Author Response: A computational model predicts sex-specific responses to calcium channel blockers in mesenteric vascular smooth muscle DOI Open Access
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Collin Matsumoto

et al.

Published: Dec. 20, 2023

The function of the smooth muscle cells lining walls systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in-silico model, which call "Hernandez-Hernandez model", electrical Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences male female from resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that KV1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger KV2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated K+ channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact anti-hypertensive drugs.

Language: Английский

The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes DOI Creative Commons
Luis F. Santana, Collin Matsumoto, Samantha C. O’Dwyer

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: July 19, 2023

Abstract In arterial myocytes, the canonical function of voltage-gated Ca V 1.2 and K 2.1 channels is to induce myocyte contraction relaxation through their responses membrane depolarization, respectively. Paradoxically, also plays a sex-specific role by promoting clustering activity channels. However, impact protein organization on remains poorly understood. We discovered that forms micro-clusters, which can transform into large macro-clusters when critical site (S590) in channel phosphorylated myocytes. Notably, female myocytes exhibit greater phosphorylation S590, macro-cluster formation compared males. Contrary current models, seems unrelated density or macro-clustering Disrupting (K S590A ) eliminated differences cluster size activity. propose degree tunes manner

Language: Английский

Citations

3
Adenosine reduces sinoatrial node cell action potential firing rate by uncoupling its membrane and calcium clocks DOI Creative Commons
Ashley Wirth, Kenta Tsutsui, Victor A. Maltsev

et al.

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 24, 2022

The spontaneous action potential (AP) firing rate of sinoatrial nodal cells (SANC) is regulated by a system intracellular Ca2+ and membrane ion current clocks driven Ca2+-calmodulin-activated adenylyl cyclase-protein kinase-A signaling. mean AP-cycle length (APCL) APCL variability inform on the effectiveness clock coupling. Endogenous ATP metabolite adenosine binds to receptors (A1, A3) that couple Gi protein-coupled receptors, reducing AP via Gβγ signaling activates IKAch,Ado. Adenosine also inhibits cyclase activity Gαi signaling, impacting cAMP-mediated protein kinase-A-dependent phosphorylation. We hypothesize in addition IKAch,Ado activation, impacts Ca2+via both effects reduce To this end, we measured characteristics enzymatically isolated single rabbit SANC. 10 µM substantially increased (on average 43%, n = 10) beat-to-beat from 5.1 ± 1.7% 7.2 2.0% (n 5.0 2.2% 10.6 5.9% 40) (assessed as coefficient SD/mean). These were mediated hyperpolarization maximum diastolic (membrane effect) suppression local Ca2+releases (LCRs) (Ca2+-clock effect): LCR size distributions shifted smaller values, time occurrence during depolarization (LCR period) became prolonged, ensemble signal reduced. tight linear relationship coupling between period presence "drifted" upward leftward, i.e. for given period, was becoming non-linear indicating uncoupling. An extreme case uncoupling occurred at higher concentrations (>100 µM): small stochastic LCRs failed self-organize synchronize clock, thus creating attempt generate an resulting arrhythmia cessation firing. Thus, activate IKACh,Ado Gαi, suppressing activity, contribute adenosine-induced increase fidelity rate.

Language: Английский

Citations

5
The paradigm shift: Heartbeat initiation without “the pacemaker cell” DOI Creative Commons
Victor A. Maltsev, Michael D. Stern

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 9, 2022

The current dogma about the heartbeat origin is based on “the pacemaker cell,” a specialized cell residing in sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated Ca signals and APs SAN are heterogeneous, with many cells generating of different rates rhythms or even remaining non-firing (dormant cells), i.e., only subthreshold signals. Here we numerically tested hypothesis community dormant can generate normal automaticity, cell” not required to initiate cardiac impulses. Our model includes 1) non-excitable oscillatory local releases 2) an excitable lacking automaticity. While each isolation was cell”, system generated APs: were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange further transferred integrated (computed) by reach its AP threshold, pacemaking. Cardiac impulse emergent property cellular network be initiated intrinsic Cell heterogeneity, weak coupling, signals, their summation critical properties new mechanism, operate signaling process basically similar “temporal summation” happening neuron input from multiple presynaptic cells. does refute classical cell-based mechanism: both mechanisms co-exist interact within tissue.

Language: Английский

Citations

4
The Central Brain of the Heart DOI Creative Commons
Nathan Grainger, Luis F. Santana

JACC. Clinical electrophysiology, Journal Year: 2022, Volume and Issue: 8(10), P. 1216 - 1218

Published: Oct. 1, 2022

Language: Английский

Citations

3
A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle DOI Creative Commons
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Collin Matsumoto

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 26, 2023

Abstract The function of the smooth muscle cells lining walls mammalian systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in-silico model, which call “Hernandez-Hernandez model”, electrical Ca 2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences male female from murine resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that K V 1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger 2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated + channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact anti-hypertensive drugs.

