Effects of NG‐nitro‐L‐arginine and L‐arginine on regional cerebral blood flow in the cat.

Kovách, A. G. B.; Szabó, Csaba; Benyó, Zoltán; Csáki, C.; Greenberg, Joel; Reivich, Martin

doi:10.1113/jphysiol.1992.sp019081

Cited by 126 publications

(45 citation statements)

References 37 publications

(65 reference statements)

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“…As L-NAME has proved to be a potent inhibitor of nitric oxide production (Moore et al, 1990;Rees et al, 1990), and the observed effects of this Control substance were reversed by L-arginine, precursor of endothelial nitric oxide synthesis (Ignarro, 1990; al.,1991a), our results suggest that the reduction in cerebral blood flow by L-NAME is due to decreases in basal nitric oxide production and, consequently, to inhibition of nitric oxide-mediated basal vasodilator tone in the cerebral vasculature under normal conditions. This is in line with observations by others in the cerebral blood flow of anaesthetized animals (Gardiner et al, 1991b;Kovach et al,1992;Kozniewska et al, 1992;Pellegrino et al, 1992) and supports the idea that an important basal vasodilator tone mediated by nitric oxide is present in the cerebral circulation as in other vascular beds (Moncada et al, 1991a). Systemic hypertension and bradycardia have been previously observed with nitric oxide inhibitors (Moncada & Higgs, 1990).…”

Section: Discussionsupporting

confidence: 79%

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Fernández

Garcia

Garcı́a-Villalón

et al. 1993

British J Pharmacology

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1 The role of nitric oxide in the cerebral circulation under basal conditions and after vasodilator stimulation was studied in instrumented, conscious goats, by examining the action of inhibiting endogenous nitric oxide production with N0-nitro-L-arginine methyl ester (L-NAME). 2 In 6 unanaesthetized goats, blood flow to one brain hemisphere (electromagnetically measured), systemic arterial blood pressure and heart rate were continuously recorded. L-NAME (35 mg kg-' by i.v. bolus) decreased resting cerebral blood flow by 43 ± 3%, increased mean arterial pressure by 21 ± 2%, and decreased heart rate by 41 ± 2%; cerebrovascular resistance increased by 114 ± 13% (P<0.01); the immediate addition of i.v. infusion of L-NAME (0.15-0.20 mg kg-' during 60-80 min) did not significantly modify these effects. Cerebral blood flow recovered at 72 h, arterial pressure and cerebrovascular resistance at 48 h, and heart rate at 6 days after L-NAME treatment. 3 A second treatment with L-NAME scheduled as above reproduced the immediate haemodynamic effects of the first treatment, which (except bradycardia) reversed with L-arginine (200-300 mg kg-' by i.v. bolus).4 Acetylcholine (0.01-0.3pg), sodium nitroprusside (3-100 g) and diazoxide (0.3-9mg), injected into the cerebral circulation of 5 conscious goats, produced dose-dependent increases in cerebral blood flow, and decreases in cerebrovascular resistance; sodium nitroprusside (30 and lOO1ig) also caused hypotension and tachycardia. 5 The reduction in cerebrovascular resistance from resting levels (in absolute values) to lower doses, but not to the highest dose, of acetylcholine was diminished, to sodium nitroprusside was increased, and to diazoxide was unaffected after L-NAME, compared to control conditions. The effects on cerebrovascular resistance to acetycholine normalized within 24 h and to sodium nitroprusside within 48 h after L-NAME treatment. 6 This study provides information about the evolution of the changes in cerebral blood flow and cerebrovascular reactivity after inhibition of endogenous nitric oxide in conscious animals. The results suggest: (a) endogenous nitric oxide is involved in regulation of the cerebral circulation by producing a resting vasodilator tone, (b) the cerebral vasodilatation to acetylcholine is mediated, at least in part, by nitric oxide release, and (c) inhibition of nitric oxide production induces supersensitivity of cerebral vasculature to nitrovasodilators.

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Section: Discussionsupporting

confidence: 79%

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Fernández

Garcia

Garcı́a-Villalón

et al. 1993

British J Pharmacology

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“…2A and B). This observation is consistent with our previous report in cats (Kovách et al, 1992) and indicates that L-arginine availability is not a rate-limiting factor of the resting NO production. L-Arginine, however, was shown to reverse L-NAME-induced cerebrovascular NOS-inhibition in a previous study (Sándor et al, 1994), and therefore we analyzed its effect also in chronically L-NAME pretreated animals (n=12).…”

