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The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure.
J Pharmacol Exp Ther. 2014 Apr; 349(1):29-38.JP

Abstract

Systemic administration of the G-protein-coupled receptor 18 (GPR18) agonist abnormal cannabidiol (Abn CBD) lowers blood pressure (BP). Whether GPR18 is expressed in the central nervous system (CNS) and plays a role in BP control is not known despite the abundance of the GPR18 ligand N-arachidonoyl glycine (NAGly) in the CNS. Therefore, we first determined whether GPR18 is expressed in the presympathetic tyrosine hydroxylase (TH) immunoreactive (ir) neurons of the brainstem cardiovascular regulatory nuclei. Second, we investigated the impact of GPR18 activation and blockade on BP and heart rate (HR) and neurochemical modulators of sympathetic activity and BP. Immunofluorescence findings revealed GPR18 expression in TH-ir neurons in the rostral ventrolateral medulla (RVLM). Intra-RVLM GPR18 activation (Abn CBD) and blockade (O-1918, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-,cyclohexen-1-yl]benzene) elicited dose-dependent reductions and elevations in BP, respectively, along with respective increases and decreases in HR in conscious male Sprague-Dawley rats. RVLM GPR18 activation increased neuronal adiponectin (ADN) and NO and reduced reactive oxygen species (ROS) levels, and GPR18 blockade reduced neuronal ADN and increased oxidative stress (i.e., ROS) in the RVLM. Finally, we hypothesized that the negligible hypotensive effect caused by the endogenous GPR18 ligand NAGly could be due to concurrent activation of CB(1)R in the RVLM. Our findings support this hypothesis because NAGly-evoked hypotension was doubled after RVLM CB(1)R blockade (SR141716, rimonabant). These findings are the first to demonstrate GPR18 expression in the RVLM and to suggest a sympathoinhibitory role for this receptor. The findings yield new insight into the role of a novel cannabinoid receptor (GPR18) in central BP control.

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Authors+Show Affiliations

Penumarti A
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Abdel-Rahman AA
No affiliation info available

MeSH

AnimalsAnisolesBlood PressureCannabinoid Receptor AgonistsCannabinoid Receptor AntagonistsCyclohexanesDose-Response Relationship, DrugHeart RateMaleMedulla OblongataNeuronsNitric OxideRatsRats, Sprague-DawleyReactive Oxygen SpeciesReceptors, CannabinoidResorcinolsTyrosine 3-Monooxygenase

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24431468

Citation

Penumarti, Anusha, and Abdel A. Abdel-Rahman. "The Novel Endocannabinoid Receptor GPR18 Is Expressed in the Rostral Ventrolateral Medulla and Exerts Tonic Restraining Influence On Blood Pressure." The Journal of Pharmacology and Experimental Therapeutics, vol. 349, no. 1, 2014, pp. 29-38.
Penumarti A, Abdel-Rahman AA. The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J Pharmacol Exp Ther. 2014;349(1):29-38.
Penumarti, A., & Abdel-Rahman, A. A. (2014). The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. The Journal of Pharmacology and Experimental Therapeutics, 349(1), 29-38. https://doi.org/10.1124/jpet.113.209213
Penumarti A, Abdel-Rahman AA. The Novel Endocannabinoid Receptor GPR18 Is Expressed in the Rostral Ventrolateral Medulla and Exerts Tonic Restraining Influence On Blood Pressure. J Pharmacol Exp Ther. 2014;349(1):29-38. PubMed PMID: 24431468.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. AU - Penumarti,Anusha, AU - Abdel-Rahman,Abdel A, Y1 - 2014/01/15/ PY - 2014/1/17/entrez PY - 2014/1/17/pubmed PY - 2014/5/16/medline SP - 29 EP - 38 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 349 IS - 1 N2 - Systemic administration of the G-protein-coupled receptor 18 (GPR18) agonist abnormal cannabidiol (Abn CBD) lowers blood pressure (BP). Whether GPR18 is expressed in the central nervous system (CNS) and plays a role in BP control is not known despite the abundance of the GPR18 ligand N-arachidonoyl glycine (NAGly) in the CNS. Therefore, we first determined whether GPR18 is expressed in the presympathetic tyrosine hydroxylase (TH) immunoreactive (ir) neurons of the brainstem cardiovascular regulatory nuclei. Second, we investigated the impact of GPR18 activation and blockade on BP and heart rate (HR) and neurochemical modulators of sympathetic activity and BP. Immunofluorescence findings revealed GPR18 expression in TH-ir neurons in the rostral ventrolateral medulla (RVLM). Intra-RVLM GPR18 activation (Abn CBD) and blockade (O-1918, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-,cyclohexen-1-yl]benzene) elicited dose-dependent reductions and elevations in BP, respectively, along with respective increases and decreases in HR in conscious male Sprague-Dawley rats. RVLM GPR18 activation increased neuronal adiponectin (ADN) and NO and reduced reactive oxygen species (ROS) levels, and GPR18 blockade reduced neuronal ADN and increased oxidative stress (i.e., ROS) in the RVLM. Finally, we hypothesized that the negligible hypotensive effect caused by the endogenous GPR18 ligand NAGly could be due to concurrent activation of CB(1)R in the RVLM. Our findings support this hypothesis because NAGly-evoked hypotension was doubled after RVLM CB(1)R blockade (SR141716, rimonabant). These findings are the first to demonstrate GPR18 expression in the RVLM and to suggest a sympathoinhibitory role for this receptor. The findings yield new insight into the role of a novel cannabinoid receptor (GPR18) in central BP control. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/24431468/The_novel_endocannabinoid_receptor_GPR18_is_expressed_in_the_rostral_ventrolateral_medulla_and_exerts_tonic_restraining_influence_on_blood_pressure_ DB - PRIME DP - Unbound Medicine ER -