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Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors sought to develop a model for assessing in vivo regulation of cerebral vasoregulation by nitric oxide (NO), originally described as endothelial-derived relaxing factor, and to use this model to establish the role of NO in the regulation of cerebral blood flow (CBF) in primates. By using regional intraarterial perfusion, the function of NO in cerebral vasoregulation was examined without producing confounding systemic physiological effects. Issues examined were: whether resting vasomotor tone requires NO; whether NO mediates vasodilation during chemoregulation and autoregulation of CBF; and whether there is a relationship between the degree of hypercapnia and hypotension and NO production. Twelve anesthetized (0.5% isoflurane) cynomolgus monkeys were monitored continuously for cortical CBF, PaCO2, and mean arterial pressure (MAP), which were systematically altered to provide control and experimental curves of chemoregulation (CBF vs. PaCO2) and autoregulation (CBF vs. MAP) during continuous intracarotid infusion of 1) saline and 2) an NO synthase inhibitor (NOSI), either L-n-monomethyl arginine or nitro L-arginine. During basal conditions (PaCO2 of 38-42 mm Hg) NOSI infusion of internal carotid artery (ICA) reduced cortical CBF from 62 (saline) to 53 ml/100 g/per minute (p<0.01), although there was no effect on MAP. Increased CBF in response to hypercapnia was completely blocked by ICA NOSI. The difference in regional (r)CBF between ICA saline and NOSI infusion increased linearly with PaCO2 when PaCO2 was greater than 40 mm Hg, indicating a graded relationship of NO production, increasing PaCO2, and increasing CBF. Diminution of CBF with NOSI infusion was reversed by simultaneous ICA infusion of L-arginine, indicating a direct role of NO synthesis in the chemoregulation of CBF. Hypotension and hypertension were induced with trimethaphan camsylate (Arfonad) and phenylephrine at constant PaCO2 (40 +/- 1 mm Hg). Autoregulation in response to changes in MAP from 50 to 140 mm Hg was unaffected by ICA infusion of NOSI. In primates, cerebral vascular tone is modulated in vivo by NO; continuous release of NO is necessary to maintain homeostatic cerebral vasodilation; vasodilation during chemoregulation of CBF is mediated directly by NO production; autoregulatory vasodilation with hypertension is not mediated by NO; and increasing PaCO2 induces increased NO production.
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PMID:Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates. 861 39

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.
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PMID:Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat. 864 7

In this study, we tested the hypothesis that nitric oxide (NO) and adenosine (ADO) are the principal mediators of severe hypoxia-induced vasodilation. In addition, we examined whether activation of N-methyl-D-aspartate (NMDA) receptors and/or perivascular nerves plays a role. A closed cranial window and intravital microscopy system was used to monitor diameter changes in pial arterioles (approximately 40 microns) in anesthetized rats. The relative contributions of ADO, NMDA, NO, and neuronal activation to hypoxic cerebrovasodilation were assessed using the blockers 8-sulfophenyltheophylline (8-SPT), MK-801, nitro-L-arginine methylester (L-NAME), and tetrodotoxin (TTX). Two experimental series were studied. In the first, we tested the effects of NOS inhibition, via topical L-NAME (1 mM), on moderate (PaO2 approximately 46 mmHg) then severe (PaO2 approximately 34 mmHg) hypoxia-induced dilation. To confirm that L-NAME was affecting specifically NO-dependent responses, we also examined, in each experiment, the vasodilatory responses to topical applications of NOS-dependent (adenosine diphosphate (ADP); acetylcholine (ACh)) and -independent (sodium nitroprusside (SNP)) agents, in the presence of L-NAME or, in controls, the presence of D-NAME or no added analogue. In the second series, topical suffusions of ADP, ADO, and NMDA were sequentially applied, followed by 5 min exposure to severe hypoxia (PaO2 approximately 32 mmHg). Following return to normoxia, a suffusion of either 8-SPT (10 microM), MK-801 (10 microM), TTX (1 microM), or 8-SPT+MK-801 was initiated (or, in controls, application of a drug-free suffusate was maintained), and the above sequence repeated. In control, TTX, and 8-SPT+MK-801 experiments, baseline conditions were then restored and hypercapnia (PaCO2 = 70-85 mmHg) was imposed. In the series 1 control groups, moderate and severe hypoxia elicited approximately 20% and 35-40% increases in diameter, respectively. L-NAME attenuated ADP- and ACh-induced dilations, did not alter the arteriolar responses to SNP or moderate hypoxia, but prevented further dilation upon imposition of severe hypoxia. This suggested that 45-50% of the severe hypoxia response was NO-dependent. In series 2, 8-SPT blocked the adenosine response and reduced severe hypoxia-induced dilation by 46%. MK-801 predictably blocked NMDA-induced relaxation and reduced the hypoxic response by 42%. When combined, 8-SPT and MK-801 affected hypoxic vasodilation additively. After TTX, the ADP and ADO responses were normal, but NMDA and hypoxia responses were completely blocked. Hypercapnia-induced dilation was unaffected by TTX or 8-SPT+MK-801. The results imply that severe hypoxia-induced release of NO and ADO, and the accompanying pial arteriolar dilation, are wholly dependent on the capacity to generate action potentials in perivascular nerves. The similarity of the L-NAME and MK-801 effects on hypoxic cerebrovasodilation suggests that the NO-dependency, to a large degree, derives from NMDA receptor activation.
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PMID:Role of nitric oxide, adenosine, N-methyl-D-aspartate receptors, and neuronal activation in hypoxia-induced pial arteriolar dilation in rats. 875 Sep 62

