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https://www.readbyqxmd.com/read/28217366/crizotinib-inhibits-hyperpolarization-activated-cyclic-nucleotide-gated-channel-4-activity
#1
Zhushan Zhang, Tai-Qin Huang, Igor Nepliouev, Hengtao Zhang, Adam S Barnett, Paul B Rosenberg, Sai-Hong I Ou, Jonathan A Stiber
BACKGROUND: Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects. METHODS: The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4...
2017: Cardiooncology
https://www.readbyqxmd.com/read/28185290/computational-analysis-of-the-human-sinus-node-action-potential-model-development-and-effects-of-mutations
#2
Alan Fabbri, Matteo Fantini, Ronald Wilders, Stefano Severi
The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart.  Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. Our aim was to construct a more comprehensive model of the electrical activity of a human SAN pacemaker cell, using recently obtained electrophysiological data from human SAN pacemaker cells...
February 9, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28057842/cyclic-amp-reverses-the-effects-of-aging-on-pacemaker-activity-and-if-in-sinoatrial-node-myocytes
#3
Emily J Sharpe, Eric D Larson, Catherine Proenza
Aerobic capacity decreases with age, in part because of an age-dependent decline in maximum heart rate (mHR) and a reduction in the intrinsic pacemaker activity of the sinoatrial node of the heart. Isolated sinoatrial node myocytes (SAMs) from aged mice have slower spontaneous action potential (AP) firing rates and a hyperpolarizing shift in the voltage dependence of activation of the "funny current," If Cyclic AMP (cAMP) is a critical modulator of both AP firing rate and If in SAMs. Here, we test the ability of endogenous and exogenous cAMP to overcome age-dependent changes in acutely isolated murine SAMs...
February 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/27895488/advances-in-the-management-of-heart-failure-the-role-of-ivabradine
#4
REVIEW
Ursula Müller-Werdan, Georg Stöckl, Karl Werdan
A high resting heart rate (≥70-75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect...
2016: Vascular Health and Risk Management
https://www.readbyqxmd.com/read/27803673/electrophysiological-mechanisms-of-brugada-syndrome-insights-from-pre-clinical-and-clinical-studies
#5
REVIEW
Gary Tse, Tong Liu, Ka H C Li, Victoria Laxton, Yin W F Chan, Wendy Keung, Ronald A Li, Bryan P Yan
Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na(+) channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na(+), K(+), Ca(2+), and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27784216/ivabradine-a-current-overview
#6
Kaushik Guha, Christopher J Allen, Adam Hartley, Rakesh Sharma
Ivabradine, acting on the funny channel in the sino-atrial node, is a promising drug in the treatment of ischaemic heart disease and heart failure. There has been much clinical research conducted exploring its role in these fields. This review discusses the drug development and trial data, and highlights future directions for research.
October 25, 2016: Current Clinical Pharmacology
https://www.readbyqxmd.com/read/27752846/ivabradine
#7
Michel Komajda
Ivabradine is a blocker of the funny current channels in the sinoatrial node cells. This results in pure heart rate reduction when elevated without direct effect on contractility or on the vessels. It was tested in a large outcome clinical trial in stable chronic heart failure (CHF) with low ejection fraction, in sinus rhythm, on a contemporary background therapy including betablockers (SHIFT: Systolic Heart Failure Treatment with the If inhibitor Trial).The primary composite endpoint (cardiovascular mortality or heart failure hospitalization) was reduced by 18% whereas the first occurrence of heart failure hospitalizations was reduced by 26%...
October 18, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27659287/emerging-role-of-ivabradine-for-rate-control-in-atrial-fibrillation
#8
REVIEW
Sarah L Turley, Kerry E Francis, Denise K Lowe, William D Cahoon
Control of ventricular rate is recommended for patients with paroxysmal, persistent, or permanent atrial fibrillation (AF). Existing rate-control options, including beta-blockers, nondihydropyridine calcium channel blockers, and digoxin, are limited by adverse hemodynamic effects and their ability to attain target heart rate (HR). Ivabradine, a novel HR-controlling agent, decreases HR through deceleration of conduction through If ('funny') channels, and is approved for HR reduction in heart failure patients with ejection fraction less than 35% and elevated HR, despite optimal pharmacological treatment...
