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Cardiac pacemaker/(f) current and its inhibition by heart rate-reducing agents
No full textThe 'funny' (If) current, first described by Brown et al. in 1979 in pacemaker myocytes, is an inward current that slowly activates on hyperpolarization to the diastolic range of voltages. Extensive work has amply demonstrated its involvement in the generation of spontaneous activity. The extent of current activation determines the slope of diastolic depolarization and hence of pacemaker rate. Since If is under cyclic adenosine monophosphate (cAMP)-mediated control by β-adrenergic and muscarinic stimulation, this mechanism underlies neurotransmitter modulation of cardiac rate and is therefore of fundamental physiological relevance. Their key role in pacemaking makes f-channels a natural target for drugs aiming at regulation of pacemaker activity and cardiac rate. Both in the past and more recently, rate-reducing drugs that slow pacemaker activity by decreasing the rate of diastolic depolarization have been developed. These drugs act as specific f-channel inhibitors. One of the latest such molecules developed, ivabradine, has a highly specific inhibitory action on f-channels, which atypically depends on the current flow across the channel. These specific properties make the If inhibition by ivabradine 'use-dependent,' a therapeutically beneficial property. Investigation of the interaction between rate-reducing molecules and specific regions of hyperpolarization-activated, cyclic nucleotidegated (HCN) channels, the molecular components of native f-channels, will provide new strategies for more specific and efficient drug design. This short review addresses the major basic properties of cardiac f-channels, with a focus on the mode of action of f-channel inhibitors and on its possible molecular interpretation
The role of the funny current in pacemaker activity
No full textPacemaking is a basic physiological process, and the cellular mechanisms involved in this function have always attracted the keen attention of investigators. The "funny" (I(f)) current, originally described in sinoatrial node myocytes as an inward current activated on hyperpolarization to the diastolic range of voltages, has properties suitable for generating repetitive activity and for modulating spontaneous rate. The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing. Because I(f) is controlled by intracellular cAMP and is thus activated and inhibited by beta-adrenergic and muscarinic M2 receptor stimulation, respectively, it represents a basic physiological mechanism mediating autonomic regulation of heart rate. Given the complexity of the cellular processes involved in rhythmic activity, an exact quantification of the extent to which I(f) and other mechanisms contribute to pacemaking is still a debated issue; nonetheless, a wealth of information collected since the current was first described more than 30 years ago clearly agrees to identify I(f) as a major player in both generation of spontaneous activity and rate control. I(f)- dependent pacemaking has recently advanced from a basic, physiologically relevant concept, as originally described, to a practical concept that has several potentially useful clinical applications and can be valuable in therapeutically relevant conditions. Typically, given their exclusive role in pacemaking, f-channels are ideal targets of drugs aiming to pharmacological control of cardiac rate. Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects. Indeed a selective f-channel inhibitor, ivabradine, is today commercially available as a tool in the treatment of stable chronic angina. Also, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known today to cause rhythm disturbances, such as for example inherited sinus bradycardia. Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biological pacemakers eventually able to replace electronic devices
Letter regarding article by G. Michels et al., "Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and I-f to cardiac arrhythmias"
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Serious workings of the funny current
No full textSince its first description in 1979 (Brown et al., 1979. Nature 280, 235-236), extensive work on the If current has amply demonstrated its role in the generation and neurotransmitter-induced modulation of pacemaker activity in heart (DiFrancesco, 1993. Annual Review of Physiology 55, 455-472). At pacemaker voltages, I-f is an inward current activated by negative voltage and by intracellular cAMP. Moderate beta-receptor stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, If at diastolic potentials via changes in cAMP level. Cloning of four isoforms of hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels in the late 1990s has shown their correlation to native f-channels. Comparison of the properties of native pacemaker channels with those of HCN channels has provided information concerning the composition and molecular features of native channels in different cardiac regions. The relevance of If to pacemaker generation and modulation makes f-channels a natural target of drugs aiming to control pharmacologically heart rate. Agents selectively reducing heart rate have been developed which act by specific inhibition of If, such as ivabradine; these drugs have a high potential for treatment of diseases where heart rate reduction is beneficial, such as angina and heart failure. Knowledge of the molecular properties of HCN clones will help the development of drugs specifically interacting with cardiac, rather than neuronal pacemaker channels. Devices able to replace electronic pacemakers and based on the delivery of a cellular source of pacemaker channels to non-pacing tissue (biological pacemakers) are likely to be developed in the near future for use in therapies for diseases of heart rhythm.
If inhibition: a novel mechanism of action
No full textAims: It is well established that the cardiac pacemaker ('funny', or I f) current plays an important role in the generation and autonomic modulation of cardiac rate by controlling the rate of diastolic depolarization. Here, the properties of If and the criteria that permit identification of If activation as the main mechanism responsible for diastolic depolarization are briefly summarized. The relationship between If inhibition by specific If channel blockers (rate-reducing agents) and reduction in pacemaker rate is also described. Methods and results: The If data reported here were collected from rabbit sinoatrial node cells that were isolated and patch-clamped. Cs + ions and, more efficiently, 'rate-reducing' agents block I f and reduce the steepness of diastolic depolarization and frequency in spontaneously active sinoatrial node myocytes. Ivabradine (Procoralan®; Servier, Neuilly-sur-Seine, France), a recently developed molecule, blocks If channels when they are open and preferentially when the current is outward. Conclusions: If controls the slope of diastolic depolarization and cardiac frequency, and its inhibition causes heart rate reduction. The current-dependent blockade of If with ivabradine leads to a specific and use-dependent, heart rate reducing effect that may have therapeutic applications in clinical settings
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