Hypercapnia-induced cerebral vasodilation in the newborn pig is a prostanoid-associated response. In some adult models, hypercapnic cerebral vasodilation is associated with the generation of nitric oxide (NO). Acetylcholine (ACh) produces a NO-dependent cerebral vasodilation in many adult models, but topical ACh is a prostanoid-associated cerebral vasoconstrictor in the newborn pig. We hypothesized that mediators influencing cerebral response can be age dependent. Juvenile domestic pigs were compared with newborn pigs, and pial arteriolar diameters were measured by use of a closed cranial window during hypercapnia and topical ACh (10(-5) M). Four different conditions were explored: control, topical N omega-nitro-L-arginine (L-NNA, 10(-3) M), indomethacin (5 mg/kg i.v.), and both L-NNA and indomethacin. All animals were anesthetized with alpha-chloralose. As opposed to the complete block in the newborn, indomethacin only partially attenuated the hypercapnic cerebral vasodilation in the juvenile pig.L-NNA, which had no effect on the response of the newborn, produced a partial attenuation of the hypercapnic response of the juvenile. The combination of indomethacin and L-NNA blocked the response in both age groups. Topical ACh in both age groups initially produced cerebral vasoconstriction, but, in the juvenile, this was followed by a sustained cerebral vasodilation. Indomethacin blocked the early vasoconstriction in both age groups. L-NNA, which had no effect in the response of the newborn to ACh, blocked the vasodilation seen in the juvenile. The combination of both inhibitors blocked all response to ACh in the juvenile. These data indicate that although the cerebral vascular responses to ACh and hypercapnia are prostanoid associated and NO independent in the newborn pig, NO assumes an increasing role in dilatory responses with development.
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PMID:Age dependence of cerebrovascular response mechanisms in domestic pigs. 877 94

The present study was designed to determine whether relaxations induced by hypercapnia depend upon nitric oxide (NO) derived from the endothelium, and whether NO-mediated relaxant response to electrical and chemical stimulation of vasodilator nerves is modulated by hypercapnia. In canine and monkey cerebral arterial strips contracted with K+, raising the level of CO2 of the aerating gas in the bathing media from 5 to 10% produced a moderate relaxation, together with an increased Pco2 (from 29.8 to 59.3 mm Hg) and a decreased pH (from 7.43 to 7.15). Relaxation was not influenced by endothelium denudation and treatment with NG-nitro-L-arginine. Contractions elicited by the NO synthase inhibitor were attenuated by the removal of the endothelium. Relaxations, caused by transmural electrical stimulation and nicotine, of canine cerebral arterial strips contracted with prostaglandin F2 alpha, were potentiated only slightly by hypercapnia, but the potentiation of the response to exogenous NO (acidified NaNO2) was clearly greater. It is concluded that as far as the arteries used are concerned, hypercapnia does not seem to liberate NO from the endothelium but does potentiate the effect of NO. The reason for lesser potentiation, by hypercapnia, of the response to nitroxidergic nerve stimulation than to NO action may be associated with an impairment by intracellular acidosis of NO synthase activation.
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PMID:Hypercapnia relaxes cerebral arteries and potentiates neurally-induced relaxation. 878 52

