scholarly journals L-NA-Sensitive rCBF Augmentation during Vibrissal Stimulation in Type III Nitric Oxide Synthase Mutant Mice

1996 ◽  
Vol 16 (4) ◽  
pp. 539-541 ◽  
Author(s):  
Cenk Ayata ◽  
Jianya Ma ◽  
Wei Meng ◽  
Paul Huang ◽  
Michael A. Moskowitz
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Regional Cerebral Blood ◽  
Doppler Flowmetry ◽  
Type Iii ◽  
Cranial Window ◽  
Window Technique ◽  
Before And After ◽  
Whisker Stimulation ◽  
Oxide Synthase

Regional cerebral blood flow (rCBF) was studied in type III nitric oxide (NO) synthase (endothelial, eNOS) mutant and wild type mice during mechanical whisker stimulation before and after nitro-L-arginine (L-NA) superfusion using the closed cranial window technique. rCBF increased equally in cortical barrel fields in both strains during stimulation, as measured by laser Doppler-flowmetry, and was inhibited by L-NA superfusion (1 m M) in both groups. Hence, coupling of blood flow and metabolism appears neuronal NOS- (nNOS) but not eNOS-dependent in cortical barrel fields of the mouse.

Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression

1996 ◽  
Vol 270 (3) ◽  
pp. H1085-H1090 ◽  
Author(s):  
J. Ma ◽  
C. Ayata ◽  
P. L. Huang ◽  
M. C. Fishman ◽  
M. A. Moskowitz
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
No Production ◽  
Type I ◽  
Regional Cerebral Blood ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Whisker Stimulation ◽  
Neuronal Nos

The role of nitric oxide (NO) in cerebral blood flow-metabolism coupling was assessed in SV-129 wild-type (WT) and neuronal (type I) NO synthase (NOS) knockout mice (Kn). Regional cerebral blood flow (rCBF; laser-Doppler flowmetry) was measured over the contralateral cortical barrel field during unilateral mechanical vibrissal deflection (2-3 Hz, 60 s) under urethan anesthesia. The rCBF response was similar in WT and Kn and did not differ when recorded over the intact skull or closed cranial window preparations. Whisker stimulation increased rCBF by 41 +/- 8% (maximum) and 27 +/- 6% (mean) in WT (n = 6) and 41 +/- 7% (maximum) and 26 +/- 6% (mean) in Kn (n = 6) when recorded through a closed cranial window. After superfusion with topical N omega-nitro-L-arginine (L-NNA; 1 mM), the rCBF response was inhibited by approximately 45% in WT mice (P < 0.05), whereas there was no inhibition in Kn. Endothelium-dependent relaxation, assessed by pial vessel dilation in response to topical acetylcholine (100 microM) and inhibition by L-NNA (1 mM), was the same in both groups. Our results suggest that 1) endothelial NO production does not mediate the rCBF coupling to neuronal activity in Kn, 2) the inhibitory effect of L-NNA on the rCBF response to whisker stimulation in WT is a consequence of type I (neuronal) NOS inhibition, and 3) NO-independent mechanisms couple rCBF and metabolism during whisker stimulation in mice lacking expression of neuronal NOS.

L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice

1996 ◽  
Vol 271 (4) ◽  
pp. H1717-H1719 ◽  
Author(s):  
J. Ma ◽  
W. Meng ◽  
C. Ayata ◽  
P. L. Huang ◽  
M. C. Fishman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
Mutant Mice ◽  
Type I ◽  
Wild Type ◽  
Regional Cerebral Blood ◽  
Doppler Flowmetry ◽  
Type Iii ◽  
Cranial Window

The effect of NG-nitro-L-arginine (L-NNA) on regional cerebral blood flow (rCBF) response to hypercapnia (5% CO2 inhalation) was studied in urethan-anesthetized wild-type (SV-129) and type III nitric oxide (NO) synthase (NOS)-deficient mice, using laser-Doppler flowmetry and the closed cranial window technique. Resting rCBF during normocapnia decreased by approximately 25% after L-NNA superfusion in wild-type mice only (n = 18), suggesting a role for type III NOS in baseline blood flow. Hypercapnia augmented rCBF approximately 50% in both wild-type and type III NOS mutant mice. L-NNA superfusion (1 mM) inhibited this increase by approximately 60% in both strains. Hence, synthesis of NO by the constitutively expressed type I NOS contributes to blood flow augmentation during hypercapnia.

scholarly journals Nitric Oxide Modulates the CBF Response to Increased Extracellular Potassium

1995 ◽  
Vol 15 (6) ◽  
pp. 914-919 ◽  
Author(s):  
J. P. Dreier ◽  
K. Körner ◽  
A. Görner ◽  
U. Lindauer ◽  
M. Weih ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Extracellular Potassium ◽  
Regional Cerebral Blood ◽  
High Potassium ◽  
Subsequent Increase ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Artificial Cerebrospinal Fluid ◽  
Oxide Synthase

