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 Nω-nitro-l-arginine methyl ester hydrochloride (10 mg/kg i.v.) or the neuronal NOS (nNOS) inhibitor Nω-propyl-l-arginine hydrochloride (150 μg/kg i.p.) but not by the endothelial NOS inhibitor N5-(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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- NMDA
- N-methyl-d-aspartate
- NMDAR
- NMDA receptor
- AP-5
- dl-2-amino-5-phosphonopentanoic acid
- BP
- blood pressure
- CNS
- central nervous system
- DAF-FM
- 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate
- DCF
- 2′,7′-dichlorofluorescein
- HR
- heart rate
- NO
- nitric oxide
- NOS
- NO synthase
- eNOS
- endothelial NOS
- iNOS
- inducible NOS
- nNOS
- neuronal NOS
- l-NAME
- Nω-nitro-l-arginine methyl ester
- l-NIO
- N5-(1-iminoethyl)-l-ornithine
- MAP
- mean arterial pressure
- Nox
- NADPH oxidase
- NOx
- nitrite/nitrate
- NPLA
- Nω-propyl-l-arginine
- PE
- phenylephrine
- R-(+)-HA-966
- R-(+)-3-amino-1-hydroxypyrrolid-2-one
- RFU
- relative fluorescence units
- ROS
- reactive oxygen species.
- Received March 16, 2012.
- Accepted May 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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