scholarly journals Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption

2001 ◽  
Vol 281 (5) ◽  
pp. H1863-H1869 ◽  
Author(s):  
Hong Sun ◽  
Kaushik P. Patel ◽  
William G. Mayhan
Keyword(s):  
Alcohol Consumption ◽  
Chronic Alcohol ◽  
Sprague Dawley ◽  
Chronic Alcohol Consumption ◽  
Sprague Dawley Rats ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Oxide Synthase ◽  
Enos Protein

We sought to investigate mechanisms that may account for impaired nitric oxide synthase (NOS)-dependent dilatation of cerebral arterioles during alcohol consumption. Our goals were to examine 1) the effect of exogenous application of a cofactor for NOS, i.e., tetrahydrobiopterin (BH4) on the reactivity of pial arterioles during alcohol consumption; and 2) endothelial NOS (eNOS) protein in nonalcohol-fed and alcohol-fed rats. Sprague-Dawley rats were fed liquid diets with or without alcohol for 2–3 mo. We measured in vivo diameter of pial arterioles in response to NOS-dependent agonists (ACh and ADP) and a NOS-independent agonist (nitroglycerin) before and during application of BH4. Blood vessels were then harvested for Western blot analysis of eNOS protein. In nonalcohol-fed rats, ACh and ADP produced vasodilatation, which was impaired in alcohol-fed rats. Vasodilatation to nitroglycerin was similar in both groups of rats. Application of BH4 did not alter vasodilatation in nonalcohol-fed rats but improved impaired vasodilatation in alcohol-fed rats. Also, eNOS protein in cerebral cortex microvessels, the basilar artery, and aorta was not different between nonalcohol-fed and alcohol-fed rats. Thus impaired NOS-dependent vasodilatation during alcohol consumption does not appear to be related to an alteration in eNOS protein but may be related to a deficiency and/or alteration in the utilization of BH4.

Temporal effect of alcohol consumption on reactivity of pial arterioles: role of oxygen radicals

2001 ◽  
Vol 280 (3) ◽  
pp. H992-H1001 ◽  
Author(s):  
Hong Sun ◽  
William G. Mayhan
Keyword(s):  
Nitric Oxide ◽  
Free Radicals ◽  
Alcohol Consumption ◽  
Nitric Oxide Synthase ◽  
Chronic Alcohol ◽  
Chronic Alcohol Consumption ◽  
Oxygen Derived Free Radicals ◽  
Pial Arterioles ◽  
Oxide Synthase

Chronic alcohol consumption reduces nitric oxide synthase-dependent responses of pial arterioles via mechanisms that remain uncertain. In addition, the temporal effects of alcohol on pial arterioles is unclear. Thus our goals were to examine the role of oxygen-derived free radicals in alcohol-induced impairment of cerebrovascular reactivity and the temporal effect of alcohol on reactivity of pial arterioles. Sprague-Dawley rats were pair-fed a liquid diet with or without alcohol for 2–3 wk, 2–3 mo, or 5–6 mo. We measured the in vivo diameter of pial arterioles in response to nitric oxide synthase-dependent dilators acetylcholine and ADP and the nitric oxide synthase-independent dilator nitroglycerin. In nonalcohol-fed rats, acetylcholine (1.0 and 10 μM) and ADP (10 and 100 μM) produced dose-related dilatation of pial arterioles. Whereas there was no difference in reactivity of arterioles to the agonists in rats fed the nonalcohol and alcohol diets for a period of 2–3 wk, there was a significant impairment in reactivity of arterioles to acetylcholine and ADP, but not nitroglycerin, in rats fed the alcohol diet for longer durations. We then found that treatment with superoxide dismutase did not alter baseline diameter of pial arterioles in nonalcohol-fed or alcohol-fed rats, but significantly improved impaired nitric oxide synthase-dependent dilatation of pial arterioles in alcohol-fed rats. Thus our findings suggest a temporal relationship in the effects of alcohol on reactivity of pial arterioles and that impaired nitric oxide synthase-dependent cerebral vasodilatation during chronic alcohol consumption may be related, in part, to enhanced release of oxygen-derived free radicals.

scholarly journals Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats

2011 ◽  
Vol 300 (3) ◽  
pp. H1013-H1020 ◽  
Author(s):  
William G. Mayhan ◽  
Denise M. Arrick ◽  
Kaushik P. Patel ◽  
Hong Sun
Keyword(s):  
Exercise Training ◽  
Brain Tissue ◽  
Diabetic Rats ◽  
Protein Levels ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Oxide Synthase ◽  
Enos Protein

