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funny current

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
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...
September 22, 2016: Therapeutic Advances in Cardiovascular Disease
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
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
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
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
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
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
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
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
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
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
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
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
Seong Woo Choi, Hyang-Ae Lee, Sung-Hwan Moon, Soon-Jung Park, Hae Jin Kim, Ki-Suk Kim, Yin Hua Zhang, Jae Boum Youm, Sung Joon Kim
Na(+)/Ca(2+) exchanger current (INCX) triggered by spontaneous Ca(2+) release from sarcoplasmic reticulum (SR) has been suggested as one of the cardiac pacemaker mechanisms ("Ca(2+) clock model"). In human embryonic stem cell-derived cardiomyocytes (hESC-CMs) showing spontaneous action potentials (APs), we found that substantial population (35 %) showed regular oscillation of inward currents (SICs) in nystatin-perforated voltage clamp between -40 and 40 mV (-80 ± 10.6 pA, at -20 mV). SICs were similarly observed between nodal, atrial, and ventricular hESC-CMs...
April 2016: Pflügers Archiv: European Journal of Physiology
Darren W Campbell, Marc G Wallace, Mandana Modirrousta, Joseph O Polimeni, Nancy A McKeen, Jeffrey P Reiss
Psychological well-being and social acumen benefit from the recognition of humourous intent and its enjoyment. The enjoyment of humour requires recognition, but humour recognition is not necessarily accompanied by humour enjoyment. Humour recognition is crucial during social interactions, while the associated enjoyment is less critical. Few neuroimaging studies have explicitly differentiated between the neural foundations of humour comprehension and humour appreciation. Among such studies, design limitations have obscured the specification of neural correlates to humour comprehension or appreciation...
December 2015: Neuropsychologia
Yukihiro Saito, Kazufumi Nakamura, Masashi Yoshida, Hiroki Sugiyama, Tohru Ohe, Junko Kurokawa, Tetsushi Furukawa, Makoto Takano, Satoshi Nagase, Hiroshi Morita, Kengo F Kusano, Hiroshi Ito
BACKGROUND: Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including the problems of battery life and electromagnetic interference. Enhancement of the funny current (If) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K+ current (IK1) flowing through inward rectifier potassium (Kir) channels are essential for generation of a biological pacemaker. Therefore, we generated HCN4-overexpressing mouse embryonic stem cells (mESCs) and induced cardiomyocytes that originally show poor IK1 currents, and we investigated whether the HCN4-overexpressing mESC-derived cardiomyocytes (mESC-CMs) function as a biological pacemaker in vitro...
2015: PloS One
Beatriz Merino, Ivan Quesada, Jesús Hernández-Cascales
This study evaluated the chronotropic and inotropic responses to glucagon in spontaneously beating isolated right atria of rat heart. For comparison, we also investigated the effects resulting from stimulating β-adrenoceptors with isoproterenol in this tissue. Isoproterenol increased both atrial frequency and contractility but glucagon only enhanced atrial rate. The transcript levels of glucagon receptors were about three times higher in sinoatrial node than in the atrial myocardium. Chronotropic responses to glucagon and isoproterenol were blunted by the funny current (If) inhibitor ZD 7288...
2015: PloS One
Angelo G Torrente, Rui Zhang, Audrey Zaini, Jorge F Giani, Jeanney Kang, Scott T Lamp, Kenneth D Philipson, Joshua I Goldhaber
In sinoatrial node (SAN) cells, electrogenic sodium-calcium exchange (NCX) is the dominant calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent...
August 4, 2015: Proceedings of the National Academy of Sciences of the United States of America
Rebecca A Capel, Neil Herring, Manish Kalla, Arash Yavari, Gary R Mirams, Gillian Douglas, Gil Bub, Keith Channon, David J Paterson, Derek A Terrar, Rebecca-Ann B Burton
BACKGROUND: Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. OBJECTIVES: The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia. METHODS: We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the "funny" current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography)...
October 2015: Heart Rhythm: the Official Journal of the Heart Rhythm Society
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