The response of the regional cerebral blood flow (rCBF) to brain topical superfusion of 20 m M K+ was characterized in a closed cranial window preparation in barbiturate anesthetized and ventilated rats; Increasing K+ in the artificial cerebrospinal fluid (ACSF) induced a rCBF elevation (measured by laser–Doppler flowmetry) of +85 ± 37% above baseline (n = 19). This elevation was stable for >3 h with continuous superfusion of increased K+ (n = 5) and partially reversible to a level of + 18 ± 19% above baseline when returning to a physiological K+ concentration. Nitric oxide synthase (NOS) inhibition by brain topical superfusion with Nω-nitro-L-arginine (L-NA) revealed (a) Addition of L-NA to high-potassium ACSF reduced the rCBF increase from + 94 ± 36% to + 21 ± 18% (p ≤ 0.01, n = 7). (b) When L-NA was superfused for 60 min before increasing K+, rCBF decreased to – 17 ± 7% below baseline. Subsequent coapplication of L-NA and increased K+ induced only an elevation of +7 ± 4% above baseline (n = 4). (c) When the NO donor S-nitroso- N-acetylpenicillamine (SNAP) was added during NOS inhibition to restore basal tissue NO levels, the resultant level of rCBF was +28 ± 54% above baseline. Subsequent increase of K+ in the presence of NOS inhibition and SNAP elevated rCBF to + 137 ± 89% above baseline (n = 4). Statistical analysis comparing K+-induced elevation of rCBF (a) without any added drugs, (b) in the presence of NOS inhibition with L-NA, and (c) in the presence of both NOS inhibition and SNAP revealed that K+-induced elevation in the presence of NOS inhibition was significantly reduced (p ≤ 0.05) whereas no statistical difference was found between K+-induced elevation of rCBF without drugs compared with the K+-induced elevation of rCBF in the presence of L-NA and SNAP. We conclude that NO is a modulator of the rCBF elevation to increased extracellular K+ concentration.

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.

scholarly journals Mechanisms of Stroke in Sickle Cell Disease: Sickle Erythrocytes Decrease Cerebral Blood Flow in Rats After Nitric Oxide Synthase Inhibition

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4591-4599 ◽  
Author(s):  
James A. French ◽  
Dermot Kenny ◽  
J. Paul Scott ◽  
Raymond G. Hoffmann ◽  
James D. Wood ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Cell Disease ◽  
Cerebral Microvessels ◽  
Doppler Flowmetry ◽  
Cranial Window

Abstract The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF ) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-ω-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

Nitric Oxide Synthase Inhibition Depresses the Height of the Cerebral Blood Flow–Pressure Autoregulation Curve during Moderate Hypotension

2003 ◽  
Vol 23 (9) ◽  
pp. 1085-1095 ◽  
Author(s):  
Stephen C. Jones ◽  
Kirk A. Easley ◽  
Carol R. Radinsky ◽  
Douglas Chyatte ◽  
Anthony J. Furlan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Lower Limit ◽  
Analysis Of Covariance ◽  
Control Group ◽  
Sprague Dawley ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Time Control ◽  
Oxide Synthase

Variations in the height of the CBF response to hypotension have been described recently in normal animals. The authors evaluated the effects of nitric oxide synthase (NOS) inhibition on these variations in height using laser Doppler flowmetry in 42 anesthetized (halothane and N2O) male Sprague-Dawley rats prepared with a superfused closed cranial window. In four groups (time control, enantiomer control, NOS inhibition, and reinfusion control) exsanguination to MABPs from 100 to 40 mm Hg was used to produce autoregulatory curves. For each curve the lower limit of autoregulation (the MABP at the first decrease in CBF) was identified; the pattern of autoregulation was classified as “peak” (15% increase in %CBF), “classic” (plateau with a decrease at the lower limit of autoregulation), or “none” (15% decrease in %CBF); and the autoregulatory height as the %CBF at 70 mm Hg (%CBF70) was determined. NOS inhibition decreased %CBF70 in the NOS inhibition group (P = 0.014), in the control (combined time and enantiomer control) group (P = 0.015), and in the reinfusion control group (P = 0.025). NOS inhibition via superfusion depressed the autoregulatory pattern (P = 0.02, McNemar test on changes in autoregulatory pattern) compared with control (P = 0.375). Analysis of covariance showed that changes induced by NOS inhibition in the parameters of autoregulatory height are not related to changes in the lower limit, but are strongly (P < 0.001) related to each other. NOS inhibition depressed the autoregulatory pattern, decreasing the seemingly paradoxical increase in CBF as blood pressure decreases. These results suggest that nitric oxide increases CBF near the lower limit and augments the hypotensive portion of the autoregulatory curve.

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.

Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice

2003 ◽  
Vol 285 (1) ◽  
pp. G154-G162 ◽  
Author(s):  
Mia Phillipson ◽  
Johanna Henriksnäs ◽  
Maria Holstad ◽  
Stellan Sandler ◽  
Lena Holm
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Gastric Mucosa ◽  
Rt Pcr ◽  
Mucosal Permeability ◽  
Doppler Flowmetry ◽  
Blood Flow Increase ◽  
Nos Inhibitor ◽  
Oxide Synthase

The role of different isoforms of nitric oxide synthase (NOS) in the gastric mucosal hyperemia, induced by 155 mM luminal hydrochloric acid (pH ≈ 0.8) without a barrier breaker, was investigated. Rats were anesthetized with Inactin (120 mg/kg ip), and mice were anesthetized with Forene (2.2% in 40% oxygen gas at 150 ml/min); the gastric mucosa was exteriorized. Gastric mucosal blood flow was measured with laser-Doppler flowmetry (LDF) in rats treated with Nω-nitro-l-arginine (l-NNA; unspecific NOS inhibitor), l- N6-(1-iminoethyl)lysine [l-NIL; inducible (i) NOS inhibitor], or S-methyl-l-thiocitrulline [SMTC; neuronal (n) NOS inhibitor], 10 mg/kg, followed by 3 mg · kg–1 · h–1 iv, in iNOS-deficient (–/–) and nNOS(–/–) mice. mRNA was isolated from the gastric mucosa in iNOS(–/–) and wild-type (wt) mice, and real-time RT-PCR was performed. The effect of 155 mM acid on gastric mucosal permeability was determined by measuring the clearance of 51Cr-EDTA from blood to lumen. LDF increased by 48 ± 13% during 155 mM HCl luminally, an increase that was abolished by l-NNA, SMTC, or l-NIL. In iNOS wt mice, LDF increased by 33 ± 8% during luminal acid. The blood flow increase was attenuated substantially in iNOS(–/–) mice. RT-PCR revealed iNOS mRNA expression in the gastric mucosa in the iNOS wt groups. The blood flow increase in response to acid was not abolished in nNOS(–/–) mice (nNOS-sufficient mice, 39 ± 18%; heterozygous mice, 25 ± 19%; –/– mice, 19 ± 7%). Mucosal permeability was transiently increased during 155 mM HCl. The results suggest that iNOS is constitutively expressed in the gastric mucosa and is involved in acid-induced hyperemia, suggesting a novel role for iNOS in gastric mucosal protection.

Isoflurane-induced Cerebral Hyperemia Is Partially Mediated by Nitric Oxide and Epoxyeicosatrienoic Acids in Mice In Vivo 

2002 ◽  
Vol 97 (6) ◽  
pp. 1528-1533 ◽  
Author(s):  
Franz Kehl ◽  
Hui Shen ◽  
Carol Moreno ◽  
Neil E. Farber ◽  
Richard J. Roman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Epoxyeicosatrienoic Acids ◽  
Acute Administration ◽  
Doppler Flowmetry ◽  
Cortical Blood Flow ◽  
Oxide Synthase ◽  
Cerebral Cortical Blood Flow

Background Despite intense investigation, the mechanism of isoflurane-induced cerebral hyperemia is unclear. The current study was designed to determine the contributions of neuronal nitric oxide synthase, prostaglandins, and epoxyeicosatrienoic acids to isoflurane-induced cerebral hyperemia. Methods Regional cerebral cortical blood flow was measured with laser Doppler flowmetry during stepwise increases of isoflurane from 0.0 to 1.2, 1.8, and 2.4 vol% end-tidal concentration in alpha-chloralose-urethane-anesthetized, C57BL/6 mice before and 45 min after administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI, 40 mg/kg, intraperitoneal), the cyclooxygenase inhibitor indomethacin (INDO, 10 mg/kg, intravenous), and the cytochrome P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 20 mg/kg, intravenous). Results Isoflurane increased regional cerebral cortical blood flow by 9 +/- 3, 46 +/- 21, and 101 +/- 26% (SD) at 1.2, 1.8, and 2.4 vol%, respectively. The increases in regional cerebral cortical blood flow were significantly (*P &lt; 0.05) smaller after 7-NI (5 +/- 6, 29 +/- 19*, 68 +/- 15%*) or PPOH (4 +/- 8, 27 +/- 17*, 67 +/- 30%*), but not after administration of INDO (4 +/- 4, 33 +/- 18 [NS], 107 +/- 35% [NS]). The effect of combined treatment with 7-NI, PPOH, and INDO was not additive and was equal to that of either 7-NI or PPOH alone (5 +/- 5, 30 +/- 12*, 76 +/- 24%*). Chronic treatment of mice for 5 days with 7-NI (2 x 40 mg/kg, intraperitoneal) produced similar decreases in regional cerebral cortical blood flow as those seen with acute administration. Neither PPOH nor INDO conferred a significant additional block of the hyperemia in these animals. Conclusions Nitric oxide and epoxyeicosatrienoic acids contribute to isoflurane-induced hyperemia. However, only approximately one third of the cerebral hyperemic response to isoflurane is mediated by autacoids. The remaining part of this response appears to be mediated by a direct action of isoflurane on smooth muscle by some yet-unknown mechanism.

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