Adenosine deaminase reduces hypoxic and hypercapnic dilatation of rat pial arterioles: evidence for mediation by adenosine

Simpson, Richard E.; Phillis, John W.

doi:10.1016/0006-8993(91)90839-n

Cited by 25 publications

(17 citation statements)

References 13 publications

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“…However, surprisingly little is known about the sequence of events from extracellular acidifica tion to smooth muscle relaxation (Busija and Hei stad, 1984). The involvement of various mediator systems for this response has been discussed, in cluding the prostaglandin system (Sakabe and Siesjo, 1979), protein kinase C (Cortey et aI., 1991), adenosine (Simpson and Phillis, 1991), and, re cently, nitric oxide (Iadecola, 1992a;Dirnagl et aI., 1993;Wang et aI., 1992;Pelligrino et aI., 1993).…”

Section: Discussionmentioning

confidence: 99%

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

Niwa

Lindauer

Villringer

et al. 1993

J Cereb Blood Flow Metab

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Summary: We tested the hypothesis that the CBF re sponse to extracellular acidosis is mediated by nitric ox ide (NO). A closed cranial window, superfused with ar tificial CSF (aCSF), was implanted over the parietal cor tex 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 (P ac02 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+ (super fusion 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 Nw nitro-L-arginine (L-NA, n = 10). After 30 min of L-NA superfusion, rCBF was reduced to 80.1 ± 6.5% of base line, and the rCBF responses to hypercapnia (P ac02 from It is widely accepted that the cerebral arteriolar dilatation in response to increases in blood or tissue P aco2 is mediated by extracellular acidification (Kontos et aI., 1977; Busija aud Heistad, 1984). The means by which H + dilates cerebral vessels is still unclear. Recently, a number of studies have dem onstrated that blockade of brain nitric oxide syn thase (NOS) activity by systemic (Wang et aI., 1992; Pelligrino et aI., 1993) or topical (Dirnagl et aI., 1993;Iadecola, 1992a) administration of argi nine analogues is capable of attenuating or abolish ing the cebrovascular response to hypercapnia. It Received March 28, 1993; final revision received February 24, 1993; accepted March 2, 1993. Address correspondence and reprint requests to Dr. U. 53530.9 ± 2.9 to 58.8 ± 7.7 mm Hg) and extracellular acido sis (aCSF pH 7.08 ± 0.06) were reduced to 0.8 ± 1.1%/ mm Hg and 10.1 ± 23.0%/pH unit, respectively (bothp < 0.001). This effect was stereospecific since aCSF contain ing 10-3 M Nw-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 in volvement 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 vas culature. We speculate that extracellular acidification triggers the production of NO. Key Words: Acidosis Hypercapnia-Laser-Doppler flow-N w-nitro-L arginine-Rat-Sodium nitroprusside.has been shown in vitro that acidosis increases NOS activity (Heinzel et aI., 1992), and extracellu lar acidosis has been linked to increased intracellu lar Ca 2 + availability, possibly activating the Ca 2 + / calmodulin-dependent constitutive NOS (Moncada et aI., 1991;. Therefore, acidosis may be the link from an increase in brain tissue P aco2 to vasodilatation by increased NO pro duction. If this is correct, blockade of brain NOS activity is expected to attenuate the reaction of the cerebral vasculature not only to hypercapnia but also to acidosis.Because i. v. applicat...

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Section: Discussionmentioning

confidence: 99%

“…This may be explained by other cGMP independent mechanisms involved in mediating these responses (f.e. cAMP, Simpson and Phillis, 1991) or the possibility that NOS was not com pletely blocked. No NOS activity measurements af ter brain topical application of arginine analogues are currently available in the literature.…”

Section: Discussionmentioning

confidence: 99%

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

Niwa

Lindauer

Villringer

et al. 1993

J Cereb Blood Flow Metab

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“…Adenosine is a mediator of the metabolic regulation of cerebral blood flow (CBF) and may be a critical factor in this regulation (1)(2)(3). Brain adenosine levels have been shown to rise in the brain interstitial fluid or cerebrospinal fluid (CSF) soon after the onset of total ischemia and hypoxia (4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Brain adenosine levels have been shown to rise in the brain interstitial fluid or cerebrospinal fluid (CSF) soon after the onset of total ischemia and hypoxia (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Adenosine in CSFis thought to be responsible for the cerebral vasodilatation which increases CBF,because a ventriculocisternal perfusion of adenosine causes an increase in CBF (14), and because the instillation of adenosine deaminase or a potent adenosine receptor blocker, 8-phenyltheophylline or theophylline into CSFreduces the hypoxic and hypercapnic dilatation or rat pial arterioles or CBF, respectively (3,15). Adenosineis also a potent neuromodulator of synaptic transmission that may funcion as an endogenous anticonvulsant ( 1 6).…”

Section: Introductionmentioning

confidence: 99%

Adenosine and Neopterin Levels in Cerebrospinal Fluid of Patients with Neurological Disorders.