We examined the role of acetylcholine and nitric oxide in the increases in cerebrocortical blood flow elicited by stimulation of a region of the basal forebrain from which the major cholinergic projection to the cerebral cortex originates. In halothane-anesthetized rats a 3 x 3 mm area of the parietal cortex was exposed and the site was superfused with Ringer (37 degrees C; pH 7.3-7). Cortical blood flow was monitored at the site of superfusion by laser-Doppler flowmetry. The basal forebrain was stimulated electrically (100 microA; 50 Hz) and stimulated sites were histologically verified at the end of the experiment. With Ringer superfusion (n = 8), basal forebrain stimulation increased neocortical flow by 185 +/- 9% (mean +/- S.E.M.). The flow increase was attenuated (-38 +/- 6%; n = 5) by superfusion with the muscarinic cholinergic antagonist atropine (100 microM). Superfusion with atropine plus the nicotinic antagonist mecamylamine (100 microM) did not attenuate the response further (P > 0.05 from atropine alone; n = 6). Superfusion with the nitric oxide synthase inhibitor nitro-L-arginine, but not with the inactive isomer nitro-D-arginine (n = 6), attenuated the vasodilation in a dose-dependent fashion (-43 +/- 4% at 1 mM; n = 7) and reduced nitric oxide synthase catalytic activity at the site of superfusion by 95 +/- 4%. Co-application of nitro-L-arginine and atropine did not attenuate the vasodilation further (P > 0.05 from nitro-L-arginine alone; n = 6). Administration of the somewhat selective inhibitor of neuronal nitric oxide synthase 7-nitroindazole (50 mg/kg, i.p.) attenuated the increases in flow produced by topical application of N-methyl-D-aspartate (40 microM; n = 5) or by hypercapnia (n = 7), but did not affect the vasodilation produced by basal forebrain stimulation (n = 5) and by topical application of acetylcholine (10 microM; n = 5). 7-nitroindazole reduced constitutive nitric oxide synthase enzymatic activity in forebrain by 72 +/- 3% (n = 8). The data suggest that the neocortical vasodilation elicited by basal forebrain stimulation is, in part, mediated by local release of acetylcholine which, in turn, leads to increased nitric oxide synthesis in endothelial cells.
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PMID:Role of nitric oxide and acetylcholine in neocortical hyperemia elicited by basal forebrain stimulation: evidence for an involvement of endothelial nitric oxide. 884 7

Since endothelium-dependent relaxation of cerebral vessels was first identified in 1980, the pivotal role of the endothelium has become evident not only in dilator responses but also in constrictor responses to various kinds of stimulation. Involvement of endothelium-derived relaxing factors (EDRFs) as well as endothelium-derived contracting factors (EDCFs) has been postulated in such vascular responses. In 1987, one of the EDRFs was determined to be nitric oxide (NO), a simple and very labile molecule, whereas endothelin composed of 21 amino acid residues was identified as one of the EDCFs in 1988. Since 1990, numerous studies which exclusively employed L-arginine analogues as specific NO synthase (NOS) inhibitors, have been undertaken to examine the role of NO in the regulation of the cerebral circulation. However, some conflicting data have emerged. The few points of consensus among the researchers may be summarized as follows: (1) NO, probably produced in the endothelium, plays an important role in the maintenance of the basal cerebral blood flow, (2) NO is not directly involved in hypoxic vasodilation, and (3) NO mediates a functional coupling of metabolism and cerebral blood flow in certain types of neural activation. Hypercapnic vasodilation and autoregulatory responses are still the main topics providing conflicting data with substantial areas of controversy. Besides ensuring appropriate experimental protocols, future studies require the precise monitoring of the degree and cellular specificity (endothelium, perivascular nerve fibers, neurons, etc.) of NOS inhibition in order to obtain concrete and reliable experimental data.
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PMID:Is nitric oxide really important for regulation of the cerebral circulation? Yes or no? 888 64

