Compensatory role of NO in cerebral circulation of piglets chronically treated with indomethacin

2002 ◽  
Vol 282 (2) ◽  
pp. R400-R410 ◽  
Author(s):  
Yifan Zhang ◽  
C. W. Leffler
Keyword(s):  
Nitric Oxide ◽  
Cerebrospinal Fluid ◽  
Methyl Ester ◽  
Cerebral Circulation ◽  
No Synthase ◽  
Inhibitory Effects ◽  
Circulatory Control ◽  
Pial Arterioles ◽  
Indomethacin Treatment

We hypothesize that inhibitory effects exist between prostanoids and nitric oxide (NO) in their contributions to cerebral circulation. Piglets (1–4 days old) were divided into three chronically treated (6–8 days) groups: control piglets, piglets treated with indomethacin (75 mg/day), and piglets treated with N ω-nitro-l-arginine methyl ester (l-NAME, 100 mg · kg−1 · day−1). Pial arterioles dilated in response to hypercapnia similarly among the three groups (41 ± 4, 40 ± 6, and 45 ± 11%). Cerebrospinal fluid cAMP increased in control piglets, while cGMP increased in indomethacin-treated piglets. l-NAME, but not 7-nitroindazole, inhibited the response to hypercapnia only in indomethacin-treated piglets (40 ± 6 vs. 17 ± 5%). Topical sodium nitroprusside or iloprost restored dilation in response to hypercapnia. Similar results were obtained when the dilator was bradykinin. Pial arterioles of control and l-NAME-treated piglets constricted in response to ACh (−24 ± 3%). However, those of indomethacin-treated piglets dilated in response to ACh (15 ± 2%). This dilation was inhibited by l-NAME. NO synthase activity, but not endothelial NO synthase expression, increased after chronic indomethacin treatment. These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets.

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 NO in goat basal cerebral circulation and after vasodilatation to hypercapnia or brief ischemias

1993 ◽  
Vol 265 (6) ◽  
pp. R1410-R1415 ◽  
Author(s):  
G. Dieguez ◽  
J. L. Garcia ◽  
N. Fernandez ◽  
A. L. Garcia-Villalon ◽  
L. Monge ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Methyl Ester ◽  
Cerebral Circulation ◽  
Systemic Arterial Pressure ◽  
Nitric Oxide Production ◽  
Hemodynamic Effects ◽  
Arterial Pco2 ◽  
Different Levels

The role of nitric oxide (NO) in the cerebral circulation under basal conditions and after vasodilatation to hypercapnia or reactive hyperemias was studied in 17 anesthetized goats. The intravenous administration of NG-nitro-L-arginine methyl ester (L-NAME, 3-4 or 8-10 mg/kg), an inhibitor of nitric oxide production, reduced middle cerebral artery (MCA) flow (electromagnetically measured) by 19 and 30% and increased systemic arterial pressure by 21 and 26%, respectively, whereas heart rate did not significantly change; MCA resistance increased by 48 and 86%, respectively. These hemodynamic effects were reversed by L-arginine (200-300 mg/kg iv; 5 goats). Different levels of hypercapnia (PCO2 of 30-35, 40-45, and 55-65 mmHg) (12 goats) produced arterial PCO2-dependent increases in MCA flow that were similar under control and L-NAME treatment. Graded cerebral hyperemia occurred after 5, 10, and 20 s of MCA occlusion in 5 goats, but its magnitude was decreased during L-NAME treatment. It suggests that, in the cerebral circulation, nitric oxide 1) produces a basal vasodilator tone and 2) is probably not involved in the vasodilatation to hypercapnia but may mediate hyperemic responses after short brain ischemias.

Role of nitric oxide in hypoxia-induced colonic dysfunction in the neonatal rat

1997 ◽  
Vol 272 (4) ◽  
pp. G760-G769 ◽  
Author(s):  
J. F. Brown ◽  
B. L. Tepperman
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Protein Content ◽  
No Synthase ◽  
Neonatal Rat ◽  
Myeloperoxidase Activity ◽  
Neonatal Rats ◽  
Colonic Tissue ◽  
Colonic Injury

