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Special Issue "Ivabradine"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

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

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Published Papers (1 paper)

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Research

Open AccessArticle Ivabradine Prevents Heart Rate Acceleration in Patients with Chronic Obstructive Pulmonary Disease and Coronary Heart Disease after Salbutamol Inhalation
Pharmaceuticals 2012, 5(4), 398-404; doi:10.3390/ph5040398
Received: 8 February 2012 / Revised: 25 March 2012 / Accepted: 5 April 2012 / Published: 16 April 2012
PDF Full-text (353 KB) | HTML Full-text | XML Full-text
Abstract
Accelerated sinus rhythm is an important side effect of inhaled salbutamol which is especially harmful in patients with chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD). Cross-over, randomized, open label study design. 20 patients (18 males and two females) with COPD stage II–IV and comorbide CHD NYHA class I–III were included. Spirometry with 400 mg salbutamol inhalation was performed at two consecutive days of the study. Patients in group I were prescribed 5 mg ivabradine per os 3 h before salbutamol inhalation solely on the first day of the study and patients of group II received 5 mg ivabradine only on the second day of the study. Salbutamol caused a significant increase of HR by 5.5 bpm (95% CI 0.8; 10.2, p < 0.03). After ivabradine ingestion salbutamol did not change HR significantly by −2.4 bpm (−7.0; 2.3, p = 0.33). The attenuation of HR elevation by ivabradine was significant, p < 0.01. Salbutamol alone increased FEV1 by 6.0% (2.7; 9.3, p < 0.01). This effect was not impaired by ivabradine (FEV1 increase by 7.7% (2.8; 12.6, p < 0.01 versus baseline, p = 0.5 versus no ivabradine). Ivabradine 5 mg per os prevents heart rate acceleration after inhalation of 400 mg salbutamol. Ivabradine has no impact on lung function in patients with moderate-to-very-severe COPD and CHD comorbidity. Full article
(This article belongs to the Special Issue Ivabradine)

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