scholarly journals Blockade of Nitric Oxide Synthesis in Rats Strongly Attenuates the CBF Response to Extracellular Acidosis

1993 ◽  
Vol 13 (3) ◽  
pp. 535-539 ◽  
Author(s):  
Kiyoshi Niwa ◽  
Ute Lindauer ◽  
Arno Villringer ◽  
Ulrich Dirnagl
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthesis ◽  
Cerebral Vasculature ◽  
Regional Cerebral Blood ◽  
Extracellular Acidification ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Extracellular Acidosis ◽  
First Time

We tested the hypothesis that the CBF response to extracellular acidosis is mediated by nitric oxide (NO). A closed cranial window, superfused with artificial CSF (aCSF), was implanted over the parietal cortex in anesthetized and ventilated Wistar rats. Regional cerebral blood flow (rCBF) was measured continuously with laser-Doppler flowmetry (LDF). The reaction of rCBF to hypercapnia (Paco2 from 30.5 ± 1.8 to 61.3 ± 5.8 mm Hg by adding CO2 to the inspiratory gas) was 2.9 ± 1.4%/mm Hg, and the reaction of rCBF to H+ (superfusion of acidic aCSF, pH 7.07 ± 0.05) was 101.7 ± 24.7%/pH unit. The regional NO synthase (NOS) activity was blocked by superfusing aCSF containing 10−3 M Nω-nitro-L-arginine (L-NA, n = 10). After 30 min of L-NA superfusion, rCBF was reduced to 80.1 ± 6.5% of baseline, and the rCBF responses to hypercapnia (Paco2 from 30.9 ± 2.9 to 58.8 ± 7.7 mm Hg) and extracellular acidosis (aCSF pH 7.08 ± 0.06) were reduced to 0.8 ± 1.1%/ mm Hg and 10.1 ± 23.0%/pH unit, respectively (both p < 0.001). This effect was stereospecific since aCSF containing 10−3 M Nω-nitro-D-arginine affected neither baseline rCBF nor the response to H+ ( n = 5). The NOS blockade did not affect the vasodilatation by the NO donor sodium nitroprusside ( n = 5, 114.3 ± 25.1% before vs. 130.2 ± 24.7% after NOS blockade). The results confirm the involvement of NO in the CBF reaction to hypercapnia and demonstrate for the first time that NOS blockade also strongly attenuates the H+ response of the cerebral vasculature. We speculate that extracellular acidification triggers the production of NO.

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 Nitric Oxide Synthesis and Regional Cerebral Blood Flow Responses to Hypercapnia and Hypoxia in the Rat

1993 ◽  
Vol 13 (1) ◽  
pp. 80-87 ◽  
Author(s):  
D. A. Pelligrino ◽  
H. M. Koenig ◽  
R. F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
No Synthase ◽  
Nitric Oxide Synthesis ◽  
Cerebral Vasculature ◽  
Regional Cerebral Blood ◽  
Generating Capacity ◽  
Baseline Values ◽  
The Brain ◽  
Hyperemic Response

The role of nitric oxide (NO) synthesis in the cerebral hyperemic responses to hypercapnia and hypoxia was investigated in anesthetized rats. Regional CBF (rCBF) measurements were obtained in the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) using radiolabeled microspheres. The rCBF responses to either hypercapnia (Paco2 = 70–80 mm Hg) or hypoxia (Paco2 = 40–45 mm Hg) were compared in rat groups studied in the presence and absence of NO synthase inhibition induced via the intravenous infusion of nitro-l-arginine methyl ester (l-NAME, 3 mg kg−1 min−1). Administration of l-NAME under normocapnic/normoxic conditions produced a 40–60% reduction in baseline rCBF values, indicating the presence of a NO “tone” in the cerebral vasculature. Infusion of l-NAME resulted in a substantial attenuation, in all regions measured, of the rCBF increases that normally accompany hypercapnia. In comparing saline-infused to l-NAME-infused rats, the percentage increases in rCBF (from normocapnic baseline values) were 351% versus 166% (CX), 446% versus 199% (SC), 443% versus 206% (BS), and 483% versus 174% (CE), respectively. The rCBF changes from baseline (ΔrCBF in ml 100 g−1 min−1) were 488 versus 57 (CX), 570 versus 60 (SC), 434 versus 72 (BS), and 393 versus 45 (CE), respectively. These differences were all statistically significant ( p < 0.05). During hypoxia, when compared to rats not given l-NAME, inhibition of NO synthase activity resulted in significantly greater ( p < 0.05) percentage increases in rCBF (from normoxic baseline values) in most regions. The changes in non-l-NAME- vs. l-NAME-infused rats were 156% versus 262% (CX), 181% versus 309% (SC), and 210% versus 462% (BS), respectively. When the ΔrCBF values (from normoxic baseline levels) were compared, the changes were greater in the l-NAME group, but the differences were statistically insignificant. The results of this study indicated that NO synthesis is critically involved in the cerebral hyperemic response to hypercapnia but not hypoxia. In fact, the data obtained in the hypoxic groups suggested that reductions in O2 supply may inhibit the NO-generating capacity in the brain.

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.

