Cardiac and neuronal HCN channelopathies

Rivolta, Ilaria; Binda, Anna; Masi, Alessio; DiFrancesco, Jacopo C.

doi:10.1007/s00424-020-02384-3

Cited by 74 publications

(55 citation statements)

References 182 publications

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“…HCN channels are expressed in the heart and are known to have a critical role in controlling cardiac pacemaker activity ( Rivolta et al, 2020 ). Ivabradine is the first clinically approved drug to efficiently treat heart failure ( Postea and Biel, 2011 ) and cancer chemotherapy-evoked left ventricular dysfunction ( Sarocchi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

Zhong

Darmani

2021

Front. Pharmacol.

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Subtypes (1–4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i.p.) and 83.3% at 10 µg (i.c.v.). HCN channel subtype (1–4) expression was assessed using immunohistochemistry in the least shrew brainstem dorsal vagal complex (DVC) containing the emetic nuclei (area postrema (AP), nucleus tractus solitarius and dorsal motor nucleus of the vagus). Highly enriched HCN1 and HCN4 subtypes are present in the AP. A 1 mg/kg (i.p.) dose of ZD7288 strongly evoked c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem DVC, but not in the in the enteric nervous system in the jejunum, suggesting a central contribution to the evoked vomiting. The ZD7288-evoked c-Fos expression exclusively occurred in tryptophan hydroxylase 2-positive serotonin neurons of the dorsal vagal complex, indicating activation of serotonin neurons may contribute to ZD7288-induced vomiting. To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca2+ channel (nifedipine); store-operated Ca2+ entry (MRS 1845); T-type Ca2+ channel (Z944), IP3R (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. All tested antiemetics except sulpride attenuated ZD7288-evoked vomiting to varying degrees. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca2+ signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

Zhong

Darmani

2021

Front. Pharmacol.

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“…There are no reported effects of a plethora of mutations of HCN channels on ventricular arrhythmias in humans: supraventricular bradycardia/tachyarrhythmias predominate [ 89 ].…”

Section: Ivabradine and Ventricular Arrhythmiasmentioning

confidence: 99%

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Oknińska

Paterek

Zambrowska

et al. 2021

JCM

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Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

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“…by HCN2-or HCN4-deficient mice which exhibit sinoatrial dysfunction [8][9][10] and also by development of bradycardic HCN channel blocking agent ivabradine [11]. On the other hand, in ventricular myocardium, their overexpression contributes to cardiac pro-arrhythmogenic potential [12].…”

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confidence: 99%

“…On the other hand, in ventricular myocardium, their overexpression contributes to cardiac pro-arrhythmogenic potential [12]. All four isoforms of HCN channels are expressed in cardiac tissue but they manifest a species-dependent regional specific distribution [10]. HCN2 and HCN4 isoforms are predominant ventricular HCN transcripts and together represent more than 90% of the ventricular HCN channels [13].…”

mentioning

confidence: 99%

“…HCN2 and HCN4 isoforms are predominant ventricular HCN transcripts and together represent more than 90% of the ventricular HCN channels [13]. However, in healthy atrial and ventricular cardiomyocytes which do not display spontaneous activity [10], HCN channels are barely expressed when compared to their stable expression in pacemaker cells [14]..An enhanced expression of myocardial HCN channels contributes to increased pacemaker current (I f ) which relates to ventricular and atrial arrhythmias in failing hearts [15]. Moreover, HCN channels, when overexpressed, were reported to prolong the repolarization of ventricular action potential and thereby increase the arrhythmogenic potential [14].…”

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confidence: 99%

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Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

Hadova

Kráľová

Doka

et al. 2021

BMC Cardiovasc Disord

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Background In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia. Methods Diabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro. Results Six weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP). Conclusions This result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.

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Cardiac and neuronal HCN channelopathies

Cited by 74 publications

References 182 publications

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

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