Impairment of Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Intravenous General Anesthetic Propofol

Cacheaux, Luisa P.; Topf, Norbert; Tibbs, Gareth R.; Schaefer, Ulrich R.; Levi, Roberto; Harrison, Neil L.; Abbott, Geoffrey W.; Goldstein, Peter A.

doi:10.1124/jpet.105.091801

Cited by 58 publications

(55 citation statements)

References 41 publications

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“…Native neuronal I h as well as heterologously expressed HCN channels are inhibited by clinically relevant concentrations (Յ0.5 mM) of the inhalational anesthetics halothane and isoflurane (59,87). Similarly, the intravenous anesthetic propofol inhibits and slows the activation of native and expressed HCN channels (67,233).…”

Section: B Blockers Of Neuronal I Hmentioning

confidence: 99%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

889

974

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

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Section: B Blockers Of Neuronal I Hmentioning

confidence: 99%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

889

974

View full text Add to dashboard Cite

show abstract

“…Several molecules are known to interact with funny channels. Early studies showed for example that external Cs ϩ and Rb ϩ ions reduce I f 94 ; these ions, however, along with other molecules also reducing I f , such as THA (9-amino-1,2,3,4-tetrahydroacridine, 95 clonidine, 96 and propofol, 97 interact with other channels and mechanisms and are far from specific. Substances able to slow heart rate by selective f-channel block were developed in the 80's and termed "pure bradycardic agents" (PBAs).…”

Section: Pharmacological Evidencementioning

confidence: 99%

The Role of the Funny Current in Pacemaker Activity

DiFrancesco

2010

Circulation Research

511

440

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Pacemaking 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 ␤-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. (Circ Res. 2010;106:434-446.)Key Words: pacemaking Ⅲ funny current Ⅲ rate modulation Ⅲ sinoatrial node Ⅲ HCN channels S elf-sustained contractile activity is a fundamental cardiac function, essential for life, and it is not surprising that its features have raised the interest of researchers since the earliest attempts at describing the anatomy and physiology of the heart.A realization of the presence of spontaneous activity can be found in the work of Claudius Galen, who in the second century AD observed that "the heart, removed from the thorax, can be seen to move...

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“…The intravenous general anesthetic propofol (2,6-diisopropylphenol) preferentially inhibits HCN1 with respect to HCN2, 3, and 4 (Cacheaux et al, 2005;Chen et al, 2005) and has a modest pharmacokinetic preference for the periphery, that is, plasma levels associated with anesthesia are higher than those in cerebrospinal fluid (CSF) ( Table 1). However, its hypnotic properties and its potentiation of type A GABA receptor (GABA A -R) activity (Franks, 2008) limit its routine use as an analgesic, even at low concentrations.…”

Section: Introductionmentioning

confidence: 99%

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarizationactivated, cyclic nucleotide-regulated (HCN)-mediated I H pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-diiso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA A receptor (GABA A -R) potentiation, and general anesthesia. Thus, 2,6-and 2,4-di-tertbutylphenol (2,6-and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6-and 2,4-di-sec-butylphenol (2,6-and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA A -R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA A -R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

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Impairment of Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Intravenous General Anesthetic Propofol

Cited by 58 publications

References 41 publications

Hyperpolarization-Activated Cation Channels: From Genes to Function

Hyperpolarization-Activated Cation Channels: From Genes to Function

The Role of the Funny Current in Pacemaker Activity

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

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