December 2016: Therapeutic Advances in Cardiovascular Disease
https://www.readbyqxmd.com/read/27555825/-the-bitter-laughter-when-parody-is-a-moral-and-affective-priming-in-political-persuasion
#9
Francesca D'Errico, Isabella Poggi
Research on socially aware systems requires fine-grained knowledge of the mechanisms of persuasion in order to promote civic knowledge and aware political participation. Within humor studies, political parody is generally considered a simple pleasant weapon for political evaluation, currently explained by referring to the so called "just a joke effect" (Nabi et al., 2007). Indeed the funny side of parody can induce positive emotions, but it also includes a discrediting act that sometimes produces a "bitter laughter...
2016: Frontiers in Psychology
https://www.readbyqxmd.com/read/27547256/strategically-funny-romantic-motives-affect-humor-style-in-relationship-initiation
#10
Theresa E DiDonato, Brittany K Jakubiak
Not all humor is the same, yet little is known about the appeal of specific humor styles in romantic initiation. The current experimental study addresses this gap by investigating how romantic motives (short-term or long-term) affect individuals' anticipated use of, and response to, positive humor and negative humor. Heterosexual participants (n = 224) imagined the pursuit of either a desired short-term or long-term relationship, indicated the extent to which they would produce positive and negative humor, and reported how their own interest would change in response to the imaginary target's use of positive or negative humor...
August 2016: Europe's journal of psychology
https://www.readbyqxmd.com/read/27295092/prenatal-nicotine-exposure-results-in-the-inhibition-of-baroreflex-sensitivity-induced-by-intravenous-injection-angiotensin-ii-in-the-adult-male-offspring-rats
#11
Feng Yu, Yuexia Li, Jian Yang, Jin Qian, Xining Li, Chongbin Liu
Epidemiological studies show that maternal cigarette smoking is associated with an increased risk of cardiovascular diseases in postnatal life. Baroreflex sensitivity (BRS) is an important index for evaluating the homeostasis of the cardiovascular system. This experiment was designed to investigate the possible mechanism of prenatal nicotine on the adult male offspring's heart rate (HR) increase due to BRS. Pregnant rats received the 0.3 ml of saline or nicotine (1.5 mg kg(-1)) by subcutaneous injection from gestational days 3 to 21...
June 13, 2016: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/27136298/-jimmy-cap-before-you-tap-developing-condom-use-messages-for-african-american-women
#12
Kristina B Hood, Natalie J Shook, Faye Z Belgrave
This study examined which characteristics of persuasive communications are most effective in changing African American women's condom use attitudes. Focus groups were convened with 40 African American women (Mage = 25.54, SD = 4.67) to assess their opinions on current effective strategies used to promote condom use among their peers. Participants discussed effective characteristics of messaging campaigns (i.e., source, message type, channel) and how these could be used in future prevention messages. Findings revealed that making messages that are fun, catchy, and informative, delivered frequently through social media, TV, or radio by a peer or celebrity would be perceived as most effective in changing young African American women's attitudes...
May 2, 2016: Journal of Sex Research
https://www.readbyqxmd.com/read/27073443/electric-pulse-current-stimulation-increases-electrophysiological-properties-of-if-current-reconstructed-in-mhcn4-transfected-canine-mesenchymal-stem-cells
#13
Yuanyuan Feng, Shouming Luo, Pan Yang, Zhiyuan Song
The 'funny' current, also known as the If current, play a crucial role in the spontaneous diastolic depolarization of sinoatrial node cells. The If current is primarily induced by the protein encoded by the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) gene. The functional If channel can be reconstructed in canine mesenchymal stem cells (cMSCs) transfected with mouse HCN4 (mHCN4). Biomimetic studies have shown that electric pulse current stimulation (EPCS) can promote cardiogenesis in cMSCs...
April 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27059112/inappropriate-sinus-tachycardia-focus-on-ivabradine
#14
REVIEW
H S Abed, J R Fulcher, M J Kilborn, A C Keech
Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta-blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node If 'funny current' inhibitor, which reduces the HR...
