Impairment of neuronal nitric oxide synthase-dependent dilation of cerebral arterioles during chronic alcohol consumption

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Abstract

Background: Although chronic alcohol consumption impairs endothelial nitric oxide synthase-dependent reactivity of cerebral arterioles, the effect of alcohol consumption on vasodilation in response to activation of neuronal nitric oxide synthase (nNOS) has not been examined. Thus, our first goal was to determine whether chronic alcohol consumption impairs nNOS-dependent reactivity of pial arterioles. Our second goal was to examine potential mechanisms for impaired responses of pial arterioles during chronic alcohol consumption. Methods: Sprague Dawley® rats were fed liquid diets with or without alcohol for 8 to 12 weeks. By using intravital microscopy, we measured the diameter of pial arterioles in response to nNOS-dependent agonists - NMDA and kainate (KA) - in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) or 7-nitroindazole (7-NI). We also measured responses of pial arterioles to nitroglycerin. Next, using Western blot analysis, we measured protein levels of the NMDA receptor subunit, KA receptor subunit, and nNOS protein in cerebral microvessels, parietal cortex, cerebellum, and brainstem of non-alcohol-fed and alcohol-fed rats. Results: Topical application of NMDA (100 and 300 μM) and KA (100 and 300 μM) produced dose-related dilation of pial arterioles in non-alcohol-fed and alcohol-fed rats. However, the magnitude of vasodilation in response to NMDA and KA, but not nitroglycerin, was significantly less in alcohol-fed compared with non-alcohol-fed rats. Topical application of L-NMMA (10 μM) or 7-NI (10 μM) significantly inhibited dilation of pial arterioles in response to NMDA and KA in non-alcohol-fed rats. In alcohol-fed rats, only NMDA-induced vasodilation was inhibited by L-NMMA. In addition, we found that NMDA receptor subunit and KA receptor subunit protein levels increased in the parietal cortex and cerebellum of alcohol-fed compared with non-alcohol-fed rats. However, no significant difference in protein level of nNOS was observed between non-alcohol-fed and alcohol-fed rats. Conclusions: Our findings suggest that chronic alcohol consumption impairs nNOS-dependent dilation of pial arterioles via a mechanism that appears to be unrelated to quantitative changes in NMDA receptors, KA receptors, or nNOS. Because the regulation of cerebral blood flow is influenced by neuronal activation, impaired reactivity of cerebral blood vessels to neuronal activation may contribute to the pathogenesis of cerebrovascular disorders observed during chronic alcohol consumption.

Original languageEnglish (US)
Pages (from-to)663-670
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume26
Issue number5
DOIs
StatePublished - Jan 1 2002

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Nitric Oxide Synthase Type I
Arterioles
Alcohol Drinking
Dilatation
Alcohols
N-Methylaspartate
omega-N-Methylarginine
Kainic Acid
Rats
Kainic Acid Receptors
N-Methyl-D-Aspartate Receptors
Vasodilation
Parietal Lobe
Nitroglycerin
Cerebellum
Cerebrovascular Circulation
Chemical activation
Cerebrovascular Disorders
Proteins
Nitric Oxide Synthase Type III

Keywords

  • 7-Nitroindazole
  • Brain
  • Kainate
  • L-NMMA
  • NMDA

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

@article{2b3c33662de247d7bc5b5e61880325a1,
title = "Impairment of neuronal nitric oxide synthase-dependent dilation of cerebral arterioles during chronic alcohol consumption",
abstract = "Background: Although chronic alcohol consumption impairs endothelial nitric oxide synthase-dependent reactivity of cerebral arterioles, the effect of alcohol consumption on vasodilation in response to activation of neuronal nitric oxide synthase (nNOS) has not been examined. Thus, our first goal was to determine whether chronic alcohol consumption impairs nNOS-dependent reactivity of pial arterioles. Our second goal was to examine potential mechanisms for impaired responses of pial arterioles during chronic alcohol consumption. Methods: Sprague Dawley{\circledR} rats were fed liquid diets with or without alcohol for 8 to 12 weeks. By using intravital microscopy, we measured the diameter of pial arterioles in response to nNOS-dependent agonists - NMDA and kainate (KA) - in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) or 7-nitroindazole (7-NI). We also measured responses of pial arterioles to nitroglycerin. Next, using Western blot analysis, we measured protein levels of the NMDA receptor subunit, KA receptor subunit, and nNOS protein in cerebral microvessels, parietal cortex, cerebellum, and brainstem of non-alcohol-fed and alcohol-fed rats. Results: Topical application of NMDA (100 and 300 μM) and KA (100 and 300 μM) produced dose-related dilation of pial arterioles in non-alcohol-fed and alcohol-fed rats. However, the magnitude of vasodilation in response to NMDA and KA, but not nitroglycerin, was significantly less in alcohol-fed compared with non-alcohol-fed rats. Topical application of L-NMMA (10 μM) or 7-NI (10 μM) significantly inhibited dilation of pial arterioles in response to NMDA and KA in non-alcohol-fed rats. In alcohol-fed rats, only NMDA-induced vasodilation was inhibited by L-NMMA. In addition, we found that NMDA receptor subunit and KA receptor subunit protein levels increased in the parietal cortex and cerebellum of alcohol-fed compared with non-alcohol-fed rats. However, no significant difference in protein level of nNOS was observed between non-alcohol-fed and alcohol-fed rats. Conclusions: Our findings suggest that chronic alcohol consumption impairs nNOS-dependent dilation of pial arterioles via a mechanism that appears to be unrelated to quantitative changes in NMDA receptors, KA receptors, or nNOS. Because the regulation of cerebral blood flow is influenced by neuronal activation, impaired reactivity of cerebral blood vessels to neuronal activation may contribute to the pathogenesis of cerebrovascular disorders observed during chronic alcohol consumption.",
keywords = "7-Nitroindazole, Brain, Kainate, L-NMMA, NMDA",
author = "Hong Sun and Patel, {Kaushik P} and William Mayhan",
year = "2002",
month = "1",
day = "1",
doi = "10.1111/j.1530-0277.2002.tb02588.x",
language = "English (US)",
volume = "26",
pages = "663--670",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Impairment of neuronal nitric oxide synthase-dependent dilation of cerebral arterioles during chronic alcohol consumption