Abstract 2305: Endothelin-1 Alters Nitric Oxide-Dependent Cerebrovascular Responses by Modulating The Phosphorylation State of eNOS via Rho Kinase

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Giuseppe Faraco ◽  
Joseph Anrather ◽  
Costantino Iadecola
Keyword(s):  
Nitric Oxide ◽  
Rho Kinase ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Rock Inhibitor ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Phosphorylation State ◽  
Endothelin 1 ◽  
Cranial Window

Hypertension (HTN) alters vital homeostatic mechanisms regulating cerebral blood flow (CBF) and increases the risk of stroke and dementia. HTN exerts some of its damaging effects by counteracting the beneficial vascular actions of nitric oxide (NO). The potent vasoconstrictor endothelin-1 (ET1) has been implicated in the pathogenesis of HTN, but its role in the cerebrovascular effects of HTN is unknown. We examined whether ET1 disrupts CBF regulation. CBF (laser-Doppler flowmetry) was assessed in the somatosensory cortex in anesthetized male C57Bl/6 mice (n=5/group) equipped with a cranial window. ET1 (35 pmol/kg/min; i.v. for 45 min) increased mean arterial pressure from 72±4 to 99±6 mmHg (p<0.05), without reducing resting CBF (p>0.05). However, ET1 attenuated the CBF increase produced by neocortical application of the endothelium-dependent vasodilator acetylcholine (ACh; -37±1%; p<0.05) and by whisker stimulation (-31±1%; p<0.05), responses dependent on NO. The CBF response to adenosine was intact (p>0.05) indicating that ET1 did not act by compromising smooth muscle relaxation. The effects of ET1 were prevented by the ET type A (ET A ) receptor antagonist BQ123 (1µM; p<0.05), by the Rho kinase (ROCK) inhibitor Y27632 (1 µM; p<0.05), but not by the ET B antagonist BQ788 (100nM; p>0.05). ET-1 did not affect the CBF increase produced by the NO donor SNAP and did not increase free radicals, suggesting that ET-1 did not act by reducing NO vasoactivity or bioavailability. However, in brain endothelial cell cultures ET1 (10-100nM) attenuated the NO production induced by ACh (-49±4% at 50nM; p<0.05), an effect blocked by BQ123 and Y27632. ET1 increased eNOS phosphorylation at Thr495, which inhibits eNOS, and reduced phosphorylation at Ser1177, which activates eNOS, effects blocked by Y27632. These findings, collectively, suggest that ET1 alters key regulatory mechanisms of the cerebral circulation by modulating the phosphorylation state of eNOS via ROCK. The resulting downregulation of eNOS activity is responsible for the neurovascular dysregulation induced by ET1. ET A receptors may be a valuable target to counteract the deleterious cerebrovascular actions of HTN.

Effects of regional inhibition of nitric oxide synthesis in intact porcine hearts

1994 ◽  
Vol 266 (4) ◽  
pp. H1516-H1527 ◽  
Author(s):  
K. A. Kirkeboen ◽  
P. A. Naess ◽  
J. Offstad ◽  
A. Ilebekk
Keyword(s):  
Nitric Oxide ◽  
Coronary Flow ◽  
Reactive Hyperemia ◽  
Nitric Oxide Synthesis ◽  
Partial Pressure Of Oxygen ◽  
Doppler Flowmetry ◽  
Flow Response ◽  
Intracoronary Infusion ◽  
Coronary Endothelium

The importance of nitric oxide (NO) in coronary blood flow (CBF) regulation was examined in anesthetized pigs. NO synthesis was inhibited by intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine (L-NNA). L-NMMA (30 mumol/min) reduced CBF (Doppler flowmetry) by 16.3% (13.1-20.2%; P < 0.001) and L-NNA (30 mumol/min) by 16.1% (13.9-18.9%; P < 0.001). During NO blockade, myocardial oxygen consumption was unaltered as an increase in oxygen extraction occurred due to a reduced partial pressure of oxygen and oxygen saturation in blood from the anterior interventricular vein. L-Arginine completely reestablished CBF after giving L-NMMA, but not after giving L-NNA. L-NNA reduced the coronary flow response to ADP by 66-83%, whereas the selected dose of L-NMMA did not affect it. The flow response to adenosine was not affected by either L-NMMA or L-NNA. L-NNA reduced reactive hyperemia after occluding the left anterior descending coronary artery for 10 and 30 s but not for 120 s. Our data show that NO produced in the coronary endothelium plays an important role in CBF regulation in vivo, accounting for approximately 16% of CBF and a major part of the flow response to ADP. NO also contributes to reactive hyperemia after brief, but not longer, ischemic periods.

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.

