scholarly journals Nitric oxide: a modulator, but not a mediator, of neurovascular coupling in rat somatosensory cortex

1999 ◽  
Vol 277 (2) ◽  
pp. H799-H811 ◽  
Author(s):  
Ute Lindauer ◽  
Dirk Megow ◽  
Hiroshi Matsuda ◽  
Ulrich Dirnagl
Keyword(s):  
Nitric Oxide ◽  
Somatosensory Cortex ◽  
Soluble Guanylyl Cyclase ◽  
No Synthase ◽  
Neuronal Activation ◽  
Regional Cerebral Blood ◽  
No Donors ◽  
Neuronal Nos ◽  
Rat Somatosensory Cortex

We investigated the role of nitric oxide (NO)/cGMP in the coupling of neuronal activation to regional cerebral blood flow (rCBF) in α-chloralose-anesthetized rats. Whisker deflection (60 s) increased rCBF by 18 ± 3%. NO synthase (NOS) inhibition by N ω-nitro-l-arginine (l-NNA; topically) reduced the rCBF response to 9 ± 4% and resting rCBF to 80 ± 8%. NO donors [ S-nitroso- N-acetylpenicillamine (SNAP; 50 μM), 3-morpholinosydnonimine (10 μM)] or 8-bromoguanosine 3′,5′-cyclic-monophosphate (8-BrcGMP; 100 μM)] restored resting rCBF andl-NNA-induced attenuation of the whisker response in the presence ofl-NNA, whereas the NO-independent vasodilator papaverine (1 mM) had no effect on the whisker response. Basal cGMP levels were decreased to 35% byl-NNA and restored to 65% of control by subsequent SNAP superfusion. Inhibition of neuronal NOS by 7-nitroindazole (7-NI; 40 mg/kg ip) or soluble guanylyl cyclase by 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 100 μM) significantly reduced resting rCBF to 86 ± 8 and 92 ± 10% and whisker rCBF response to 7 ± 4 and 12 ± 3%, respectively. ODQ reduced tissue cGMP to 54%. 8-BrcGMP restored the whisker response in the presence of 7-NI or ODQ. We conclude that NO, produced by neuronal NOS, is a modulator in the coupling of neuronal activation and rCBF in rat somatosensory cortex and that this effect is mainly mediated by cGMP.l-NNA-induced vasomotion was significantly reduced during increased neuronal activity and after restoration of basal NO levels, but not after restoration of cGMP.

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.

Coupling of cerebral blood flow to neuronal activation: role of adenosine and nitric oxide

1994 ◽  
Vol 267 (1) ◽  
pp. H296-H301 ◽  
Author(s):  
U. Dirnagl ◽  
K. Niwa ◽  
U. Lindauer ◽  
A. Villringer
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Receptor Antagonist ◽  
Barrel Cortex ◽  
No Synthase ◽  
Neuronal Activation ◽  
Whisker Stimulation ◽  
Relationship Of

We studied the role and relationship of the putative mediators of coupling of cerebral blood flow (CBF) and neuronal activation, adenosine (Ado) and nitric oxide (NO). Topical brain application over the whisker barrel cortex of anesthetized rats (n = 24) of the Ado receptor antagonist theophylline (Theo, 5 x 10(-5) M) for 30 min reduced the CBF response to deflection of the contralateral whiskers from 17.9 +/- 3.0% of baseline to 10.6 +/- 2.7% (P < 0.05). Coapplication of Theo (5 x 10(-5) M) and the NO synthase blocker N omega-nitro-L-arginine (L-NNA, 10(-3) M) for 30 min led to a further reduction in the CBF response to whisker stimulation to 7.5 +/- 1.3% (P < 0.05 compared with Theo alone). The CBF effect of sodium nitroprusside (10(-5) M) was not affected by Theo-L-NNA coapplication (122 +/- 25 vs. 140 +/- 25%, n = 5). Application of adenosine deaminase (1 U/ml, n = 5) reduced the CBF response to whisker stimulation from 18.2 +/- 0.7 to 10.7 +/- 1.9% (P < 0.05). Superfusion of L-NNA (10(-3) M, 30 min, n = 7) attenuated the CBF response to application of Ado (10(-4) M) from 39.4 +/- 10.4 to 22.9 +/- 10.5% (P < 0.05). N omega-nitro-D-arginine did not affect the CBF response to Ado (n = 5). We conclude that 1) Ado is involved in coupling of CBF to neuronal activation, 2) NO is involved in this response as well, and 3) there is an interaction between the vasodilator pathways of Ado and NO.

scholarly journals Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 94
Author(s):  
Joel Mintz ◽  
Anastasia Vedenko ◽  
Omar Rosete ◽  
Khushi Shah ◽  
Gabriella Goldstein ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Current Knowledge ◽  
Soluble Guanylyl Cyclase ◽  
Phosphodiesterase Inhibitors ◽  
Anticancer Therapy ◽  
The Body ◽  
No Donors ◽  
Preclinical And Clinical Studies ◽  
Sgc Activators

Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.

Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets

2004 ◽  
Vol 286 (1) ◽  
pp. H304-H309 ◽  
Author(s):  
Padmaja Koneru ◽  
Charles W. Leffler
Keyword(s):  
Nitric Oxide ◽  
Cerebrospinal Fluid ◽  
Soluble Guanylyl Cyclase ◽  
Cellular Level ◽  
No Synthase ◽  
Dimanganese Decacarbonyl ◽  
Pial Arterioles ◽  
Cerebral Vasodilation ◽  
Permissive Role

The hypothesis was addressed that CO-induced cerebral vasodilation requires a permissive cGMP signal that can be produced by nitric oxide (NO). Anesthetized piglets were implanted with cranial windows for measurement of pial arteriolar responses to stimuli. Pial arterioles dilated in response to isoproterenol (Iso), sodium nitroprusside (SNP), and CO or the CO-releasing molecule Mn2(CO)10 [dimanganese decacarbonyl (DMDC)]. 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, decreased cerebrospinal fluid (CSF) cGMP and selectively inhibited dilations to SNP and DMDC without affecting the dilation to Iso. However, DMDC did not cause an increase in cortical periarachnoid CSF cGMP concentration. cGMP clamp with a threshold dilator level of 8-bromo-cGMP (10–4 M) and ODQ restored the dilation to DMDC that had been blocked by ODQ alone. Under these conditions, cGMP was present but could not increase. Inhibition of the pial arteriolar dilation to glutamate by N-nitro-l-arginine, which blocks NO synthase, was similar to that by heme oxygenase inhibitors, which block endogenous CO production. The dilation to glutamate, similar to dilation to DMDC, was partially restored by 8-bromo-cGMP and completely restored by SNP (5 × 10–7 M). These data suggest that the permissive role of NO in CO- and glutamate-induced vasodilation involves maintaining the minimum necessary cellular level of cGMP to allow CO to cause dilation independently of increasing cGMP.

Role of neuronal NO synthase in relationship between NO and opioids in hypoxia-induced pial artery dilation

1997 ◽  
Vol 273 (4) ◽  
pp. H1807-H1815 ◽  
Author(s):  
M. J. Wilderman ◽  
W. M. Armstead
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Sodium Salt ◽  
No Synthase ◽  
Cyclic Monophosphate ◽  
Cranial Window ◽  
Pial Artery ◽  
Nos Inhibitor ◽  
Neuronal Nos

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, via the formation of guanosine 3′,5′-cyclic monophosphate (cGMP) and subsequent release of Met-enkephalin and Leu-enkephalin in the newborn pig. In separate studies, these opioids were also observed to elicit NO-dependent pial dilation. The present study was designed to investigate the role of the neuronal isoform of NO synthase (NOS) in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. Tetrodotoxin (10−6 M) attenuated the dilation resulting from hypoxia ([Formula: see text]∼35 mmHg; 25 ± 1 vs. 14 ± 1%). Similarly, 7-nitroindazole, sodium salt (7-NINA, 10−6M), a purported neuronal NOS inhibitor, attenuated hypoxic pial dilation (26 ± 1 vs. 14 ± 2%). Hypoxic dilation was accompanied by elevated cerebrospinal (CSF) cGMP, which was blocked by 7-NINA (433 ± 19 and 983 ± 36 vs. 432 ± 19 and 441 ± 19 fmol/ml for control and hypoxia in absence and presence of 7-NINA, respectively). Additionally, hypoxic dilation was also accompanied by elevated CSF Met-enkephalin, which was attenuated by 7-NINA (1,027 ± 47 and 2,871 ± 134 vs. 779 ± 78 and 1,551 ± 42 pg/ml for control and hypoxia in absence and presence of 7-NINA, respectively). In contrast, Met-enkephalin (10−10, 10−8, and 10−6 M) induced dilation that was unchanged by 7-NINA (7 ± 1, 12 ± 1, and 18 ± 1 vs. 6 ± 1, 10 ± 1, and 17 ± 1%, respectively). N-methyl-d-aspartate (NMDA, 10−8 and 10−6 M), an activator of neuronal NOS, induced pial dilation that was blocked by 7-NINA (10 ± 1 and 20 ± 2 vs. 1 ± 1 and 2 ± 1%, respectively). However, sodium nitroprusside-induced dilation was unchanged by 7-NINA. These data indicate that neuronal NOS contributes to hypoxic pial artery dilation but not to opioid-induced dilation. Furthermore, these data suggest that neuronally derived NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

1994 ◽  
Vol 267 (1) ◽  
pp. R84-R88 ◽  
Author(s):  
M. Huang ◽  
M. L. Leblanc ◽  
R. L. Hester
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Output ◽  
No Synthase ◽  
Before And After ◽  
Regional Hemodynamics ◽  
Autonomic Blockade ◽  
Infusion Of Norepinephrine ◽  
Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

Role of nitric oxide, adenosine,N-methyl-d-aspartate receptors, and neuronal activation in hypoxia-induced pial arteriolar dilation in rats

1995 ◽  
Vol 704 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Dale A. Pelligrino ◽  
Qiong Wang ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Neuronal Activation
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