Neuronal NOS-derived NO plays permissive role in cerebral blood flow response to hypercapnia

1997 ◽  
Vol 272 (1) ◽  
pp. H559-H566 ◽  
Author(s):  
H. Okamoto ◽  
A. G. Hudetz ◽  
R. J. Roman ◽  
Z. J. Bosnjak ◽  
J. P. Kampine
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Selective Inhibition ◽  
Intracerebroventricular Administration ◽  
Doppler Flowmetry ◽  
No Donors ◽  
Vasodilatory Response ◽  
Oxide Synthase ◽  
Permissive Role

The aim of the present study was to determine whether neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) plays a permissive role in the regulation of cerebral blood flow (CBF) response to hypercapnia. To this end, we examined whether the administration of NO donors could reestablish the regional CBF (rCBF) response to hypercapnia after nNOS inhibition with 7-nitroindazole (7-NI). Rats were anesthetized with 1% halothane, and rCBF in the cortex was measured by laser-Doppler flowmetry. The administration of 7-NI (40 mg/kg ip) decreased resting rCBF by 17 +/- 5% (n = 6, P < 0.05) and attenuated the rCBF response to hypercapnia by 30 +/- 8% in comparison with the response seen in rats treated with the vehicle (peanut oil) alone. Intracerebroventricular administration of NO donors, sodium nitroprusside (SNP; n = 7) and (Z)-1-[N-methyl-N-[6(N-methylammoniohexyl)aminol]]diazen+ ++-1-ium-1,2-diolate (MAHMA NONOate; n = 6) in a dose of 0.1-1 nmol/min after 7-NI restored both resting rCBF to baseline and the vasodilatory response to hypercapnia. In contrast, intravenous infusion of SNP (0.05-0.5 nmol/min, n = 6) or intracerebroventricular administration of an NO-independent vasodilator, the stable prostaglandin I2 analog iloprost (0.01-0.1 nmol/min, n = 6), after 7-NI failed to restore the vasodilatory response to hypercapnia, despite the fact that it restored the resting rCBF to baseline. nNOS activity, assessed by the conversion of labeled arginine to citrulline, was inhibited by 70 +/- 7% after the administration of 7-NI. These findings confirm that the selective inhibition of nNOS decreases resting rCBF and attenuates the rCBF response of hypercapnia. They further indicate that the repletion of intraparenchymal NO allows the hypercapnic cerebrocortical vasodilation to occur. Therefore, it is suggested that the nNOS-derived NO plays a permissive role in the CBF response to hypercapnia.

scholarly journals Endothelial Nitric Oxide Synthase-Dependent Cerebral Blood Flow Augmentation by L-Arginine After Chronic Statin Treatment

2000 ◽  
Vol 20 (4) ◽  
pp. 709-717 ◽  
Author(s):  
Masaru Yamada ◽  
Zhihong Huang ◽  
Turgay Dalkara ◽  
Matthias Endres ◽  
Ulrich Laufs ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Laser Doppler Flowmetry ◽  
Brain Blood Flow ◽  
Arginine Infusion ◽  
Doppler Flowmetry ◽  
Ischemic Brain ◽  
Oxide Synthase

Nitric oxide, a product of nitric oxide synthase activity, relaxes vascular smooth muscle and elevates brain blood flow. We evaluated the importance of eNOS to cerebral blood flow augmentation after L-arginine infusion and increases in flow after eNOS upregulation in SV-129 mice. Blood flow was measured by laser-Doppler flowmetry before and after L-arginine infusion (450 mg/kg during a 15-minute period) or measured by 14C-iodoamphetamine indicator fractionation or 14C-iodoantipyrine tissue equilibration techniques. rCBF increased by 26% (laser Doppler flowmetry) after L-arginine infusion but did not change in mutant mice deficient in eNOS expression. After eNOS upregulation by chronic simvastatin treatment (2 mg/kg subcutaneously, daily for 14 days), L-arginine amplified and sustained the hyperemia (38%) and increased absolute brain blood flow from 86 ± 7 to 119 ± 10 mL/100 g per minute. Furthermore, pretreatment with simvastatin enhanced blood flow within ischemic brain tissue after middle cerebral artery occlusion. Together, these findings suggest that eNOS activity is critical for blood flow augmentation during acute L-arginine infusion, and chronic eNOS upregulation combined with L-arginine administration provides a novel strategy to elevate cerebral blood flow in the normal and ischemic brain.

