Enhanced Vascular Neuronal Nitric-Oxide Synthase-Derived Nitric-Oxide Production Underlies the Pressor Response Caused by Peripheral<i>N</i>-Methyl-d-Aspartate Receptor Activation in Conscious Rats

McGee, Marie; Abdel‐Rahman, Abdel A.

doi:10.1124/jpet.112.194464

Cited by 26 publications

(45 citation statements)

References 38 publications

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“…ROS level was calculated by relative DCF fluorescence per microgram of protein. Positive and negative controls were used to validate the assay as in our previous studies (McGee and Abdel-Rahman, 2012).…”

Section: Methodsmentioning

confidence: 99%

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

Penumarti

Abdel‐Rahman

2014

J Pharmacol Exp Ther

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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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Section: Methodsmentioning

confidence: 99%

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

Penumarti

Abdel‐Rahman

2014

J Pharmacol Exp Ther

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“…The optimal NMDA dose/infusion rate that produced an approximately 25-mmHg increase in BP was established in our recent study (McGee & Abdel-Rahman, 2012). The rats were pretreated with water (vehicle) or ethanol (1 g/kg; 10 mL/kg of 13% ethanol diluted in water) 30 min prior to NMDA (180 μg/kg/min) or saline infusion at a rate of 9 μL/min (Harvard compact pump, Model 975) for 30 min.…”

Section: Experimental Groups and Protocolsmentioning

confidence: 99%

“…The selected DL-AP-5 dose (5 mg/kg, i.v. ), which does not cross the blood-brain barrier, caused no change in BP or HR, but virtually abolished the pressor response elicited by NMDA infusion (McGee & Abdel-Rahman, 2012). Groups 1 and 2 received AP-5, 30 min before ethanol (1 g/kg) or water; notably, the effects of ethanol (1 g/kg), compared to water, on BP and HR were investigated under Experiment 1.…”

Section: Experimental Groups and Protocolsmentioning

confidence: 99%

“…The vascular tissues collected at the peak of the pressor response elicited by the 1000 μg/kg NMDA or at the end of the 15-min NMDA infusion were used for measurements of vascular NO and ROS, as detailed in our recent study (McGee & Abdel-Rahman, 2012). …”

Section: Experimental Groups and Protocolsmentioning

confidence: 99%

“…However, the NMDAR is also expressed within peripheral tissues including the kidney, sex organs, keratinocytes, and the cardiovascular system (Deng, Valdivielso, Munger, Blantz, & Thomson, 2002; Gill & Pulido, 2001; Morhenn, Murakami, O'Grady, Nordberg, & Gallo, 2004). Specifically, the NMDAR is localized within the heart and vascular (aorta and mesenteric arteries) tissues (Carlton, Chung, Ding, & Coggeshall, 1998; Gill & Pulido, 2001; Leung et al, 2002; McGee & Abdel-Rahman, 2012), and its activation causes dose-related pressor responses in conscious rats (McGee & Abdel-Rahman, 2012). Similar to its neuronal action (Gunasekar, Kanthasamy, Borowitz, & Isom, 1995; Reyes, Brennan, Shen, Baldwin, & Swanson, 2012), peripheral NMDAR mediates vascular oxidative stress (McGee & Abdel-Rahman, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response

McGee

Abdel‐Rahman

2015

Alcohol

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There are no studies on the acute effect of ethanol on peripheral N-methyl-D-aspartate receptor (NMDAR)-mediated increases in reactive oxygen species (ROS) and blood pressure (BP). We tested the hypothesis that ethanol antagonism of peripheral NMDAR dampens systemic NMDA-evoked increases in vascular ROS and BP. We investigated the effect of ethanol (1 g/kg) on BP and heart rate (HR) responses elicited by systemic bolus (125–1000 μg/kg, intra-venous [i.v.]) or infused (180 μg/kg/min) NMDA in conscious male Sprague-Dawley rats. We also hypothesized that peripheral NMDAR blockade with DL-2-Amino-5-phosphonopentanoic acid (AP-5; 5 mg/kg, i.v.) uncovers an ethanol- (1 or 1.5 g/kg) evoked hypotensive response. Ethanol attenuated the peripheral NMDAR-mediated pressor and bradycardic responses caused by NMDA infusion, and ex vivo studies revealed parallel ethanol attenuation of peripheral NMDAR-mediated increases in vascular ROS. While ethanol (1 or 1.5 g/kg) alone had no effect on BP, the higher dose caused a hypotensive response in the presence of NMDAR blockade (AP-5). Blood ethanol concentrations were not statistically different in the groups that received ethanol alone or along with NMDA or AP-5. These findings are the first to demonstrate ethanol attenuation of peripheral NMDAR-mediated pressor response, and the uncovering of ethanol-evoked hypotension in the presence of peripheral NMDAR blockade.

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Functional Distribution and Regulation of the NMDAR in the Kidney, Heart and Parathyroid Gland

Božić

Valdivielso

2017

The NMDA Receptors

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Enhanced Vascular Neuronal Nitric-Oxide Synthase-Derived Nitric-Oxide Production Underlies the Pressor Response Caused by PeripheralN-Methyl-d-Aspartate Receptor Activation in Conscious Rats

Cited by 26 publications

References 38 publications

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

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

Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response

Functional Distribution and Regulation of the NMDAR in the Kidney, Heart and Parathyroid Gland

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