GPR18-Mediated Relaxation of Human Isolated Pulmonary Arteries

GPR18 receptor protein was detected in the heart and vasculature and appears to play a functional role in the cardiovascular system. We investigated the effects of the new GPR18 agonists PSB-MZ-1415 and PSB-MZ-1440 and the new GPR18 antagonist PSB-CB-27 on isolated human pulmonary arteries (hPAs) an...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-01, Vol.23 (3), p.1427
Main Authors: Kozłowska, Hanna, Malinowska, Barbara, Baranowska-Kuczko, Marta, Kusaczuk, Magdalena, Nesterowicz, Miłosz, Kozłowski, Mirosław, Müller, Christa E, Kieć-Kononowicz, Katarzyna, Schlicker, Eberhard
Format: Article
Language:English
Subjects:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology
Agonists
Arachidonic Acids - pharmacology
Cannabidiol
Cardiovascular system
Endothelium
Humans
Hypercholesterolemia
Hypertension
Ligands
Male
Molecular biology
mRNA
Patients
Potassium
Proteins
Pulmonary arteries
Pulmonary artery
Pulmonary Artery - metabolism
Receptors, G-Protein-Coupled - metabolism
Tetrahydrocannabinol
THC
Thromboxane A2
Veins & arteries
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Summary:GPR18 receptor protein was detected in the heart and vasculature and appears to play a functional role in the cardiovascular system. We investigated the effects of the new GPR18 agonists PSB-MZ-1415 and PSB-MZ-1440 and the new GPR18 antagonist PSB-CB-27 on isolated human pulmonary arteries (hPAs) and compared their effects with the previously proposed, but unconfirmed, GPR18 ligands NAGly, Abn-CBD (agonists) and O-1918 (antagonist). GPR18 expression in hPAs was shown at the mRNA level. PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD fully relaxed endothelium-intact hPAs precontracted with the thromboxane A analog U46619. PSB-CB-27 shifted the concentration-response curves (CRCs) of PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD to the right; O-1918 caused rightward shifts of the CRCs of PSB-MZ-1415 and NAGly. Endothelium removal diminished the potency and the maximum effect of PSB-MZ-1415. The potency of PSB-MZ-1415 or NAGly was reduced in male patients, smokers and patients with hypercholesterolemia. In conclusion, the novel GPR18 agonists, PSB-MZ-1415 and PSB-MZ-1440, relax hPAs and the effect is inhibited by the new GPR18 antagonist PSB-CB-27. GPR18, which appears to exhibit lower activity in hPAs from male, smoking or hypercholesterolemic patients, may become a new target for the treatment of pulmonary arterial hypertension.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23031427