In addition to being an important mediator in the regulation of intestinal integrity, nitric oxide (NO), when produced in large quantities by the inducible isoform of NO synthase, can also be cytotoxic. The aim of this study was to examine the role of NO in hypoxia-induced colonic injury in neonatal rats. Rats (10-12 days old) were exposed to a hypoxic environment of 14% O2-86% N2 for 30 min. NO synthase activity in colonic tissue was measured via the conversion of L-[14C]arginine to L-[14C]citrulline. Epithelial permeability was assessed by measuring the plasma-to-lumen flux of [3H]mannitol or the luminal protein content of colonic lavage. The role of neutrophils was assessed by pretreatment with antineutrophil serum (200 microl/kg ip) and measurement of tissue myeloperoxidase activity. Hypoxia resulted in an elevation in the activity of the inducible Ca2+-independent isoform of NO synthase in colonic tissue, which was maximal between 4 and 6 h posthypoxia and was associated with an increase in myeloperoxidase activity, [3H]mannitol flux, luminal protein content, and histological damage. These effects were attenuated by pretreatment with dexamethasone or the NO synthase inhibitors aminoguanidine and N(G)-nitro-L-arginine methyl ester, whereas the inactive stereoisomer N(G)-nitro-D-arginine methyl ester was without effect. Pretreatment with antineutrophil serum significantly reduced circulating neutrophils, myeloperoxidase activity, and Ca2+-independent NO synthase activity. These findings demonstrate that hypoxia-induced colonic injury in neonatal rats is associated with elevated NO synthase activity, which is related to an increase in neutrophil infiltration.

5-HT-induced colonic contractions: enteric locus of action and receptor subtypes

1997 ◽  
Vol 273 (1) ◽  
pp. G68-G74 ◽  
Author(s):  
S. Graf ◽  
S. K. Sarna
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Contractile Response ◽  
No Synthase ◽  
Enteric Neurons ◽  
Receptor Subtypes ◽  
Arterial Infusion ◽  
Stimulation Of

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and the receptor subtypes involved in the stimulation of in vivo phasic contractions in the colon were investigated by close intra-arterial infusions in conscious dogs. The contractile response to 5-HT was blocked completely by prior close intra-arterial infusion of atropine and reduced significantly by prior close intra-arterial infusions of tetrodotoxin and hexamethonium. The contractile response was, however, enhanced by the inhibition of nitric oxide (NO) synthase by a prior close intra-arterial infusion of N omega-nitro-L-arginine methyl ester. Prior close intra-arterial infusions of 5-HT1A/5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptor antagonists had no significant effect on the contractile response to 5-HT. By contrast, 5-HT3 receptor antagonist significantly and dose dependently inhibited the contractile response to 5-HT. We conclude that the in vivo phasic contractile response to 5-HT in the colon is mediated mainly by 5-HT3 receptors located on pre- and postsynaptic cholinergic enteric neurons. 5-HT receptors may also be localized on nonadrenergic, noncholinergic inhibitory motoneurons that use NO as a neurotransmitter.

scholarly journals Role of Nitric Oxide in Regulating Cerebrocortical Oxygen Consumption and Blood Flow during Hypercapnia

1994 ◽  
Vol 14 (3) ◽  
pp. 503-509 ◽  
Author(s):  
Ildiko Horvath ◽  
Norbert T. Sandor ◽  
Zoltan Ruttner ◽  
Alan C. McLaughlin
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Oxygen Consumption ◽  
Methyl Ester ◽  
Superior Sagittal Sinus ◽  
No Synthase ◽  
Sagittal Sinus ◽  
No Synthase Inhibitor ◽  
Synthase Inhibitor

The effect of the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) on the response of cerebrocortical oxygen consumption (CMRO2) and blood flow (CBF) to two levels of hypercapnia (Paco2 ∼ 60 mm Hg and Paco2 ∼ 90 mm Hg) was investigated in ketamine-anesthetized rats. CBF was calculated using the Kety–Schmidt approach and CMRO2 was calculated from the product of CBF and the arteriovenous (superior sagittal sinus) difference for oxygen. l-NAME treatment did not have a significant effect on either CMRO2 or CBE under normocapnic conditions but inhibited the hypercapnic increase of CMRO2 and the hypercapnic increase in CBF. These results suggest that NO plays a role in the response of CMRO2 and CBF during hypercapnia and are consistent with the suggestion that at least part of the increase in CBF observed during hypercapnia is coupled to an increase in CMRO2.

Role of tyrosine phosphorylation in the regulation of cerebral vascular tone in newborn pig in vivo

1999 ◽  
Vol 276 (1) ◽  
pp. H185-H193 ◽  
Author(s):  
Helena Parfenova ◽  
Alex Fedinec ◽  
Charles W. Leffler
Keyword(s):  
Arachidonic Acid ◽  
Methyl Ester ◽  
Tyrosine Phosphorylation ◽  
Cerebral Circulation ◽  
No Synthase ◽  
Prostaglandin E ◽  
Phenylarsine Oxide ◽  
Newborn Pigs