Our goal was to examine whether exercise training (ExT) could normalize impaired nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during type 1 diabetes (T1D). We measured the in vivo diameter of pial arterioles in sedentary and exercised nondiabetic and diabetic rats in response to an endothelial NOS (eNOS)-dependent (ADP), an neuronal NOS (nNOS)-dependent [ N-methyl-d-aspartate (NMDA)], and a NOS-independent (nitroglycerin) agonist. In addition, we measured superoxide anion levels in brain tissue under basal conditions in sedentary and exercised nondiabetic and diabetic rats. Furthermore, we used Western blot analysis to determine eNOS and nNOS protein levels in cerebral vessels/brain tissue in sedentary and exercised nondiabetic and diabetic rats. We found that ADP and NMDA produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic rats. In contrast, ADP and NMDA produced only minimal vasodilation in sedentary diabetic rats. ExT restored impaired ADP- and NMDA-induced vasodilation observed in diabetic rats to that observed in nondiabetics. Nitroglycerin produced a dilation of pial arterioles that was similar in sedentary and exercised nondiabetic and diabetic rats. Superoxide levels in cortex tissue were similar in sedentary and exercised nondiabetic rats, were increased in sedentary diabetic rats, and were normalized by ExT in diabetic rats. Finally, we found that eNOS protein was increased in diabetic rats and further increased by ExT and that nNOS protein was not influenced by T1D but was increased by ExT. We conclude that ExT can alleviate impaired eNOS- and nNOS-dependent responses of pial arterioles during T1D.

scholarly journals Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

2021 ◽  
Author(s):  
Tengfei Ma ◽  
Zhenbo Huang ◽  
Xueyi Xie ◽  
Xiaowen Zhuang ◽  
Matthew Childs ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Cognitive Flexibility ◽  
Alcohol Drinking ◽  
Long Term Potentiation ◽  
D1 Receptor ◽  
Chronic Alcohol ◽  
Glutamatergic Transmission ◽  
Chronic Alcohol Consumption ◽  
Cholinergic Interneurons

Exposure to addictive substances impairs flexible decision-making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 d) reduction of excitatory thalamic inputs onto CINs and reduced pause response of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.

scholarly journals Fluoxetine improves behavioural deficits induced by chronic alcohol addiction by alleviating RNA editing of 5-HT2C receptors in astrocytes

2019 ◽  
Author(s):  
Zexiong Li ◽  
Shanshan Liang ◽  
Shuai Li ◽  
Beina Chen ◽  
Manman Zhang ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Rna Editing ◽  
Alcohol Intake ◽  
Motor Coordination ◽  
Alcohol Addiction ◽  
Chronic Alcohol ◽  
Chronic Alcohol Consumption ◽  
Adenosine Deaminases ◽  
Underlying Pathology

AbstractThe alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2CR) by regulating adenosine deaminases acting on RNA (ADARs) in neurones. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol addiction increased editing of RNA of 5-HT2CR via up-regulating the expression of ADAR2, consequnetly reducing the release of ATP from astrocytes induced by 5-HT2CR agonist, MK212. At the same time SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. Reduction in ADAR2 activity eliminated the RNA editing of 5-HT2CR in vivo and increased release of astroglial ATP which was suppressed by chronic alcohol consumption. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.

Distensibility and wall composition of rat cerebral arterioles in hypertension induced by chronic blockade of nitric oxide synthase

1996 ◽  
Vol 54 ◽  
pp. 754-755
Author(s):  
S. M. Ghoneim ◽  
J. M. Chillon ◽  
G.L. Baumbach
Keyword(s):  
Nitric Oxide ◽  
Vessel Wall ◽  
Mass Composition ◽  
Chronic Hypertension ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Sprague Dawley Rats ◽  
Cacodylate Buffer ◽  
Cerebral Arterioles ◽  
Oxide Synthase

We have previously reported that, during chronic hypertension, cerebral arterioles undergo hypertrophy of the vessel wall, accompanied by a paradoxical increase in passive distensibility. We have proposed that this increase may be due to a reduction in the proportion of nondistensible (collagen and basement membrane) to the distensible (smooth muscle, elastin and endothelium) components of the vessel wall. We have recently observed in stroke-prone spontaneously hypertensive rats(SHRSP), that an endothelium derived factor, endothelin, may contribute to hypertrophy, but not to increases in passive ditensibility, of cerebral arterioles vessel wall.The goal of this study was to examine wall mass, composition and passive ditensibility of cerebral arterioles in chronic hypertension induced by decreased availability of another endothelium derived factor, nitric oxide (NO).Four weeks old male Sprague-Dawley rats were treated with LG-nitro-L-arginine methyl ester (LNAME; 10 mg /kg/day) in the drinking water. We examined distensibility of maximally dilated cerebral arterioles in 4 months old Sprague-Dawley rats. Arterioles were then fixed at physiological pressure (2.25% gluterladehyde in 0.10 mol/L cacodylate buffer), the arteriolar segment used for distensibility measurements was removed then immerse fixed, rinsed briefly in 0.1 M cacodylate buffer, osmicated and processed routinely for electron microscopy (TEM).

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