Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure

Abstract

Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Dysregulation of Neuronal Ca 2+ Channel Linked to Heightened Sympathetic Phenotype in Prohypertensive States

“…Another study found that inhibition of this channel restores cardiac autonomic imbalance and prevents lethal arrhythmias in a mouse model of heart failure (Yamada et al, 2014). Similarly, we also observed increased whole-cell neuronal Ca 2ϩ currents in the prohypertensive SHR , suggesting that channel dysregulation is an early molecular event that may be highly conserved over several developmental stages from the prediseased phenotype to advanced heart failure (Li and Paterson, 2016).…”

“…cAMP and cGMP act via PKA and PKG to cause activation and inhibition of the channel current, respectively (Bannister et al, 2005;Catterall, 2011;Zamponi et al, 2015). This occurs either via direct phosphorylation of the channels (Tohse and Sperelakis, 1991;Jiang et al, 2000) or through cross-play between the two CN pathways via PDEs (Conti and Beavo, 2007;Zaccolo and Movsesian, 2007;Stangherlin et al, 2011;Stangherlin and Zaccolo, 2012a).…”

“…Interestingly, this sympathetic impairment occurs in young, prohypertensive animals Shanks et al, 2013c), suggesting that it is an early hallmark of the disease itself, although the exact mechanisms that underpin the phenotype remain poorly understood. When postganglionic sympathetic stellate neurons (PGSNs) that predominantly innervate the heart from age-matched prohypertensive SHRs are compared with PGSNs from normotensive rats (WKY), the SHR neurons have increased intracellular calcium transients ([Ca 2ϩ ] i ) and enhanced neurotransmission (Zugck et al, 2003;Li et al, 2007;Shanks and Herring, 2013;Shanks et al, 2013c). This translates into increased postsynaptic excitability of the sinoatrial node due to a greater conductance of ICa L 2ϩ and an increase in heart rate (Heaton et al, 2006).…”

Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure

“…Similarly, a previous report showed that Ca v 2.2 −/− mice exhibited lower SBP than control mice because of vasodilatation, reduction of heart contractile activity, and inhibition of sympathetic nerve activity25. Most notably in our study, urinary albumin excretion was reduced by 70% and renal hyperfiltration was normalized in db/db Ca v 2.2 −/− mice.…”

Characteristics of diurnal ventricular premature complex variation in right ventricular outflow tract arrhythmias after catheter ablation

“…Similar results have also been demonstrated in animal studies and revealed the importance of cardiac autonomic balance in preventing lethal arrhythmia. [21] In addition, we did not routinely use isoproterenol to induce VAs for every study patient, especially for patients with frequent spontaneous VPCs in our study. Thus, we could not obtain enough information regarding the response of VPCs or VT under isoproterenol infusion during ablation, which might present autonomic characteristics between 2 groups.…”