Language: Английский

Citations

1
Cardiac Pacemaker Cells Harness Stochastic Resonance to Ensure Fail-Safe Operation at Low Rates Bordering on Sinus Arrest DOI Creative Commons
Akihiro Okamura,

Isabella K. He,

Michael Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

ABSTRACT BACKGROUND The sinoatrial node (SAN) is primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) exit SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This sets up a new problem cardiac biology how these contribute to heartbeat generation. Here we tested hypothesis cells harness stochastic resonance ensure their fail-safe operation, especially at low rates bordering on sinus arrest. METHODS We measured membrane potential and Ca isolated rabbit hearts response external currents form sine waves or white noise. Protocols were applied via perforated patch while either basal state presence cholinergic receptor stimulation. Additionally, performed multiscale model simulations respective sub-cellular, cellular, tissue levels. RESULTS Noise awakened dormant fire APs substantially improved rate rhythm firing infrequent, dysrhythmic APs. Rhythmic AP generation applications wave different frequencies outlined spectrum cells: capability responding, resonance, specific frequency components embedded Cholinergic stimulation shifted towards lower frequencies, i.e. responded but could not process higher signals. added single cell– tissue-models expanded parametric space beyond bifurcation line where failed operate without Both numerical models our simultaneous recordings dynamics also demonstrated amplified by coupled electrical signaling, enhancing noise CONCLUSIONS membrane-Ca signaling rhythmic initiation rates, providing last-resort mechanism avoid arrest when signal synchronization decreases increases, such as during strong parasympathetic stimulation, disease aging heart slows high-frequency wanes.

Language: Английский

Citations

0
Unique spatiotemporal synchronization solutions of heterogeneous local Ca2+dynamics underlie the formation of each impulse that emerges from the cardiac sinoatrial node DOI Creative Commons
Syevda Tagirova, Alexander V. Maltsev, Georgiana Luisa Baca

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Abstract Spontaneous, stochastic, local Ca 2+ oscillations (LCOs) that are heterogeneous in phase, frequency, and amplitude incessantly occur throughout the neuronal-like cytoarchitecture of heart’s pacemaker, sinoatrial node (SAN). How information encoded within ensembles these LCOs is linked to incessant emergence formation rhythmic SAN impulses, however, an unsolved problem. We applied a wide range analytical techniques adapted from dynamical systems neuroscience map fine details spatiotemporal distributions dynamics time-series high-speed acquisition panoramic images mouse SANs ex vivo. Phase analysis delineated network functional pacemaker cell clusters, which dynamic amplitudes, kinetics, phases were similar, but still differed each other, those other clusters. Local clusters formed global with mean rate identical recorded by reference sharp electrode right atria. Initial conditions impulse initiation due mostly stochastic nature small cluster located near crista terminalis, having highest intrinsic power, earliest rotor-like energy transfer, most frequent point-to-point instability, acrophase, greatest impulse-to-impulse variability A spontaneous, slowly increasing ensemble signal this forms foot CaT. Following foot, CaT increased rapidly, rapid increases kinetics amplitudes some adjacent In inter-atrial septum, delayed, increase occurred when relaxation phase had already begun. Orbit plots Lyapunov exponent analyses detected both deterministic features Ca2+ dynamics. Correlation cross-talk among different varied, not only impulse, also one next, forming unique small-world networks, assessed as ratios correlation coefficientsand shortest path lengths, ultimately creating synchronization solution for Thus, individual during cycle underlies length SAN, recapitulating spontaneous CaTs isolated, single, cells.

Language: Английский

Citations

0
The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes DOI Open Access
Collin Matsumoto, Samantha C. O’Dwyer, Declan Manning

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 29, 2023

In arterial myocytes, the canonical function of voltage-gated Ca

Language: Английский

Citations

0
HYDROACOUSTICS OF THE MECHANICAL BILEAFLET HEART VALVE DOI Open Access
V. A. Voskoboinick, Alberto Redaelli,

Bengamino Fiore

et al.

Bulletin of the National Technical University KhPI Series Mathematical modeling in engineering and technologies, Journal Year: 2023, Volume and Issue: 1, P. 67 - 74

Published: Aug. 1, 2023

The results of experimental researches hydrodynamic noise generated by a jet flow through the mechanical bileaflet mitral valve prosthesis Italian company Sorin are given. Physical simulation was carried out in laboratory conditions on model left atrial chamber and ventricular heart. artificial increased with increasing water flow. It found that greatest intensity its spectral components observed near central valve. obtained average pressure values wake open side (10 – 20) % higher than jet. determined power densities fluctuations jet, especially frequency range 100) Hz. established small-scale vortex structures, which broke away from leaflets (20 70) Hz, degenerated starting distance 2.5 diameters downstream. Increased levels were more (12 13) dB relative to inside (5 7) 15) With an increase valve, (60 80) Hz observed. At below noises jets became approximately equal entire under consideration. research showed hydroacoustic diagnostics operation heart can be effective means diagnosing thrombus formation leaflets.

Language: Английский

Citations

0
Reviewer #3 (Public Review): A computational model predicts sex-specific responses to calcium channel blockers in mesenteric vascular smooth muscle DOI Open Access
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Collin Matsumoto

et al.

Published: Sept. 12, 2023

The function of the smooth muscle cells lining walls systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in silico model, which call “Hernandez-Hernandez model”, electrical Ca2+ signaling arterial myocytes based on new experimental data indicating sex-specific differences male female from resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that KV1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger KV2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated K+ channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact anti-hypertensive drugs.

Language: Английский

Citations

0