Effects of Nitric Oxide on Blood Flow and Mucociliary Activity in the Human Nose

1998 ◽  
Vol 107 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Thomas Runer ◽  
Sven Lindberg
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Maximum Increase ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Human Nose

In an animal model, nitric oxide (NO) has been shown to increase mucociliary activity in vivo and ciliary beat frequency in vitro. The aim of the present study was to investigate the effects of NO on blood flow and mucociliary activity in the human nose. The concentration of NO in nasal air was measured with a chemiluminescence technique after nebulizing the NO donor sodium nitroprusside (SNP) at a dose of 3.0 mg into the nose in six volunteers, and was found to increase by 50.1% ± 10.0% (mean ± SEM; p <.001) after the SNP challenge. Blood flow measured by laser Doppler flowmetry increased by 67.3% ± 15.5% (p <.05) after challenge with SNP at 1.0 mg, and by 75.4% ± 18.5% at 3.0 mg (p <.01; n = 6). The higher dose, which produced no subjective side effects, was then used in the mucociliary experiments. The maximum increase in nasal mucociliary activity was 57.2% ± 6.7% at 3.0 mg of SNP (n = 5). The findings support the view that NO regulates mucociliary activity and blood flow in the human nasal mucosa.

scholarly journals The Role of Endothelium and Nitric Oxide in Rat Pial Arteriolar Dilatory Responses to CO2 in vivo

1994 ◽  
Vol 14 (6) ◽  
pp. 944-951 ◽  
Author(s):  
Qiong Wang ◽  
Dale A. Pelligrino ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Topical Application ◽  
Light Exposure ◽  
Endothelial Injury ◽  
Sodium Fluorescein ◽  
Muscarinic Agonist ◽  
No Donor ◽  
Functional Changes ◽  
Cranial Window

Using a closed cranial window system and intravital microscopy/videometry, we studied the rat pial arteriolar (30–60 μm) responses to CO2 before and following a light/dye (L/D) endothelial injury or topical application of the nitric oxide synthase (NOS) inhibitor, nitro-l-arginine (L-NA) or its inactive form, D-NA. L/D treatment consisted of intravenous injection of sodium fluorescein and the illumination (for 90 s) of arteriolar discrete segments on the cortical surface with light from a mercury lamp. Functional changes in pial arteriolar endothelium were characterized by evaluating responses to topical application of acetylcholine (Ach, 5 × 10−4 M) and to intravenous (i.v.) oxotremorine (OXO, a stable blood–brain barrier permeant muscarinic agonist, 1 μg kg−1 min−1). After the L/D injury, dilation to Ach was absent whereas dilations to the NO donor, S-nitrosoacetyl-penicillamine (SNAP, 10−5 M) and to CO2 (5%) were unchanged (Paco2 = 70 mm Hg). Loss of Ach response but intact SNAP response confirmed functional endothelial injury and intact smooth-muscle function. The global endothelium-dependent vasodilation induced by i.v. OXO was markedly attenuated when expanding the L/D injury field from 300 μm to 6 mm in diameter. However, the global vasodilation induced by inhalation of CO2 was still unaffected by this increase in the area of light exposure. This provides evidence that the expanded exposure was capable of impairing global vasodilation resulting from endothelium-dependent stimuli but not from inhalation of CO2. The intact CO2 response despite an endothelial dysfunction suggests that the reported NO dependence of hypercapnia-induced cerebral hyperemia in rats cannot be attributed to an endothelial NO source. Topical suffusion of L-NA (1 m M) for 45–60 min in our preparation blocked the pial arteriolar response to Ach, whereas CO2 and SNAP responses were unaffected. An attenuation (by 50%) of the response to CO2 was achieved if suffusion of L-NA was given for ≥2 h. Suffusion of D-NA, applied in the same manner, did not influence responses to any of the above applications. This demonstrates that there is a NO-dependent component for hypercapnic cerebral vasodilation even at the pial arteriolar level. The strikingly different time-related effect of topical L-NA on the Ach and CO2 responses, together with the lack of effect of endothelial injury on CO2-induced dilation, strongly suggest a nonendothelial source of NO in hypercapnic cerebrovascular dilation.

scholarly journals Artemisinin mimics nitric oxide to reduce adipose weight by targeting mitochondrial complexes

2017 ◽  
Author(s):  
Qian Gao ◽  
Jiang He ◽  
Tao Liao ◽  
Yan-Ping Chen ◽  
Li-Li Tan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Visceral Obesity ◽  
Obese Mouse ◽  
No Donor ◽  
Mitochondrial Dysfunctions ◽  
Mitochondrial Functions ◽  
Mitochondrial Complexes ◽  
First Time

It remains obscure how to medically manage visceral obesity that predisposes metabolic disorders. Here, we show for the first time that a trace amount of artemisinin (0.25 mg/kg) reduces adipose weight in an inflammatory obese mouse model induced by a high-fat diet with lipopolysaccharide (HFD+LPS). HFD+LPS trigger pro-inflammatory responses, upregulate NOS2 expression, elicit potent nitric oxide (NO) burst, and reinforce adipose mitochondrial dysfunctions that facilitate adipogenesis for visceral weight gain. By targeting mitochondrial complexes, artemisinin resembles the NO donor nitroglycerin to exert anti-inflammatory effects, downregulate NOS2 expression, maintain stable NO release, and augment adipose mitochondrial functions that necessitate adipolysis for visceral weight loss. Taken together, artemisinin plays adipose weight-reducing roles by rectifying inflammation-driven mitochondrial dysfunctions.

Sign in / Sign up

Export Citation Format

Share Document