Bogomoletz Institute of Physiology NAS of Ukraine

Kiev, Ukraine

Bogomoletz Institute of Physiology NAS of Ukraine

Kiev, Ukraine
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Bondarenko A.I.,Bogomoletz Institute of Physiology NAS of Ukraine | Bondarenko A.I.,Medical University of Graz | Montecucco F.,University of Genoa | Montecucco F.,IRCCS AOU San Martino IST Instituto Nazionale per la Ricerca sul Cancro | And 5 more authors.
Vascular Pharmacology | Year: 2017

Lysophosphatidylinositol (LPI) and lysophosphatidylcholine (LPC) are lipid signaling molecules that induce endothelium-dependent vasodilation. In addition, LPC suppresses acetylcholine (Ach)-induced responses. We aimed to determine the influence of LPC and LPI on hyperpolarizing responses in vitro and in situ endothelial cells (EC) and identify the underlying mechanisms. Using patch-clamp method, we show that LPI and LPC inhibit EC hyperpolarization to histamine and suppress Na+/Ca2 + exchanged (NCX) currents in a concentration-dependent manner. The inhibition is non-mode-specific and unaffected by intracellular GDPβS infusion and tempol, a superoxide dismutase mimetic. In excised mouse aorta, LPI strongly inhibits the sustained and the peak endothelial hyperpolarization induced by Ach, but not by SKA-31, an opener of Ca2 +-dependent K+ channels of intermediate and small conductance. The hyperpolarizing responses to consecutive histamine applications are strongly reduced by NCX inhibition. In a Ca2 +-re-addition protocol, bepridil, a NCX inhibitor, and KB-R7943, a blocker of reversed NCX, inhibit the hyperpolarizing responses to Ca2 +-re-addition following Ca2 + stores depletion. These finding indicate that LPC and LPI inhibit endothelial hyperpolarization to Ach and histamine independently of G-protein coupled receptors and superoxide anions. Reversed NCX is critical for ER Ca2 + refilling in EC. The inhibition of NCX by LPI and LPC underlies diminished endothelium-dependent responses and endothelial dysfunction accompanied by increased levels of these lipids in the blood. © 2017 Elsevier Inc.


Bondarenko A.I.,Bogomoletz Institute of Physiology NAS of Ukraine | Bondarenko A.I.,Medical University of Graz | Panasiuk O.,Bogomoletz Institute of Physiology NAS of Ukraine | Okhai I.,Bogomoletz Institute of Physiology NAS of Ukraine | And 3 more authors.
European Journal of Pharmacology | Year: 2017

Endocannabinoid anandamide induces endothelium-dependent relaxation commonly attributed to stimulation of the G-protein coupled endothelial anandamide receptor. The study addressed the receptor-independent effect of anandamide on large conductance Ca2+-dependent K+ channels expressed in endothelial cell line EA.hy926. Under resting conditions, 10 µM anandamide did not significantly influence the resting membrane potential. In a Ca2+-free solution the cells were depolarized by ~10 mV. Further administration of 10 µM anandamide hyperpolarized the cells by ~8 mV. In voltage-clamp mode, anandamide elicited the outwardly rectifying whole-cell current sensitive to paxilline but insensitive to GDPβS, a G-protein inhibitor. Administration of 70 µM Mn2+, an agent used to promote integrin clustering, reversibly stimulated whole-cell current, but failed to further facilitate the anandamide-stimulated current. In an inside-out configuration, anandamide (0.1–30 µM) facilitated single BKCa channel activity in a concentration-dependent manner within a physiological Ca2+ range and a wide range of voltages, mainly by reducing mean closed time. The effect is essentially eliminated following chelation of Ca2+ from the cytosolic face and pre-exposure to cholesterol-reducing agent methyl-β-cyclodextrin. O-1918 (3 µM), a cannabidiol analog used as a selective antagonist of endothelial anandamide receptor, reduced BKCa channel activity in inside-out patches. These results do not support the existence of endothelial cannabinoid receptor and indicate that anandamide acts as a direct BKCa opener. The action does not require cell integrity or integrins and is caused by direct modification of BKCa channel activity. © 2017 Elsevier B.V.


PubMed | Melitopol State Pedagogical University, Medical University of Graz, University of Genoa, Bogomoletz Institute of Physiology NAS of Ukraine and University of Geneva
Type: | Journal: Vascular pharmacology | Year: 2017

Lysophosphatidylinositol (LPI) and lysophosphatidylcholine (LPC) are lipid signaling molecules that induce endothelium-dependent vasodilation. In addition, LPC suppresses acetylcholine (Ach)-induced responses. We aimed to determine the influence of LPC and LPI on hyperpolarizing responses in vitro and in situ endothelial cells (EC) and identify the underlying mechanisms. Using patch-clamp method, we show that LPI and LPC inhibit EC hyperpolarization to histamine and suppress Na

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