Spinal cord infarcts during long-term inhibition of nitric oxide synthase in rats.

Blot, Stéphane; Arnal, Jean‐François; Xu, Yichun; Gray, Françoise; Michel, Jeffrey B.

doi:10.1161/01.str.25.8.1666

Cited by 54 publications

(24 citation statements)

References 48 publications

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“…It would appear therefore that the increased constrictor tone which results from acute L-NAME treatment, provides a degree of cerebrovascular protection against hypertension similar to that found with sympathetic stimulation (McKenzie et al, 1979). It is a matter of interest therefore that the protection afforded by acute L-NAME treatment is apparently lost in the course of chronic treatment (Blot et al, 1994), despite the fact that the peripheral effects, as reflected in vasoconstriction-induced hypertension, are maintained. In contrast to these previous studies, we used a parental intraperitoneal (i.p.)…”

Section: Discussionmentioning

confidence: 95%

Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester

Kelly

Ritchie

Collins

1995

British J Pharmacology

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1 Acute treatment with the nitric oxide synthase (NOS) inhibitor N`-nitro-L-arginine methyl ester (L-NAME) produces cerebral oligaemia. The effects of repeated exposure to L-NAME upon cerebral blood flow were examined to determine whether the enhanced NOS inhibition reported following chronic treatment might reduce cerebral perfusion to ischaemic levels.2 Rats were treated with L-NAME (75 mg kg-', i.p.) once daily for 10 days. Local cerebral blood flow and glucose utilization were measured by ['4C]-iodoantipyrine and ['4C]-2-deoxyglucose quantitative autoradiography respectively, either 1 h or 15 h after the last injection. A second group of rats was injected (i.p.) only once with L-NAME, either 1 h or 15 h prior to the measurement procedures. 3 Mean arterial blood pressure (MABP) was significantly increased (+ 35%) 1 h after a single injection of L-NAME. Although the hypertension was reduced 15 h after the injection (+ 13%), MABP remained significantly higher than control. 4 Local cerebral blood flow was significantly decreased 1 h after a single injection of L-NAME (ranging from -45% to -54%), and remained so even after 15 h (-39% to -48%). At neither time-point was there any change in glucose utilization. 5 At 15 h after the final injection of the chronic L-NAME treatment protocol, MABP was significantly elevated from control (+ 58%) and was also significantly higher than at 1 h following a single injection (+ 20%). There was no effect upon the established hypertension when rats treated chronically with L-NAME were challenged with a further injection of the drug and MABP was measured 1 h later, suggesting saturation of NOS inhibition. 6 Although reduced, cerebral blood flow was not significantly different from control when measured 15 h after the last injection of the chronic L-NAME treatment. When rats treated chronically with L-NAME were subjected to a further challenge with the drug, cerebral blood flow was reduced when measured 1 h after the acute injection (ranging from -34% to -41 %). There was however evidence of some attenuation in the response when compared to that measured 1 h after a single injection of L-NAME (ranging from -45% to -54%). Thus, the cerebral circulation shows no evidence of either sustained L-NAME-induced vasoconstriction or saturated NOS inhibition following 10 daily injections of L-NAME. Chronic L-NAME treatment had no effect upon cerebral glucose use. 7 The trend towards re-establishment of cerebrovascular dilator tone and the normalization of cerebral flow-metabolism relationships could explain the lack of any ischaemic damage found in chronically treated rats, but the loss of an extended autoregulatory range afforded by acute L-NAME treatment may be responsible for an increased incidence of stroke.

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Section: Discussionmentioning

confidence: 95%

Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester

Kelly

Ritchie

Collins

1995

British J Pharmacology

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“…At autopsy, spinal cord infarcts were encountered in 90% of these animals; 30% exhibited brain lesions as well. 106 These observations may help to explain the high mortality observed in the chronic NOS inhibition model. 28,51,62 …”

Section: Chronic Nos Inhibition As a Model Of Organ Damagementioning

confidence: 94%

Chronic Nitric Oxide Inhibition Model Six Years On

1998

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Keywords models; cardiovascular diseases; nitric oxide synthase; nitric oxide; blood pressure; reninangiotensin system; vasodilationThe discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists 1,2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by L-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data. Ubiquity and Heterogeneity of NO BiosynthesisNO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates L-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function. 3,4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney 5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS). 6,7 Both eNOS and particularly bNOS are abundant in the kidney, glomeruli, and vasculature as well as in most segments of the tubule, 3,5 and NOS activity in medulla is considerably greater than in cortex. 8 NO generated within the kidney controls the glomerular filtration rate (GFR), total renal and medullary blood flow, pressure natriuresis, epithelial sodium transport, and production of various vasoactive factors including renin. 3-5 eNOS is distributed throughout most parts of the arterial and venous circulation, although there is considerable heterogeneity in the extent to which NO controls tone in regional circulations. 9 Although there is some basal NO release from eNOS, shear stress is the physiologically important regulator of vascular NO production. 3 In the CNS, NO is made in the nucleus tractus solitarius, the paraventricular nucleus, and the ventral medulla and can control sympathetic outflow. 6,10 In addition to central regulation of efferent renal sympathetic nerve activity, there is direct nitrergic innervation to several locations including the renal vasculature. 7