August 2016: Internal Medicine Journal
https://www.readbyqxmd.com/read/26910057/role-of-the-funny-current-inhibitor-ivabradine-in-cardiac-pharmacotherapy-a-systematic-review
#15
Sarah E Petite, Bryan M Bishop, Vincent F Mauro
The pharmacology, pharmacokinetics, efficacy and safety of ivabradine are reviewed. Ivabradine is an oral medication that directly and selectively inhibits the hyperpolarization-activated cyclic-nucleotide gated funny (If) current in the sinoatrial node resulting in heart rate reduction. It has a plasma elimination half-life of 6 hours and is administered twice daily. Ivabradine is extensively metabolized by cytochrome P450 3A4, and its metabolism is affected by inducers and inhibitors of the 3A4 enzyme. Studies in patients with heart failure indicate that ivabradine improves surrogate markers such as exercise tolerance...
February 23, 2016: American Journal of Therapeutics
https://www.readbyqxmd.com/read/26900737/pathological-joking-or-witzelsucht-revisited
#16
Elias D Granadillo, Mario F Mendez
Humor, or the perception or elicitation of mirth and funniness, is distinguishable from laughter and can be differentially disturbed by neuropsychiatric disease. The authors describe two patients with constant joking, or Witzelsucht, in the absence of pseudobulbar affect and review the literature on pathological humor. These patients had involvement of frontal structures, impaired appreciation of nonsimple humor, and a compulsion for disinhibited joking. Current neuroscience suggests that impaired humor integration from right lateral frontal injury and disinhibition from orbitofrontal damage results in disinhibited humor, preferentially activating limbic and subcortical reward centers...
2016: Journal of Neuropsychiatry and Clinical Neurosciences
https://www.readbyqxmd.com/read/26835093/hcn4-sinus-bradycardia-and-atrial-fibrillation
#17
Dario DiFrancesco
Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/ hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit...
May 2015: Arrhythmia & Electrophysiology Review
https://www.readbyqxmd.com/read/26797824/ivabradine-in-management-of-heart-failure-a-critical-appraisal
#18
Gabriela Orasanu, Sadeer G Al-Kindi, Guilherme H Oliveira
Elevated resting heart rate has been linked to poor outcomes in patients with chronic systolic heart failure. Blockade of funny current channel with ivabradine reduces heart rate without inotropic effects. Ivabradine was recently approved by US Food and Drug Administration for patients with stable, symptomatic chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35 %, who are in sinus rhythm with resting heart rate (HR) ≥ 70 bpm and either are on maximally tolerated doses of beta-blockers, or have a contraindication to beta-blockers...
February 2016: Current Heart Failure Reports
https://www.readbyqxmd.com/read/26781742/current-understanding-of-the-pathophysiological-mechanisms-responsible-for-inappropriate-sinus-tachycardia-role-of-the-if-funny-current
#19
Mirko Baruscotti, Elisabetta Bianco, Annalisa Bucchi, Dario DiFrancesco
BACKGROUND: Together with the afferent branches of the autonomic nervous system, the sinoatrial node (SAN) forms a functional unit whose function is to fire rhythmic action potentials at a rate optimal for coping with the metabolic needs of the body. Dysfunctional behavior of this complex unit may thus result in SAN rhythm disorders. Among these disorders, there is the inappropriate sinus tachycardia (IST) which occurs when an unjustified fast SAN rate is present. METHODS: We here present a critical review of the role of pacemaker f/HCN channels in cardiac rhythm generation and modulation and their involvement in IST...
June 2016: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
https://www.readbyqxmd.com/read/26721645/ivabradine-heart-failure-and-beyond
#20
Rahul Chaudhary, Jalaj Garg, Parasuram Krishnamoorthy, Neeraj Shah, Gregg Lanier, Mathew W Martinez, Ronald Freudenberger
Heart failure affects over 5 million people in the United States and carries a high rate of mortality. Ivabradine, a new agent has been added to the current medical options for managing heart failure. It is a selective funny current (If) inhibitor in sinoatrial node and slows its firing rate, prolonging diastolic depolarization without a negative inotropic effect. Ivabradine was only recently approved by Food and Drug administration after the results of Systolic Heart Failure Treatment with the If Inhibitor Ivabradine (SHIFT) trial, for a reduction in rehospitalizations from chronic heart failure...
July 2016: Journal of Cardiovascular Pharmacology and Therapeutics
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