Brain cholesterol metabolite 24-hydroxycholesterol modulates inotropic responses to β-adrenoceptor stimulation: The role of NO and phosphodiesterase.

Autor: Odnoshivkina UG; Department of Normal Physiology, Kazan State Medical University, Butlerova st. 49, Kazan 420012, Russia., Sytchev VI; Department of Normal Physiology, Kazan State Medical University, Butlerova st. 49, Kazan 420012, Russia., Starostin O; Department of Normal Physiology, Kazan State Medical University, Butlerova st. 49, Kazan 420012, Russia., Petrov AM; Institute of Neuroscience, Kazan State Medical University, Butlerova st. 49, Kazan 420012, Russia; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center 'Kazan Scientific Center of RAS', P. O. Box 30, Lobachevsky Str., 2/31, Kazan 420111, Russia. Electronic address: aleksey.petrov@kazangmu.ru.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2019 Mar 01; Vol. 220, pp. 117-126. Date of Electronic Publication: 2019 Jan 30.
DOI: 10.1016/j.lfs.2019.01.054
Abstrakt: Aims: 24-Hydroxycholesterol (24HC) is the main brain cholesterol metabolite, which level in the circulation is significantly changed under physiological and pathological conditions. Here, we have studied the effect of 24HC on the inotropic responses to β-adrenoceptor (AR) stimulation.
Main Methods: Electrical stimulation-evoked contractions were recorded in isolated atria from mice. Fluorescent dyes, Fluo-4 and DAF-FM, were used for estimation of Ca 2+ transient and NO production, respectively.
Key Findings: We revealed that 24HC in the submicromolar range attenuated β-AR-induced positive inotropy in isolated atria. This was accompanied by a decrease in Ca 2+ transient and unchanged nitric oxide (NO) production. However, β1-AR-induced positive inotropy and enhancement of Ca 2+ transient were increased by 24HC due to suppression of NO production. Only β2-AR-dependent inotropy and enhancement of Ca 2+ transient were decreased by 24HC in a NO-independent manner. Inhibition of phosphodiesterase (PDE) suppressed effect of 24HC on β2-AR-dependent contractility as well as on non-subtype specific β-AR activation. Moreover, 24HC counteracted positive inopropic action of PDE inhibitors, IBMX and rolipam. Thus, 24HC modulates the effects of β1- and β2-AR stimulation via different mechanisms linked with change in activity of NO synthase or PDE, respectively. Under conditions of non-selective activation of β-ARs, the depressant effect of 24HC related with β2-AR-dependent signaling dominates.
Significance: We suggest that 24HC could serve as a modulator of atrial β-AR signaling, contributing to regulation of contractility.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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