The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects
GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of se...
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doaj-90df7f750537417e973b05928031cf162021-08-26T14:12:27ZengMDPI AGPharmaceuticals1424-82472021-08-011479979910.3390/ph14080799The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant EffectsMagdalena Kotańska0Monika Kubacka1Marek Bednarski2Noemi Nicosia3Małgorzata Szafarz4Wojciech Jawień5Christa E. Müller6Katarzyna Kieć-Kononowicz7Department of Pharmacological Screening, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandDepartment of Pharmacodynamics, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandDepartment of Pharmacological Screening, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandDepartment of Pharmacological Screening, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandDepartment of Pharmacokinetics and Physical Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandDepartment of Pharmaceutical Biophysics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandPharma Center Bonn, Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, GermanyDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, PolandGPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K<sup>+</sup> channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation—an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.https://www.mdpi.com/1424-8247/14/8/799agonistcannabinoidGPCRGPR18orphan receptorvasodilation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Magdalena Kotańska Monika Kubacka Marek Bednarski Noemi Nicosia Małgorzata Szafarz Wojciech Jawień Christa E. Müller Katarzyna Kieć-Kononowicz |
spellingShingle |
Magdalena Kotańska Monika Kubacka Marek Bednarski Noemi Nicosia Małgorzata Szafarz Wojciech Jawień Christa E. Müller Katarzyna Kieć-Kononowicz The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects Pharmaceuticals agonist cannabinoid GPCR GPR18 orphan receptor vasodilation |
author_facet |
Magdalena Kotańska Monika Kubacka Marek Bednarski Noemi Nicosia Małgorzata Szafarz Wojciech Jawień Christa E. Müller Katarzyna Kieć-Kononowicz |
author_sort |
Magdalena Kotańska |
title |
The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects |
title_short |
The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects |
title_full |
The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects |
title_fullStr |
The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects |
title_full_unstemmed |
The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects |
title_sort |
gpr18 agonist psb-kd-107 exerts endothelium-dependent vasorelaxant effects |
publisher |
MDPI AG |
series |
Pharmaceuticals |
issn |
1424-8247 |
publishDate |
2021-08-01 |
description |
GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K<sup>+</sup> channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation—an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified. |
topic |
agonist cannabinoid GPCR GPR18 orphan receptor vasodilation |
url |
https://www.mdpi.com/1424-8247/14/8/799 |
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