title: Enhanced vascular neuronal nitric-oxide synthase-derived nitric-oxide production underlies the pressor response caused by peripheral N-methyl-D-aspartate receptor activation in conscious rats.
abstract: Although the N-methyl-D-aspartate (NMDA) receptor (NMDAR) obligatory unit NMDAR1 is expressed in the vasculature and myocardium, the impact of peripheral NMDAR activation on blood pressure (BP) has received little attention. We demonstrate, for the first time, dose-related pressor responses elicited by systemic NMDA (125, 250, 500, and 1000 μg/kg) in conscious rats. The pressor response was peripheral NMDAR-mediated because: 1) it persisted after ganglion blockade (hexamethonium; 5 mg/kg i.v.); 2) it was attenuated by the selective NMDAR blocker DL-2-amino-5-phosphonopentanoic acid (5 mg/kg, i.v.) or the glycine/NMDAR antagonist R-(+)-3-amino-1-hydroxypyrrolid-2-one [R-(+)-HA-966; 10 mg/kg i.v.]; and 3) NMDA (1.25-10 mM) increased contractile force of rat aorta in vitro. It is noteworthy that ex vivo studies revealed enhanced nitric oxide (NO) and reactive oxygen species (ROS) generation in vascular tissues collected at the peak of the NMDAR-mediated pressor response. Pharmacological, ex vivo, and in vitro findings demonstrated attenuation of the NMDAR-mediated increases in BP and vascular NO and ROS by the nonselective NO synthase (NOS) inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride (10 mg/kg i.v.) or the neuronal NOS (nNOS) inhibitor N(ω)-propyl-L-arginine hydrochloride (150 μg/kg i.p.) but not by the endothelial NOS inhibitor N(5)-(1-iminoethyl)-L-ornithine (4 or 10 mg/kg i.v.). Furthermore, R-(+)-HA-966 attenuated NMDA-evoked generation of vascular NO and ROS. The findings suggest a pivotal role for enhanced vascular nNOS-derived NO in ROS generation and in the subsequent pressor response elicited by peripheral NMDAR in conscious rats.
authors.affiliation: Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Marie A
authors.initials: MA
authors.lastname: McGee
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002319:Cardiovascular System / Q000201:enzymology / Q000378:metabolism; D003243:Consciousness; D045888:Ganglion Cysts / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016202:N-Methylaspartate; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate