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

Abstract

Aims24-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 methodsElectrical stimulation-evoked contractions were recorded in isolated atria from mice. Fluorescent dyes, Fluo-4 and DAF-FM, were used for estimation of Ca2+ transient and NO production, respectively. Key findingsWe revealed that 24HC in the submicromolar range attenuated β-AR-induced positive inotropy in isolated atria. This was accompanied by a decrease in Ca2+ transient and unchanged nitric oxide (NO) production. However, β1-AR-induced positive inotropy and enhancement of Ca2+ transient were increased by 24HC due to suppression of NO production. Only β2-AR-dependent inotropy and enhancement of Ca2+ 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. SignificanceWe suggest that 24HC could serve as a modulator of atrial β-AR signaling, contributing to regulation of contractility.