The role of tyrosine phosphorylation was investigated using protein tyrosine phosphatase inhibitors in newborn pigs equipped with a cranial window in vivo. We tested the hypothesis that cyclooxygenase and nitric oxide (NO) synthase are physiological targets for tyrosine phosphorylation in cerebral circulation. Phenylarsine oxide dilated pial arterioles and increased prostacyclin and prostaglandin E2 in cortical periarachnoid fluid; these responses were inhibited by indomethacin. N ω-nitro-l-arginine methyl ester (l-NAME) and N ω-nitro-l-arginine (l-NNA) inhibited the vasodilation to phenylarsine oxide; the effects of NO synthase inhibitors and indomethacin were additive. Cyclooxygenase-mediated vascular responses were assessed using topical application of arachidonic acid. Phenylarsine oxide and sodium orthovanadata potentiated vasodilation and prostanoid synthesis in response to arachidonic acid. N ω-nitro-l-arginine methyl ester and N ω-nitrol-arginine did not affect vasodilation or prostanoid production in response to arachidonic acid, indicating no cross talk between cyclooxygenase and NO synthase. These data indicate that cyclooxygenase and NO synthase are physiological targets for tyrosine phosphorylation in the cerebral circulation of newborn pigs.

Cerebral arteriolar dilation to hypoxia: role of prostanoids

1997 ◽  
Vol 272 (1) ◽  
pp. H418-H424 ◽  
Author(s):  
C. W. Leffler ◽  
H. Parfenova
Keyword(s):  
Cerebrospinal Fluid ◽  
Rapid Decrease ◽  
Primary Mechanism ◽  
Pial Arterioles ◽  
Newborn Pigs ◽  
Cerebral Vasodilation ◽  
Arteriolar Diameter ◽  
Indomethacin Treatment

Experiments addressed the hypothesis that dilator prostanoids contribute to maintenance of low cerebral microvascular tone during hypoxia in the newborn. Anesthetized newborn pigs equipped with closed cranial windows were used to measure responses of pial arterioles (approximately 60 microns) to treatments. Hypoxia (Pao2 approximately equal to 25 mmHg) caused dilation of pial arterioles (approximately 50% increase in diameter). Hypoxia (5 min) caused an increase in cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha concentration from 907 +/- 171 (normoxia) to 1,408 +/- 213 pg/ml (hypoxia). Pretreatment with indomethacin (5 mg/kg) did not affect pial arteriolar dilation to hypoxia. Conversely, indomethacin treatment during hypoxia caused a rapid decrease in arteriolar diameter to nearly the normoxia diameter within 3 min, returning to the original hypoxia diameter by 10 min. Ibuprofen treatment (30 mg/kg) had no effect on pial arteriolar diameter during normoxia or hypoxia, and pretreatment did not alter dilation to hypoxia. However, pretreatment with ibuprofen abolished the constrictor effect of indomethacin given during hypoxia. These data suggest that the primary mechanism by which hypoxia produces cerebral vasodilation does not involve prostanoids, but prostanoids can contribute to cerebral vasodilation in response to hypoxia.

Differential effects of l-NAME on rat venular hydraulic conductivity

2000 ◽  
Vol 279 (4) ◽  
pp. H2017-H2023 ◽  
Author(s):  
Rolando E. Rumbaut ◽  
Jianjie Wang ◽  
Virginia H. Huxley
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Methyl Ester ◽  
Hydraulic Conductivity ◽  
No Synthase ◽  
Vascular Effects ◽  
Nos Inhibitors ◽  
Before And After ◽  
Nos Inhibitor

The role of nitric oxide (NO) in microvascular permeability remains unclear because both increases and decreases in permeability by NO synthase (NOS) inhibitors have been reported. We sought to determine whether blood-borne constituents modify venular permeability responses to the NOS inhibitor N G-nitro-l-arginine methyl ester (l-NAME). We assessed hydraulic conductivity ( L p) of pipette-perfused rat mesenteric venules before and after exposure to 10−4 M l-NAME. In the absence of blood-borne constituents, l-NAME reduced L p by nearly 50% (from a median of 2.4 × 10−7cm · s−1 · cmH2O−1, n = 17, P < 0.001). The reduction in L p by l-NAME was inhibited by a 10-fold molar excess of l-arginine but notd-arginine ( n = 6). In a separate group of venules, blood flow was allowed to resume during exposure tol-NAME. In vessels perfused by blood duringl-NAME exposure, L p increased by 78% (from 1.4 × 10−7cm · s−1 · cmH2O−1, n = 10, P < 0.01). N G-nitro-d-arginine methyl ester did not affect L p in either of the two groups. These data imply that NO has direct vascular effects on permeability that are opposed by secondary changes in permeability mediated by blood-borne constituents.

Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats

Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 723-728
Author(s):  
Takuji Machida ◽  
Akari Inotani ◽  
Saki Shiga ◽  
Shuto Kon ◽  
Takumi Yanada ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Small Intestine ◽  
Methyl Ester ◽  
No Synthase ◽  
Rat Small Intestine ◽  
Combined Administration ◽  
Ileal Tissue

This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. <i>N</i><sup>G</sup>-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.

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.

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