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Special Issue "Ivabradine"

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 May 2012)

Special Issue Editor

Guest Editor
Dr. Graziano Riccioni (Website)

Studio Medico Polispecialistico, Via Magenta 106, San Severo, 71016 Foggia, Italy
Fax: +39 882227022
Interests: atherosclerosis; statins; ivabradine; ischemic cardiac disease; antioxidants; endothelial dyfunction and metabolities; carotenoids

Special Issue Information

Dear Colleagues,

Ivabradine (IVA) is a novel specific heart rate (HR) lowering agent that acts in sinoatrial 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 reducing HR at rest and during exercise with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction.

The cardiac pacemaker cells, the first cells which generate the electrical impulse and form SAN, have the specific  feature of spontaneous electrical activity generating repetitive action potentials at a specific controlled rate.

Among the different currents at the basis of the mechanisms contributing to electrical stimulus, the If current has a major role in providing pacemaking competence. Originally this current was described in the SAN the funny current and its properties in cardiac pacemaker cells have been the object of intense investigations. Funny channels underlie the cardiac pacemaker If current, originally described as an inward current activated on hyperpolarization to the diastolic range of voltages in SAN myocytes.

SAN cells can depolarize spontaneously. This depolarization is due to the movement of ions (sodium and potassium) across specialized membrane channels, which directly modulates the rate of spontaneous diastolic depolarization. The If current is important in the generation of pacemaking not only for diastolic–depolarization but also for its involvement in neurotransmitter–induced control of cardiac rate. It was shown since its first description that If mediates the acceleratory effect of adrenaline on pacemaker rate and a later study showed its strongly modulation by acetylcholine but with opposite action regard that of catecholamines.

The molecular basis of the If current and its related equivalent in non–cardiac cells If have been characterized by cloning a family of ionic channels, known as hyperpolarization–activated cyclic nucleotide–gated channels (HCN). Four isoforms of HCN have been identified, HCN1–4 which show typical characteristics of pacemaker currents, activation on hyperpolarization, current carried by sodium and potassium ions, modulation by cyclic adenosine monophosphate and sensitivity to caesium.

Detailed patch–clamp studies in rabbit SAN cells have shown that the drug blocks If channels  and that it interacts with the channels from the intracellular side.33 More recently, also in SAN cells, IVA has been shown to be an open channel blocker, indicating that it cannot reach its binding site when the channels are closed, and its blocking effect is current–dependent and is attenuated during very long hyperpolarized pulses (more than 20 seconds of hyperpolarization).

The possibility to modulate the If current offers new therapeutic options for the control of cardiac chronotropism. The development of molecules that interact specifically with funny channels is the basis of new pharmacological approaches to the management of HR. The aim of this special issue is to examinate the most important aspects will regard the synthesis, biological activities and pharmacokinetic-pharmacodynamic aspects.

Dr. Graziano Riccioni
Guest Editor

Keywords

  • ivabradine
  • medicinal chemistry
  • If current
  • sino-atrial node
  • synthesis
  • HCN channels
  • heart rate
  • funny current

Related Special Issue

Published Papers (4 papers)

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Research

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Open AccessArticle The “Funny” Current (If) Inhibition by Ivabradine at Membrane Potentials Encompassing Spontaneous Depolarization in Pacemaker Cells
Molecules 2012, 17(7), 8241-8254; doi:10.3390/molecules17078241
Received: 21 May 2012 / Revised: 3 July 2012 / Accepted: 4 July 2012 / Published: 9 July 2012
Cited by 8 | PDF Full-text (927 KB)
Abstract
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 I [...] Read more.
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. Full article
(This article belongs to the Special Issue Ivabradine)

Review

Jump to: Research

Open AccessReview Ivabradine: An Intelligent Drug for the Treatment of Ischemic Heart Disease
Molecules 2012, 17(11), 13592-13604; doi:10.3390/molecules171113592
Received: 10 October 2012 / Revised: 30 October 2012 / Accepted: 30 October 2012 / Published: 16 November 2012
Cited by 10 | PDF Full-text (189 KB)
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Ivabradine)
Open AccessReview The Biological Effects of Ivabradine in Cardiovascular Disease
Molecules 2012, 17(5), 4924-4935; doi:10.3390/molecules17054924
Received: 17 January 2012 / Revised: 27 March 2012 / Accepted: 16 April 2012 / Published: 30 April 2012
Cited by 10 | PDF Full-text (178 KB)
Abstract
A large number of studies in healthy and asymptomatic subjects, as well as patients with already established cardiovascular disease (CAD) have demonstrated that heart rate (HR) is a very important and major independent cardiovascular risk factor for prognosis. Lowering heart rate reduces [...] Read more.
A large number of studies in healthy and asymptomatic subjects, as well as patients with already established cardiovascular disease (CAD) have demonstrated that heart rate (HR) is a very important and major independent cardiovascular risk factor for prognosis. Lowering heart rate reduces cardiac work, thereby diminishing myocardial oxygen demand. Several experimental studies in animals, including dogs and pigs, have clarified the beneficial effects of ivabradine associated with HR lowering. Ivabradine is a selective inhibitor of the hyperpolarisation activated cyclic-nucleotide-gated funny current (If) involved in pacemaker generation and responsiveness of the sino-atrial node (SAN), which result in HR reduction with no other apparent direct cardiovascular effects. Several studies show that ivabradine substantially and significantly reduces major risks associated with heart failure when added to guideline-based and evidence-based treatment. However the biological effect of ivabradine have yet to be studied. This effects can appear directly on myocardium or on a systemic level improving endothelial function and modulating immune cell migration. Indeed ivabradine is an ‘open-channel’ blocker of human hyperpolarization-activated cyclic nucleotide gated channels of type-4 (hHCN4), and a ‘closed-channel’ blocker of mouse HCN1 channels in a dose-dependent manner. At endothelial level ivabradine decreased monocyte chemotactin protein-1 mRNA expression and exerted a potent anti-oxidative effect through reduction of vascular NADPH oxidase activity. Finally, on an immune level, ivabradine inhibits the chemokine-induced migration of CD4-positive lymphocytes. In this review, we discuss the biological effects of ivabradine and highlight its effects on CAD. Full article
(This article belongs to the Special Issue Ivabradine)
Open AccessReview HCN Channels and Heart Rate
Molecules 2012, 17(4), 4225-4235; doi:10.3390/molecules17044225
Received: 1 November 2011 / Revised: 21 March 2012 / Accepted: 30 March 2012 / Published: 5 April 2012
Cited by 8 | PDF Full-text (188 KB) | HTML Full-text | XML Full-text
Abstract
Hyperpolarization and Cyclic Nucleotide (HCN) -gated channels represent the molecular correlates of the “funny” pacemaker current (If), a current activated by hyperpolarization and considered able to influence the sinus node function in generating cardiac impulses. HCN channels are a family [...] Read more.
Hyperpolarization and Cyclic Nucleotide (HCN) -gated channels represent the molecular correlates of the “funny” pacemaker current (If), a current activated by hyperpolarization and considered able to influence the sinus node function in generating cardiac impulses. HCN channels are a family of six transmembrane domain, single pore-loop, hyperpolarization activated, non-selective cation channels. This channel family comprises four members: HCN1-4, but there is a general agreement to consider HCN4 as the main isoform able to control heart rate. This review aims to summarize advanced insights into the structure, function and cellular regulation of HCN channels in order to better understand the role of such channels in regulating heart rate and heart function in normal and pathological conditions. Therefore, we evaluated the possible therapeutic application of the selective HCN channels blockers in heart rate control. Full article
(This article belongs to the Special Issue Ivabradine)
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