Because arginine analogues have been reported to block the vasodilator response to hypercapnia, we investigated the effect of nitro-L-arginine (L-NNA) on the dilation of pial arterioles to arterial hypercapnia induced by inhalation of 3, 5, and 7% CO2 in anesthetized cats equipped with cranial windows. L-NNA at 250 microM, but not at lower concentrations, significantly reduced hypercapnia-induced dilation. This effect could be reversed by L-arginine. However, hypercapnic hyperemia is not the result of increased guanosine 3',5'-cyclic monophosphate via the usual NO-mediated activation of guanylate cyclase, because application of LY-83583, which blocks guanylate cyclase, did not alter the vessel response to CO2. L-NNA at 250 microM also abolished the pial arteriolar dilation in response to cromakalim, minoxidil, and pinacidil, three known openers of ATP-sensitive K+ channels, and this effect could be reversed by L-arginine. Application of glyburide, which blocks ATP-sensitive K+ channels, also reduced the response to CO2. Subsequent application of L-NNA in these experiments had no additional effect. Vasodilation induced by sodium nitroprusside and 3-morpholinosydnonimine, two known NO donors, was unaffected by glyburide. NG-monomethyl-L-arginine had effects similar to those of L-NNA in the cat and rat at concentrations as low as 20 microM. Our findings suggest that arginine analogues inhibit hypercapnic vasodilation by blocking ATP-sensitive K+ channels, independently of activation of guanylate cyclase via increased production of NO. Furthermore, the data suggest that ATP-sensitive K+ channels may have an arginine site that influences their function.
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PMID:Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels. 889 45

The effect of NG-nitro-L-arginine (L-NNA) on regional cerebral blood flow (rCBF) response to hypercapnia (5% CO2 inhalation) was studied in urethan-anesthetized wild-type (SV-129) and type III nitric oxide (NO) synthase (NOS)-deficient mice, using laser-Doppler flowmetry and the closed cranial window technique. Resting rCBF during normocapnia decreased by approximately 25% after L-NNA superfusion in wild-type mice only (n = 18), suggesting a role for type III NOS in baseline blood flow. Hypercapnia augmented rCBF approximately 50% in both wild-type and type III NOS mutant mice. L-NNA superfusion (1 mM) inhibited this increase by approximately 60% in both strains. Hence, synthesis of NO by the constitutively expressed type I NOS contributes to blood flow augmentation during hypercapnia.
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PMID:L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice. 889 69

Inhibition of nitric oxide (NO) synthesis attenuates the hypercapnic cerebrovasodilation or the increases in cerebral blood flow (CBF) produced by acetylcholine (ACh), either topically applied or endogenously released in neocortex by stimulation of the basal forebrain cholinergic system. We investigated whether exogenous administration of NO, using NO donors, can reverse the attenuation of these responses by NO synthase (NOS) inhibitors. In halothane-anesthetized, ventilated rats the frontoparietal cortex was exposed and superfused with Ringer. CBF was monitored at the super fusion site by laser-Doppler flowmetry. The basal forebrain was stimulated (100 microA; 50 Hz) with microelectrodes stereotaxically implanted. Superfusion with the NOS inhibitor NG-nitro-L-arginine (L-NNA; 1 mM) reduced resting CBF (-38 +/- 2%; mean +/- SE) and attenuated the vasodilation elicited by hypercapnia (Pco2, 50-60 mmHg; -79 +/- 3%), ACh (10 microM; -83 +/- 7%), or basal forebrain stimulation (-44 +/- 2%) (P < 0.05, analysis of variance and Tukey's test). After L-NNA, topical application of 3-morpholinosydnonimine (SIN-1) (n = 7), S-nitroso-N-acetylpenicillamine (SNAP) (n = 6), or 8-bromoguanosine 3',5'-monophosphate (8-BrcGMP, n = 4) reestablished resting CBF (P > 0.05 from Ringer) and reversed the attenuation of the response to hypercapnia (P > 0.05 from Ringer). However, SIN-1 or SNAP failed to reverse the attenuation of the response to basal forebrain stimulation or topical ACh (P > 0.05 from L-NNA). After L-NNA, the NO-independent vasodilator papaverine (n = 4) reestablished resting CBF (P > 0.05 from Ringer) but failed to restore the hypercapnic vasodilation (P > 0.05 from L-NNA). The attenuation of hypercapnic response by the neuronal NOS inhibitor 7-nitroindazole was counteracted only partially by SIN-1 (n = 4) or 8-BrcGMP (n = 4). The data support the hypothesis that the vasodilation elicited by hypercapnia requires resting levels of NO for its expression, whereas the response to endogenous or exogenous ACh depends on agonist-induced NOS activation. In hypercapnia NO may act as a permissive factor by facilitating the action of other vasodilators, whereas in the vascular response initiated by ACh NO is likely to be the major mediator of smooth muscle relaxation.
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PMID:Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine. 889 92


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