Section: Resultssupporting

confidence: 83%

“…This conclusion is not obvious since the constitutive NOS activity of the hypothalamus is only reduced by approximately 90% during chronic oral L-NAME treatment (Benyó et al, 1995). Taken into account that in case of diminished NO production the cerebrovascular reactivity to NO increases (Kovách et al, 1992;Moncada et al, 1991), the remnant 10% NOS activity could contribute significantly to the maintenance of the cerebral blood flow. Indeed, acute L-NAME treatment was shown to reduce the blood flow in the neocortex, hippocampus and striatum of rats subjected to chronic NOS blockade (Kelly et al, 1995), indicating that the remnant NO production contributes to the maintenance of the blood flow in these brain regions.…”

Section: Discussionmentioning

confidence: 91%

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

et al. 2007

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The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous L-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute L-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous L-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI 2 , PGE 2 and PGD 2 ) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA 2 and PGF 2α ) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic L-NAME treatment. Although urinary excretion of PGI 2 and PGE 2 metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

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“…NO synthase inhibition results in a significant re duction of the steady-state rCBF values not only after L-NAME administration, but also following � -nitro-L-arginine treatment, as was shown by Kovach et al (1992) in the same species under the same anesthesia. The question arises of whether the regional differences in the steady-state rCBF and rSBF values following L-NAME administration may determine in some way the extent of the re duction of the CO2 responsiveness in those regions.…”

Section: Discussionmentioning

confidence: 73%

Major Role of Nitric Oxide in the Mediation of Regional CO₂ Responsiveness of the Cerebral and Spinal Cord Vessels of the Cat

Sándor

Komjáti

Reivich

et al. 1994

J Cereb Blood Flow Metab

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Summary: The role of nitric oxide (NO) in the mediation of cerebrovascular CO2 responsiveness was studied in 10 distinct brain and spinal cord regions of the anesthetized, ventilated, temperature-controlled, normoxic cat. Re gional CBF was measured with 15-f.Lm radiolabeled mi crospheres in hypocapnic, normocapnic, and hypercap nic conditions. CO2 responsiveness of each region was determined from the equation of the best-fit regression lines to the obtained flow values. The effect of altered endothelial and/or neuronal NO synthesis on CO2 respon siveness was studied following either selective blockade of the NO synthase enzyme by N"'-nitro-L-arginine methyl ester (L-NAME; 3 or 30 mg/kg i.v.) or simulta neous administration of L-NAME (3 mg/kg i.v.) and a large dose of the NO precursor L-arginine (30 mg/kg i.v.). it functions as a small, lipophilic, chemically unsta ble molecule, sparingly soluble in aqueous medium, which rapidly diffuses through all types of biologi cal membrane barriers (Ignarro, 1989(Ignarro, , 1990 Abbreviations used: L-NAME, NW-nitro-L-arginine methyl es ter; rCBF, regional CBF; rSBF, regional spinal cord blood flow. 49in a significant reduction of the steady-state regional blood flow values and in an almost complete abolition of the CO2 sensitivity in each region studied. Changes of the basal flow values as well as the reduction of the regional CO2 sensitivity were dose dependent. Hypothalamic, sensorimotor cortical, and cerebellar regions were the ar eas most sensitive to the NO blockade. Impaired CO2 responsiveness following NO synthase inhibition, how ever, was reversed in these regions by simultaneous ad ministration of a large dose of intravenously injected L-ar ginine. These findings suggest a major role of nitric oxide in the mediation of regional cerebrovascular CO2 respon siveness in cats. Key Words: L-Arginine-Cerebral blood flow-C02 responsiveness-Endothelium-derived relax ing factor-Nitric oxide-Nitric oxide synthase-Spinal cord blood flow. 1990) and astrocytes (Murphy et aI., 1990).Although NO is a very small and highly diffusible molecule, the extent of its transcellular communi cation is limited by the fact that it has an ultra-short half-life (estimated to be <5 s in biological tissues), and its diffusion distance during this time is in the range of 50-100 /.Lm. The responses to NO, there fore, are likely to be regional, localized responses (Ignarro, 1990). In the present study, it was hypoth esized that nitric oxide might mediate one of the most characteristic reactions of the cerebrovascular

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Effects of NG‐nitro‐L‐arginine and L‐arginine on regional cerebral blood flow in the cat.

Cited by 126 publications

References 37 publications

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

Major Role of Nitric Oxide in the Mediation of Regional CO₂ Responsiveness of the Cerebral and Spinal Cord Vessels of the Cat

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Effects of NG‐nitro‐L‐arginine and L‐arginine on regional cerebral blood flow in the cat.

Cited by 126 publications

References 37 publications

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Cerebral blood flow and cerebrovascular reactivity after inhibition of nitric oxide synthesis in conscious goats

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

Major Role of Nitric Oxide in the Mediation of Regional CO2 Responsiveness of the Cerebral and Spinal Cord Vessels of the Cat

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Major Role of Nitric Oxide in the Mediation of Regional CO₂ Responsiveness of the Cerebral and Spinal Cord Vessels of the Cat