Key result
Extracellular β-NAD suppresses myocardial contractility by ~50% through P2Y receptor signaling.
Why the study?
The study sought to reveal the functional interplay of diverse ion currents and channels implicated in controlling cardiac contractility using hyperpolarizing and depolarizing agents.
How do β-NAD and ammonia interact to regulate rat papillary muscle contractility and cardiomyocyte electrophysiological properties, and which ion channels and exchangers mediate this interplay?
How do β-NAD and ammonia interact to regulate rat papillary muscle contractility and cardiomyocyte electrophysiological properties, and which ion channels and exchangers mediate this interplay?
This preclinical study demonstrates that extracellular β-NAD suppresses cardiac papillary muscle contractility via P2Y receptor signaling, an effect antagonized by ammonia through the cooperative recruitment of Kir2.x, HCN, L-type Ca2+, Ca2+-activated K+ channels (BK, IK, SK), and reverse-mode NCX.
Answers are grounded in this paper and cite their sources.
No clinical translation warranted; hypothesis-generating for β-NAD-P2Y ion channel effects in myocardium.
Various models, including stem cells derived and isolated cardiomyocytes with overexpressed channels, are utilized to analyze the functional interplay of diverse ion currents involved in cardiac automaticity and excitation–contraction coupling control. Here, we used β-NAD and ammonia, known hyperpolarizing and depolarizing agents, respectively, and applied inhibitory analysis to reveal the interplay of several ion channels implicated in rat papillary muscle contractility control. We demonstrated that: 4 mM β-NAD, having no strong impact on resting membrane potential (RMP) and action potential duration (APD90) of ventricular cardiomyocytes, evoked significant suppression of isometric force (F) of paced papillary muscle. Reactive blue 2 restored F to control values, suggesting the involvement of P2Y-receptor-dependent signaling in β-NAD effects. Meantime, 5 mM NH4Cl did not show any effect on F of papillary muscle but resulted in significant RMP depolarization, APD90 shortening, and a rightward shift of I–V relationship for total steady state currents in cardiomyocytes. Paradoxically, NH4Cl, being added after β-NAD and having no effect on RMP, APD, and I–V curve, recovered F to the control values, indicating β-NAD/ammonia antagonism. Blocking of HCN, Kir2.x, and L-type calcium channels, Ca2+-activated K+ channels (SK, IK, and BK), or NCX exchanger reverse mode prevented this effect, indicating consistent cooperation of all currents mediated by these channels and NCX. We suggest that the activation of Kir2.x and HCN channels by extracellular K+, that creates positive and negative feedback, and known ammonia and K+ resemblance, may provide conditions required for the activation of all the chain of channels involved in the interplay. Here, we present a mechanistic model describing an interplay of channels and second messengers, which may explain discovered antagonism of β-NAD and ammonia on rat papillary muscle contractile activity.
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Аверин et al. (2022) studied Cardiac contractility and excitation-contraction coupling regulation. β-NAD and NH4Cl (ammonia) with ion channel/exchanger blockers vs. Control (untreated baseline / Tyrode or Hank's solution) was evaluated on Maximal isometric force of contraction (FMAX) of paced papillary muscle and electrophysiological parameters (RMP, APD90, I-V relationship) in isolated cardiomyocytes (p=<0.05). Extracellular β-NAD (4 mM) suppressed rat papillary muscle isometric force by 48–50%, an effect reversed by P2Y antagonist Reactive Blue 2 or 5 mM NH4Cl via multi-channel interplay.
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