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“…Rats of both strains were randomly divided into two groups: (1) a control group (BN n = 20, Fischer n = 25); and (2) a group receiving L-NAME (BN n = 21, Fischer n = 26) at the dose of 50 mg/kg per d for 30 d in the drinking water (1). Another group of Fischer rats received both L-NAME and losartan (25 mg/kg, 30 d; MSD-Chibret laboratory, Paris, France; n = 10).…”

Section: Animalsmentioning

confidence: 99%

“…Chronic blockade of nitric oxide (NO) production by administration of L-NAME is a well-established model of hypertension in rats, in which animals develop an intensive molecular and cellular response in the arterial wall leading to a significantly reduced survival rate (1,2).…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension

Delbosc

Haloui

Louedec

et al. 2008

Mol Med

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INTRODUCTIONHypertension is a well-recognized risk factor for vascular diseases. Although there is no need for biomarkers to assess blood pressure, markers of vascular remodeling in response to high blood pressure would be of interest to evaluate arterial damage before the onset of clinical complications.Chronic blockade of nitric oxide (NO) production by administration of L-NAME is a well-established model of hypertension in rats, in which animals develop an intensive molecular and cellular response in the arterial wall leading to a significantly reduced survival rate (1,2).To explore new potential markers of the arterial wall response to L-NAME-induced hypertension, we used SELDI-TOF mass spectrometry technology, a differential proteomic approach allowing assessment of the differences in abundance of various proteins between different experimental and biological conditions (3-5). In a previous, unpublished study, we showed that survival rates of Brown Norway (BN) and Fischer rat strains differ significantly after L-NAME administration. BN survival was 80% after 90 d, whereas all Fischer rats had died by this time. In the present study, we thus selected these two rat strains with different susceptibilities to L-NAME-induced hypertension for identifying new potential biomarkers of hypertension and endothelial dysfunction-induced arterial wall remodeling. We also used a second model of hypertension (renovascular 2 kidney-1 clip [2K-1C] in which renin secretion is increased) (6) to validate the biomarkers identified as being specific for hypertensive pathology. We used the SELDI-TOF-MS approach to compare the profiles of proteins released from the arterial wall of hypertensive, compared with normotensive, rats.We report differential susceptibility of Fischer and BN rats to L-NAME administration and we show that hypertension and the pattern of secreted aortic proteins provides evidence of this differential susceptibility. We have detected by SELDI-TOF MS four proteins released by the aortas of hypertensive Fischer rats that could be linked to the pathological vascular remodeling observed in this model of hypertension. Losartan, an angiotensin II-type I receptor (AT1) Hypertension represents one of the main risk factors for vascular diseases. Genetic susceptibility may influence the rate of its development and the associated vascular remodeling. To explore markers of hypertension-related morbidity, we have used surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry to study changes in proteins released by the aorta of two rat strains with different susceptibilities to hypertension. Fischer and Brown Norway (BN) rats were divided into a control group and a group receiving low-dose N(Ω)-nitro-L-arginine methyl ester (L-NAME), a hypertensive drug, interfering with endothelial function. In spite of a significant elevation of blood pressure in both strains in response to L-NAME, BN rats exhibited a lower vascular remodeling in response to hypertension. Proteomic analysis of secreted a...

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Spinal cord infarcts during long-term inhibition of nitric oxide synthase in rats.

Cited by 54 publications

References 48 publications

Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester

Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester

Chronic Nitric Oxide Inhibition Model Six Years On

Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension

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Spinal cord infarcts during long-term inhibition of nitric oxide synthase in rats.

Cited by 54 publications

References 48 publications

Cerebrovascular consequences of repeated exposure to NG‐nitro‐L‐arginine methyl ester

Cerebrovascular consequences of repeated exposure to NG‐nitro‐L‐arginine methyl ester

Chronic Nitric Oxide Inhibition Model Six Years On

Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension

Contact Info

Product

Resources

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Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester

Cerebrovascular consequences of repeated exposure to N^G‐nitro‐L‐arginine methyl ester