AU - Sun, Hong

AU - Patel, Kaushik P

AU - Mayhan, William

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Background: Although chronic alcohol consumption impairs endothelial nitric oxide synthase-dependent reactivity of cerebral arterioles, the effect of alcohol consumption on vasodilation in response to activation of neuronal nitric oxide synthase (nNOS) has not been examined. Thus, our first goal was to determine whether chronic alcohol consumption impairs nNOS-dependent reactivity of pial arterioles. Our second goal was to examine potential mechanisms for impaired responses of pial arterioles during chronic alcohol consumption. Methods: Sprague Dawley® rats were fed liquid diets with or without alcohol for 8 to 12 weeks. By using intravital microscopy, we measured the diameter of pial arterioles in response to nNOS-dependent agonists - NMDA and kainate (KA) - in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) or 7-nitroindazole (7-NI). We also measured responses of pial arterioles to nitroglycerin. Next, using Western blot analysis, we measured protein levels of the NMDA receptor subunit, KA receptor subunit, and nNOS protein in cerebral microvessels, parietal cortex, cerebellum, and brainstem of non-alcohol-fed and alcohol-fed rats. Results: Topical application of NMDA (100 and 300 μM) and KA (100 and 300 μM) produced dose-related dilation of pial arterioles in non-alcohol-fed and alcohol-fed rats. However, the magnitude of vasodilation in response to NMDA and KA, but not nitroglycerin, was significantly less in alcohol-fed compared with non-alcohol-fed rats. Topical application of L-NMMA (10 μM) or 7-NI (10 μM) significantly inhibited dilation of pial arterioles in response to NMDA and KA in non-alcohol-fed rats. In alcohol-fed rats, only NMDA-induced vasodilation was inhibited by L-NMMA. In addition, we found that NMDA receptor subunit and KA receptor subunit protein levels increased in the parietal cortex and cerebellum of alcohol-fed compared with non-alcohol-fed rats. However, no significant difference in protein level of nNOS was observed between non-alcohol-fed and alcohol-fed rats. Conclusions: Our findings suggest that chronic alcohol consumption impairs nNOS-dependent dilation of pial arterioles via a mechanism that appears to be unrelated to quantitative changes in NMDA receptors, KA receptors, or nNOS. Because the regulation of cerebral blood flow is influenced by neuronal activation, impaired reactivity of cerebral blood vessels to neuronal activation may contribute to the pathogenesis of cerebrovascular disorders observed during chronic alcohol consumption.

AB - Background: Although chronic alcohol consumption impairs endothelial nitric oxide synthase-dependent reactivity of cerebral arterioles, the effect of alcohol consumption on vasodilation in response to activation of neuronal nitric oxide synthase (nNOS) has not been examined. Thus, our first goal was to determine whether chronic alcohol consumption impairs nNOS-dependent reactivity of pial arterioles. Our second goal was to examine potential mechanisms for impaired responses of pial arterioles during chronic alcohol consumption. Methods: Sprague Dawley® rats were fed liquid diets with or without alcohol for 8 to 12 weeks. By using intravital microscopy, we measured the diameter of pial arterioles in response to nNOS-dependent agonists - NMDA and kainate (KA) - in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) or 7-nitroindazole (7-NI). We also measured responses of pial arterioles to nitroglycerin. Next, using Western blot analysis, we measured protein levels of the NMDA receptor subunit, KA receptor subunit, and nNOS protein in cerebral microvessels, parietal cortex, cerebellum, and brainstem of non-alcohol-fed and alcohol-fed rats. Results: Topical application of NMDA (100 and 300 μM) and KA (100 and 300 μM) produced dose-related dilation of pial arterioles in non-alcohol-fed and alcohol-fed rats. However, the magnitude of vasodilation in response to NMDA and KA, but not nitroglycerin, was significantly less in alcohol-fed compared with non-alcohol-fed rats. Topical application of L-NMMA (10 μM) or 7-NI (10 μM) significantly inhibited dilation of pial arterioles in response to NMDA and KA in non-alcohol-fed rats. In alcohol-fed rats, only NMDA-induced vasodilation was inhibited by L-NMMA. In addition, we found that NMDA receptor subunit and KA receptor subunit protein levels increased in the parietal cortex and cerebellum of alcohol-fed compared with non-alcohol-fed rats. However, no significant difference in protein level of nNOS was observed between non-alcohol-fed and alcohol-fed rats. Conclusions: Our findings suggest that chronic alcohol consumption impairs nNOS-dependent dilation of pial arterioles via a mechanism that appears to be unrelated to quantitative changes in NMDA receptors, KA receptors, or nNOS. Because the regulation of cerebral blood flow is influenced by neuronal activation, impaired reactivity of cerebral blood vessels to neuronal activation may contribute to the pathogenesis of cerebrovascular disorders observed during chronic alcohol consumption.

KW - 7-Nitroindazole

KW - Brain

KW - Kainate

KW - L-NMMA

KW - NMDA

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U2 - 10.1111/j.1530-0277.2002.tb02588.x

DO - 10.1111/j.1530-0277.2002.tb02588.x

M3 - Article

VL - 26

SP - 663

EP - 670

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 5

ER -