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Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level.

ABSTRACT: The relationship between cardiac excitability and contractility depends on when Ca²⁺ influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca²⁺ influx through the L-type Ca²⁺ channels occurs during AP phase 2. However, in murine models, experimental evidence shows Ca²⁺ influx takes place during phase 1. Interestingly, Ca²⁺ influx that activates contraction is highly regulated by the autonomic nervous system. Indeed, autonomic regulation exerts multiple effects on Ca²⁺ handling and cardiac electrophysiology. In this paper, we explore autonomic regulation in endocardial and epicardial layers of intact beating mice hearts to evaluate their role on cardiac excitability and contractility. We hypothesize that in mouse cardiac ventricles the influx of Ca²⁺ that triggers excitation-contraction coupling (ECC) does not occur during phase 2. Using pulsed local field fluorescence microscopy and loose patch photolysis, we show sympathetic stimulation by isoproterenol increased the amplitude of Ca²⁺ transients in both layers. This increase in contractility was driven by an increase in amplitude and duration of the L-type Ca²⁺ current during phase 1. Interestingly, the ?-adrenergic increase of Ca²⁺ influx slowed the repolarization of phase 1, suggesting a competition between Ca²⁺ and K⁺ currents during this phase. In addition, cAMP activated L-type Ca²⁺ currents before SR Ca²⁺ release activated the Na⁺-Ca²⁺ exchanger currents, indicating Ca_v1.2 channels are the initial target of PKA phosphorylation. In contrast, parasympathetic stimulation by carbachol did not have a substantial effect on amplitude and kinetics of endocardial and epicardial Ca²⁺ transients. However, carbachol transiently decreased the duration of the AP late phase 2 repolarization. The carbachol-induced shortening of phase 2 did not have a considerable effect on ventricular pressure and systolic Ca²⁺ dynamics. Interestingly, blockade of muscarinic receptors by atropine prolonged the duration of phase 2 indicating that, in isolated hearts, there is an intrinsic release of acetylcholine. In addition, the acceleration of repolarization induced by carbachol was blocked by the acetylcholine-mediated K⁺ current inhibition. Our results reveal the transmural ramifications of autonomic regulation in intact mice hearts and support our hypothesis that Ca²⁺ influx that triggers ECC occurs in AP phase 1 and not in phase 2.

SUBMITTER: Aguilar-Sanchez Y

PROVIDER: S-EPMC6616252 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level.

Aguilar-Sanchez Yuriana Y Rodriguez de Yurre Ainhoa A Argenziano Mariana M Escobar Ariel L AL Ramos-Franco Josefina J

Frontiers in physiology 20190703

The relationship between cardiac excitability and contractility depends on when Ca2+ influx occurs during the ventricular action potential (AP). In mammals, it is accepted that Ca2+ influx through the L-type Ca2+ channels occurs during AP phase 2. However, in murine models, experimental evidence shows Ca2+ influx takes place during phase 1. Interestingly, Ca2+ influx that activates contraction is highly regulated by the autonomic nervous sys ...[more]

PMID: 31333477

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Project description:Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.Laboratory/clinical investigations.University laboratory/medical centers.Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of <6?ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

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Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level.

Publications

Transmural Autonomic Regulation of Cardiac Contractility at the Intact Heart Level.

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