Abstract
Endocannabinoids contract, relax or do not affect vessels with different calibre and tone in the pulmonary circulation in four species. The aim of the present study was to determine the mechanisms involved in the anandamide-induced relaxation of human pulmonary arteries (hPAs). Studies were performed in the isolated hPAs pre-constricted with the prostanoid TP receptor agonist, U-46619. To detect fatty acid amide hydrolase (FAAH) expression, Western blots were used. Anandamide concentration dependently relaxed the endothelium-intact hPAs pre-constricted with U-46619. The anandamide-induced relaxation was virtually abolished by removal of the endothelium and strongly attenuated by inhibitors of cyclooxygenases (indomethacin, COX-1/COX-2, and nimesulide, COX-2), nitric oxide synthase (N G-nitro-l-arginine methyl ester) given separately or in combination, FAAH (URB597), and the prostanoid IP receptor antagonist, RO1138452. The anandamide-evoked relaxation in the endothelium-intact vessels was attenuated in KCl pre-constricted preparations or by the inhibitor of large-conductance Ca2+-activated K+ channels, iberiotoxin. In experiments performed in the presence of URB597 to exclude effects of anandamide metabolites, the antagonist of the endothelial cannabinoid receptor, O-1918, diminished the anandamide-evoked relaxation whereas the antagonists of cannabinoid CB1, CB2 and vanilloid TRPV1 receptors, AM251, SR144528 and capsazepine, respectively, had no effect. Western blot studies revealed the occurrence of FAAH protein in the hPAs. The present study shows that anandamide breakdown products, cyclooxygenase pathways, nitric oxide, potassium channels and the O-1918-sensitive cannabinoid receptor play a role in the anandamide-induced relaxation of the hPAs with intact endothelium.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive, potentially lethal disease
We found that the anandamide-induced vasorelaxation is strongly endothelium dependent and involves arachidonic acid degradation products, nitric oxide (NO) and big-conductance Ca2+-activated K+ channels (BKCa) and, in addition, is related to the activation of O-1918-sensitive receptors but not cannabinoid CB1, CB2 or vanilloid TRPV1 receptors
Influence of anandamide on the human pulmonary arteries (hPAs) pre-constricted with U-46619 or serotonin significantly from that induced by 5-HT 1 μM or KCl 60 mM (Table 1)
Summary
Pulmonary arterial hypertension (PAH) is a progressive, potentially lethal disease. Patients with PAH have increased levels of potent vasoconstrictors and decreased levels of the endothelial vasodilator nitric oxide (NO) and prostacyclin (PGI2), leading to enhanced vasoconstriction, thrombosis, and pulmonary vascular remodelling (Frumkin 2012). Available therapies for PAH target the imbalance of vasoconstricting and vasodilating mediators leading to vasorelaxation in pulmonary vasculature (Frumkin 2012; Waxman and Zamanian 2013; Benyahia et al 2013). The two best known endocannabinoids, anandamide (N-arachidonoylethanolamine) and 2arachidonoylglycerol (2-AG), influence the diameter of systemic blood vessels by various mechanisms (Montecucco and Di Marzo 2012), and their possible role has been studied in the pulmonary vasculature. Fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide degradation, was detected in rabbit and murine lungs (Wahn et al 2005; Wenzel et al 2013) and in human pulmonary artery smooth muscle cells (Meng et al 2008; Wenzel et al 2013). Only few functional studies concerning direct actions of endocannabinoids on the pulmonary vasculature have been published in the latter four mammalian species in vivo or in vitro
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