Yoshida

Une²,

Utatsu

et al. 1999

Intern. Med.

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Wedetermined the cerebrospinal fluid (CSF) levels of adenosine, a mediator of cerebral blood flow regulation, and neopterin, a macrophage-producing compound, in patients with neurological disorders. Compared to control subjects, the adenosine levels were significantly increased in the patients with acute-stage cerebral infarction (n=12, p<0.0001), acute meningitis (n=10, p<0.0001), or amyotrophic lateral sclerosis (ALS, n=12, p<0.05) (Mann-Whitney U-test). The neopterin levels were significantly increased in the 41 patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP,p<0.0001), acute meningitis (p<0.0001), ALS (p<0.05) (Mann-Whitney U-test), or acute-stage cerebral infarction (p<0.005, Student's t-test). In the analysis of 41 HAM/TSPpatients, the neopterin levels were significantly correlated with the cell number and glucose levels in the CSF, and were a sensitive marker of inflammation. Several of the HAM/TSP patients with increased adenosine levels were probably complicated with other diseases. The increased neopterin levels in the HAM/TSPgroup persisted, suggesting that the mononuclear cellular infiltration remained for a long time. (Internal Medicine 38: 133-139, 1989)

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“…induced increases in CBF (Phillis and DeLong, 1987) and enzymatic destruction of adenosine with adenosine deaminase reduced hypercapnia-induced dilations of pial arterioles (Simpson and Phillis, 1991). However, these findings, which predict an increase in adenosine production and/or smooth muscle sensitivity to adenosine in response to CO2-generated hydrogen ions, are at odds with results from cat pial window preparations in which hyper capnia (Gregory et aI., 1980) and local acidosis (Wahl and Kuschinsky, 1977) attenuated the va sodilative action of adenosine.…”

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confidence: 99%

Effect of 2-Chloroadenosine on Cerebrovascular Reactivity to Hypercapnia in Newborn Pig

Gidday

Park

1992

J Cereb Blood Flow Metab

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Summary:The effect of local administration of vasodila tive concentrations of the adenosine receptor agonist 2-chloroadenosine (2-CADO) on the hyperemic responses of the pial and parenchymal microcirculations to graded hypercapnia was determined. The cranial window and brain microdialysis-hydrogen clearance techniques were utilized in two groups of isoflurane-anesthetized newborn pigs to measure changes in pial diameters and local CBF, respectively, in response to graded hypercapnia in the absence and presence of 2-CADO. Progressive size dependent dilations of pial arterioles [small = 41 ± 7 !-Lm (mean ± SD), intermediate = 78 ± 13 !-Lm, and large = 176 ± 57 !-Lm in diameter 1 occurred in response to graded hypercapnia alone (P aco2 = 58 and 98 mm Hg) and to superfusions of 2-CADO 00-5 M) during normocapnia; the magnitude of the dilative response to each of these The mechanism underlying hypercapnic hyper emia in brain is not well understood. A hypercap nia-induced increase in extracellular hydrogen ion concentration is likely to be the initial step of this process (Kontos et aI., 1977), but hydrogen ion may not be the final effector. There is evidence that the hyperemia in newborn animals results from hydro gen ion-stimulated production of vasodilative pros tanoids (Wagerle and Mishra, 1988; Leffler et aI., 1989). The purine metabolite adenosine has also been hypothesized to participate in the mediation of hypercapnic vasodilation, based on studies in which adenosine receptor blockade reduced hypercapnia- Abbreviations used: ANOYA, analysis of variance; 2-CADO, 2-chloroadenosine. 656stimuli was inversely proportional to vessel size. When hypercapnia was induced concomitantly with 2-CADO superfusion, the dilative effects of each stimulus were directly additive. Similarly, local microdialysis infusion of 10-5 M 2-CADO, which doubled CBF during normo capnia, did not affect the hyperemic response of the pa renchymal circulation to graded hypercapnia (P aco2 = 69 and 101 mm Hg). Our findings are consistent with the participation of adenosine in the mediation of cerebral hypercapnic hyperemia. If, however, adenosine is not in volved in this dilative response, our results indicate that concomitant vascular and neuromodulatory actions in duced by adenosine receptor stimulation do not affect the mechanism responsible for the hypercapnic hyperemic response.

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Adenosine deaminase reduces hypoxic and hypercapnic dilatation of rat pial arterioles: evidence for mediation by adenosine

Cited by 25 publications

References 13 publications

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

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

Adenosine and Neopterin Levels in Cerebrospinal Fluid of Patients with Neurological Disorders.

Effect of 2-Chloroadenosine on Cerebrovascular Reactivity to Hypercapnia in Newborn Pig

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