The Novel Endocannabinoid Receptor GPR18 Is Expressed in the Rostral Ventrolateral Medulla and Exerts Tonic Restraining Influence on Blood Pressure

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.

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

“…Five days after the surgical procedures, an ML870 (PowerLab 8/30, AD Instruments, Colorado Springs, CO) system was used to measure BP and heart rate (HR) in conscious unrestrained rats. The data were analyzed and displayed using LabChart (version 7) prosoftware (AD Instruments, Colorado Springs, CO) as in our reported studies (Ibrahim and Abdel-Rahman, 2011;Nassar et al, 2011;Penumarti and Abdel-Rahman, 2014).…”

“…BP and HR were allowed to stabilize at baseline, for at least 30 minutes, before intra-RVLM microinjections started. All injections (100 nl) were made unilaterally into the RVLM according to established protocol in our laboratory (Penumarti and Abdel-Rahman, 2014). Control rats received 100 nl of 1% dimethylsulfoxide in the artificial cerebrospinal fluid that was used as a vehicle.…”

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

“…Our recent findings (Penumarti and Abdel-Rahman, 2014) demonstrated GPR18 expression in rostral ventrolateral (RVLM) neurons, which modulate the sympathetic activity (Sved et al, 2003;Kishi et al, 2004;Guyenet, 2006), and suggested a restraining influence for RVLM GPR18 on blood pressure (BP). N-Arachidonoyl glycine (NAGly), a metabolite of the endocannabinoid anandamide, serves as an endogenous GPR18 agonist (McHugh et al, 2010).…”

“…Furthermore, GPR18 activation by its synthetic agonist, abnormal cannabidiol (Abn CBD; trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol), mediates cannabinoid receptor 1 (CB 1 R)-and cannabinoid receptor 2-independent responses, such as nitric oxide (NO)-dependent vasorelaxation (Offertáler et al, 2003;McHugh et al, 2010). However, it must be remembered that indirect activation of CB 1 R by NAGly, but not Abn CBD, influences the GPR18-mediated responses in tissues that contain both receptors, particularly in whole animal studies (Penumarti and Abdel-Rahman, 2014).…”

“…Therefore, we considered the possibility that NO-dependent elevation of a downstream antioxidant or prooxidant molecule in the RVLM might determine the final redox state, and the ultimate BP response. In this regard, we reported preliminary "correlative" evidence that adiponectin (ADN), which reduces oxidative stress (Song et al, 2013), is a potential downstream mediator of the hypotension caused by RVLM GPR18 activation (Penumarti and Abdel-Rahman, 2014). …”