scholarly journals NITRIC OXIDE SYNTHASE DYSFUNCTION UNDERLIES CEREBROVASCULAR DEFICITS IN A MOUSE MODEL OF TAUOPATHY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S91-S91
Author(s):  
Candice E Van Skike ◽  
Stacy A Hussong ◽  
Andy Banh ◽  
Veronica Galvan
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Mouse Model ◽  
Doppler Flowmetry ◽  
Cerebrovascular Dysfunction ◽  
Oxide Synthase

Abstract We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer’s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer’s disease and potentially other tauopathies.

Examination of the role of nitric oxide for the hypercapnic rise of cerebral blood flow in rats

1994 ◽  
Vol 266 (4) ◽  
pp. H1457-H1464 ◽  
Author(s):  
M. Fabricius ◽  
M. Lauritzen
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Topical Application ◽  
Baseline Level ◽  
Spreading Depression ◽  
Doppler Flowmetry ◽  
Perivascular Nerves ◽  
Oxide Synthase

We examined the effect of nitric oxide synthase (NOS) inhibition and tetrodotoxin (TTX) on the increase of cerebral blood flow (CBF) in parietal (CoBF) and cerebellar cortex (CeBF) in response to hypercapnia. Rats were anesthetized with halothane and artificially ventilated. Hypercapnia was induced by adding 5% CO2 to the inhalation mixture. CoBF and CeBF were measured by laser-Doppler flowmetry. NOS inhibition was achieved by intravenous (30 mg/kg) and/or topical application (1 mM) of NG-nitro-L-arginine (L-NNA). Activity in perivascular nerves around pial and cortical vessels was inhibited by topical application of TTX (20 microM). Under control conditions, hypercapnia (66 +/- 1 mmHg) increased CoBF by 70 +/- 4% and CeBF by 96 +/- 5%. Systemic L-NNA decreased the baseline level of CoBF and CeBF by 11 +/- 3%, but topical L-NNA did not affect baseline flow. Intravenous L-NNA attenuated the hypercapnic increase of CoBF by 77 +/- 5% and CeBF by 63 +/- 4% within 10-20 min. Topical L-NNA attenuated the hypercapnic increase of CoBF by 52 +/- 6% and CeBF by 29 +/- 5% after 45-min exposure. Both CoBF and CeBF decreased rapidly when L-NNA was infused during sustained hypercapnia, but not when L-NNA was applied topically. Effect of intravenous L-NNA was partially prevented by pretreatment with intravenous L-arginine. Intravenous or topical L-NNA enhanced the rise of CBF elicited by cortical spreading depression, adenosine (1 mM), or sodium nitroprusside (300 microM), except in the cerebellum where topical L-NNA attenuated the rise of CBF elicited by adenosine by 53%.(ABSTRACT TRUNCATED AT 250 WORDS)

NOS activity in brain and endothelium: relation to hypercapnic rise of cerebral blood flow in rats

1996 ◽  
Vol 271 (5) ◽  
pp. H2035-H2044 ◽  
Author(s):  
M. Fabricius ◽  
I. Rubin ◽  
M. Bundgaard ◽  
M. Lauritzen
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Cerebellar Cortex ◽  
Laser Doppler Flowmetry ◽  
Doppler Flowmetry ◽  
Nos Inhibitor ◽  
Neuronal Nos ◽  
Oxide Synthase

