Last update 01 Nov 2024

VDCCs x M2 receptor x Potassium channel

Last update 01 Nov 2024

Basic Info

Related Targets

VDCCsM2 receptorPotassium channel

Drugs associated with VDCCs x M2 receptor x Potassium channel

Pirmenol Hydrochloride Hydrate

Target

M2 receptor x Potassium channel x VDCCs

Mechanism

M2 receptor antagonists [+2]

Active Org.

Dainippon Pharmaceutical Co., Ltd. [+2]

Originator Org.

Pfizer Inc.

Active Indication

Arrhythmias, Cardiac [+1]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date05 Oct 1994

100 Clinical Results associated with VDCCs x M2 receptor x Potassium channel

100 Translational Medicine associated with VDCCs x M2 receptor x Potassium channel

0 Patents (Medical) associated with VDCCs x M2 receptor x Potassium channel

Literatures (Medical) associated with VDCCs x M2 receptor x Potassium channel

07 Jul 2021·Cardiovascular ResearchQ1 · MEDICINE

Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control

Q1 · MEDICINE

Article

Author: Zimmermann, Wolfram-Hubertus ; Jungmann, Andreas ; Fabritz, Larissa ; Noack, Claudia ; Zafeiriou, Maria-Patapia ; Dewenter, Matthias ; Blenkle, Alica ; Renger, Anke ; Müller, Oliver J ; Syeda, Fahima ; Iyer, Lavanya M ; El-Armouche, Ali ; Toischer, Karl ; Rathjens, Franziska S ; Zelarayan, Laura C

AbstractAims Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.Methods and results We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced.Conclusions This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.

15 Apr 2015·The Journal of PhysiologyQ2 · MEDICINE

Rebuttal from Alicia D'Souza, Sanjay Sharma and Mark R. Boyett

Q2 · MEDICINE

Article

Author: Sharma, Sanjay ; Boyett, Mark R. ; D'Souza, Alicia

We read with great interest the arguments presented by Coote & White (2015) in favour of the traditional view that exercise training decreases resting heart rate by an increase in the tonic discharge of the vagal nerves. However, we are not persuaded. Coote & White (2015) quote Maciel et al. (1985); however, Maciel et al. (1985) showed that the intrinsic heart rate of trained athletes remains lower after full vagal nerve block. Although Ordway et al. (1982) reported that there was no training-induced bradycardia in six cardiac-denervated dogs, there is evidence to the contrary: Kavanagh et al. (1988) reported that in eight highly compliant cardiac transplant patients (with no evidence of cardiac reinnervation) there was. Coote & White (2015) state that the high frequency (HF) component of heart rate variability (HRV) is a robust surrogate for vagal tone and the increase in the HF component in athletes is evidence of increased vagal tone. However, we have argued that HRV cannot be used in any simple way to measure autonomic nerve activity (Monfredi et al. 2014). Our arguments are based on those of Zaza & Lombardi (2001), who showed that the HF component (like other measures of HRV) is highly sensitive to the heart rate. For example, on training Al-Ani et al. (1996) observed a 12 beats min–1 decrease in the resting heart rate (69 decreased to 57 beats min–1) and a 1.5-fold increase in the HF component, whereas Zaza & Lombardi (2001) calculated that a 10 beats min–1 decrease (70 to 60 beats min–1) will cause a 3-fold increase simply because of the decrease in heart rate alone. Coote & White (2015) mention the sensitivity of the baroreceptor–heart rate reflex; this is a commonly used index of autonomic balance, but this too relies on HRV and is therefore flawed (Zaza & Lombardi (2001). The data from Danson & Paterson (2003) quoted by Coote & White (2015) showing a training-induced upregulation of NOS-1 in intracardiac cholinergic ganglia are fascinating; the data indicate an improvement in vagal neurotransmission but this does not prove it is responsible for the training-induced bradycardia. For example, our own data demonstrate a training-induced reduction in the sinus node of mRNA for the M2 receptor and Kir3.1, Kir3.4, HCN4, Cav1.2 and Cav1.3 channels (responsible for the ACh-sensitive currents IK,ACh, If and ICa,L) (D'Souza et al. 2014); these changes potentially reduce the sensitivity of the sinus node to vagal tone. Overall, given that direct recording of cardiac vagal activity is currently unfeasible, the available evidence tips the balance in favour of electrophysiological remodelling of the sinus node to explain the resting bradycardia in athletes. A challenge for neuroscientists is to measure vagal activity to the sinus node directly and not rely on questionable surrogates.

01 Apr 2011·The Journal of PhysiologyQ2 · MEDICINE

BK channel β1 subunits regulate airway contraction secondary to M2 muscarinic acetylcholine receptor mediated depolarization

Q2 · MEDICINE

Article

Author: Iurii Semenov ; Bin Wang ; Robert Brenner ; Jeremiah T. Herlihy

Non‐technical summary Parasympathetic nerve activation of M3 and M2 muscarinic acetylcholine receptors initiates and modulates calcium release from the sarcoplasmic reticulum to control airway smooth muscle contraction. Here we investigate M2 acetylcholine receptors that also contribute to contraction through depolarization and recruitment of voltage‐dependent calcium channels (VDCCs). We find that the calcium‐ and voltage‐activated potassium channel (BK channel) and its β1 accessory subunit are important proteins that oppose M2‐mediated contraction of airway smooth muscle. BK channels contribute to a negative baseline membrane voltage from which M2‐mediated depolarization only weakly activates VDCCs. The role of BK β1 to oppose M2 signalling is evidenced by a greater than fourfold increase in the contribution of L‐type VDCCs to contraction that otherwise does not occur with M2 receptor antagonist or with β1 containing BK channels. These findings provide a better understanding of how cholinergic second messenger signalling impinges on voltage‐dependent mechanisms and excitation–contraction coupling of smooth muscle.

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