nM, with IC50 of 8.34nM. Ang II type 1 (AT1) receptor antagonist valsartan (1μM) abolished the inhibitory effect. In contrast, Ang II type 2 (AT2) receptor antagonist, PD123319 (1μM) didn't affect the action of Ang II. Ang II had no significant effect on hyperpolarization-activated current (If) in SA node cells. However, it significantly slowed the deactivation of the slowly activated delayed rectifier K+ current (Iks) and increased the tail current density. Furthermore, Ang II decreased the current density of L-type Ca2+ current in SA node cells. Our data demonstrate that Ang II reduces the auto rhythm of SA node cells via enhancing Iks and reducing ICaL. The result suggests a potential mechanism by which elevated levels of Ang II may be involved in the occurrence of SA node dysfunction in cardiac pathophysiology.