We examined whether attenuation of the hypercapnic increase of cerebral blood flow (CBF) associated with nitric oxide synthase (NOS) inhibition is related to local neuronal or aortic endothelial NOS activity or local endothelial/neuronal NOS-dependent vasodilation. Halothane-anesthetized rats were ventilated, and CBF was measured by laser-Doppler flowmetry over the parietal and cerebellar cortex. Intravenous N omega-nitro-L-arginine (L-NNA; 30 mg/kg) inhibited brain and aortic NOS activity by 67-70%. Topical L-NNA (1 mM) inhibited brain NOS activity by 91-94%, whereas aortic NOS activity remained constant. In contrast, intravenous L-NNA attenuated the hypercapnic CBF rise much more efficiently than topical L-NNA. 7-Nitroindazole, another NOS inhibitor, attenuated endothelial and neuronal NOS activity equally well and inhibited the hypercapnic CBF increase as effectively as L-NNA. Topical L-NNA and 7-nitroindazole abolished local endothelial NOS-dependent vasodilation after 15 min, whereas hypercapnic CBF was only slightly reduced. L-NNA injected into the tissue abolished neuronal NOS-dependent vasodilation, whereas hypercapnic CBF was unchanged. The findings suggest that local NOS activity, whether neuronal or endothelial, is unimportant for the hypercapnic rise of CBF.

NO synthase inhibition modulates NMDA-induced changes in cerebral blood flow and EEG activity

1996 ◽  
Vol 271 (3) ◽  
pp. H990-H995 ◽  
Author(s):  
D. A. Pelligrino ◽  
R. L. Gay ◽  
V. L. Baughman ◽  
Q. Wang
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Excitatory Amino Acid ◽  
Brain Activity ◽  
Treatment Protocols ◽  
Doppler Flowmetry ◽  
Eeg Activity ◽  
Induced Changes ◽  
Oxide Synthase

The effects of nitric oxide synthase (NOS) inhibition on the cerebral blood flow (CBF) and electroencephalographic (EEG) changes accompanying intravenous administration of the excitatory amino acid receptor agonist, N-methyl-D-aspartate (NMDA), were examined in anesthetized rats. Two NOS inhibition strategies were used: chronic N omega-nitro-L-arginine (L-NNA) administration (100 mg.kg-1.day-1 ip, over 4 days) and acute L-NNA administration (100 mg/kg iv infused over 1 h). In both cases, cortical CBF was continuously monitored on study days using laser-Doppler flowmetry, and EEG was recorded, along with measurements of total EEG power. In all rats, the NMDA was given as a 1-min intravenous infusion (20 mg/kg). During all experiments, arterial pressure was controlled within the autoregulatory range. We compared the results from rats treated chronically with L-NNA or its enantiomer. N omega-nitro-D-arginine. In the acute treatment group, two NMDA infusions were given, separated by 90 min, interposed by a 1-h L-NNA infusion. Control rats received saline in place of the L-NNA. Both L-NNA treatment protocols significantly increased the duration of NMDA-induced alterations in EEG activity, relative to controls. NMDA induced a transient 40-100% increase in cortical CBF that was blocked by acute but not chronic L-NNA administration. These results indicate that 1) under normal circumstances nitric oxide is the principal mediator of NMDA-induced cerebrovasodilation; 2) with chronic NOS inhibition, NMDA-induced vasodilation returns to normal, implying replacement of nitric oxide by other factors; and 3) nitric oxide acts as a negative feedback modulator of NMDA-induced changes in brain activity.

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen

2000 ◽  
Vol 88 (4) ◽  
pp. 1381-1389 ◽  
Author(s):  
Ivan T. Demchenko ◽  
Albert E. Boso ◽  
Thomas J. O'Neill ◽  
Peter B. Bennett ◽  
Claude A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Methyl Ester ◽  
No Production ◽  
No Donors ◽  
Mk 801 ◽  
Neuronal Excitation ◽  
Synthase Inhibitor ◽  
Electroencephalogram Eeg

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO2 exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO2, but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.

scholarly journals Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

2003 ◽  
Vol 111 (5) ◽  
pp. 759-759
Author(s):  
Florian P. Limbourg ◽  
Zhihong Huang ◽  
Jean-Christophe Plumier ◽  
Tommaso Simoncini ◽  
Masayuki Fujioka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

scholarly journals The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

1995 ◽  
Vol 15 (5) ◽  
pp. 774-778 ◽  
Author(s):  
Qiong Wang ◽  
Dale A. Pelligrino ◽  
Verna L. Baughman ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Inhibitory Action ◽  
Neuronal Nitric Oxide Synthase ◽  
Muscarinic Agonist ◽  
Doppler Flowmetry ◽  
Nos Inhibitors ◽  
Oxide Synthase

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg−1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19–27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood–brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

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