GPR18-Mediated Relaxation of Human Isolated Pulmonary Arteries.

Hanna Kozłowska,Katarzyna Kieć-Kononowicz,Marta Baranowska-Kuczko,Eberhard Schlicker,Christa E Müller,Barbara Malinowska,Magdalena Kusaczuk,Miłosz Nesterowicz,Mirosław Kozłowski

doi:10.3390/ijms23031427

Abstract

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 A2 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.

Highlights

GPR18 is an orphan G protein-coupled receptor, which, showing little structural similarity to cannabinoid CB1 and CB2 receptors, responds to the natural cannabinoid ∆9-tetrahydrocannabinol (THC)
Taking into account the fact that GPR18 protein is expressed in the human pulmonary artery [18], the aim of the present study was to investigate the effects of the three novel GPR18 ligands on isolated human pulmonary arteries (hPAs) and to compare their effects with the previously proposed, but unconfirmed, GPR18 ligands NAGly, abnormal cannabidiol (Abn-CBD), and O-1918
PSB-MZ-1415 produced a full concentration-dependent relaxation of endothelium-intact isolated hPAs precontracted with U46619; endothelial removal re

Summary

Introduction

GPR18 is an orphan G protein-coupled receptor, which, showing little structural similarity to cannabinoid CB1 and CB2 receptors (identity of amino acid sequence of 13 and 8%, respectively; [1]), responds to the natural cannabinoid ∆9-tetrahydrocannabinol (THC). GPR18 is located in the central nervous system, the gastrointestinal tract, in the lymphoid system [2,3], in peripheral blood leukocytes, several hematopoietic cell lines [4,5] and in the eye [6,7]. GPR18 expression has recently been verified in skeletal muscle from obese rats [8]. In humans, this receptor is expressed in the brain including the hypothalamus [9], in cells of the immune system [4,5], and in the colon [10]. GPR18 is expressed in cultured cells, including human lymphoid cells [4], HEC-1B endometrial cells [11], BV2 murine microglial cells [12], and metastatic melanoma [13]. The (patho)physiological role of GPR18 is controversial and unclear, it is believed that it may be involved in immunological processes, inhibition of inflammatory reactions including intestinal inflammation [10,14] and in lowering intraocular pressure in mice [7,15]

Objectives

Methods

Results

Discussion

Conclusion