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

The role of cyclic nucleotides and prostanoids in cerebrovascular reactivity to increased carbon dioxide was investigated in anesthetized and artificially ventilated newborn pigs equipped with closed cranial windows. Pial arteriolar diameter was measured, and cortical periarachnoid cerebrospinal fluid (CSF) was collected from beneath the cranial window for determination of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and prostanoids. Progressively increasing arterial PCO2 (PaCO2) from normocapnia (33 +/- 1 mmHg) to hypercapnia (final PaCO2, 83 +/- 2 mmHg) resulted in dose-dependent pial arteriolar dilation and concomitant increases in cAMP, cGMP, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical CSF. N omega-methyl-L-arginine, N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, methylene blue, and LY 83583 did not inhibit cerebral vasodilation or the increases in cortical cAMP/cGMP induced by hypercapnia. Indomethacin abolished the vasodilatory response to hypercapnia and attenuated the hypercapnia-induced increases in cAMP and cGMP. Prostacyclin analogues increased both cAMP and cGMP levels in cortical CSF and induced pial arteriolar dilation (iloprost > carbaprostacyclin). The present data suggest that in newborn pigs cyclic nucleotides are involved in cerebral vasodilation in response to hypercapnia via a prostanoid-dependent mechanism.
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PMID:CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation. 751 62

We sought to determine whether the attenuation of the hypercapnic cerebrovasodilation associated with inhibition of nitric oxide synthase (NOS) can be reversed by exogenous NO. Rats were anesthetized (halothane) and ventilated. Neocortical cerebral blood flow (CBF) was monitored by a laser-Doppler probe. The NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg iv) reduced resting CBF [-36 +/- 5% (SE); P < 0.01, analysis of variance] and attenuated the increase in CBF elicited by hypercapnia (partial pressure of CO2 = 50-60 mmHg) by 66% (P < 0.01). L-NAME reduced forebrain NOS catalytic activity by 64 +/- 3% (n = 10; P < 0.001). After L-NAME, intracarotid infusion of the NO donor 3-morpholinosydnonimine (SIN-1; n = 6) increased resting CBF and reestablished the CBF increase elicited by hypercapnia (P > 0.05 from before L-NAME). Similarly, infusion of the guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-bromo-cGMP (n = 6) reversed the L-NAME-induced attenuation of the hypercapnic cerebrovasodilation. The NO-independent vasodilator papaverine (n = 6) increased resting CBF but did not reverse the attenuation of the CO2 response. SIN-1 did not affect the attenuation of the CO2 response induced by indomethacin (n = 6). The observation that NO donors reverse the L-NAME-induced attenuation of the CO2 response suggests that a basal level of NO is required for the vasodilation to occur. The findings are consistent with the hypothesis that NO is not the final mediator of smooth muscle relaxation in hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SIN-1 reverses attenuation of hypercapnic cerebrovasodilation by nitric oxide synthase inhibitors. 751 10

The relaxant effect of hypercapnia (15% CO2) was studied in isolated circular segments of rat basilar arteries with intact endothelium. The nitric oxide synthase inhibitor nitro-L-arginine (L-NOARG) and the cytosolic guanylate cyclase inhibitor methylene blue (MB), significantly reduced this relaxation by 54% and 70%, respectively. The effect of L-NOARG was completely reversed by L-arginine. Blockade of nerve excitation with tetrodotoxin (TTX) had no affect on the 15% CO2 elicited vasodilatation. Measurements of cGMP in vessel segments showed no significant increase in cGMP content in response to hypercapnia. L-NOARG and MB, but not TTX, significantly reduced the basal cGMP content in cerebral vessels. Adding 1.5% halothane to the incubation medium did not result in a significant increase in cGMP content. Lowering the pH by cumulative application of 0.12 M HCl resulted in relaxation identical to that obtained by lowering the pH with 15% CO2. In vessel segments in which the endothelium had been removed beforehand 15% CO2 induced relaxation that was not different from that seen in vessels with intact endothelium. L-NOARG had no affect in endothelium denuded vessels. The results suggest that high CO2 elicits vasodilatation of isolated rat basilar arteries by a mechanism independent of nitric oxide synthase (NOS) activity. The markedly reduced basal cGMP levels in cerebral vessels by L-NOARG and MB suggest that there exists a basal NO formation in the cerebral vessel wall.
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PMID:Hypercapnic vasodilatation in isolated rat basilar arteries is exerted via low pH and does not involve nitric oxide synthase stimulation or cyclic GMP production. 753 5

Relationships between cyclic nucleotides and cerebrovascular tone were investigated using closed cranial windows in anesthetized newborn pigs. Pial arteriolar diameter was monitored and cerebrospinal fluid (CSF) was collected from beneath the cranial window. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations in CSF were 1,690 +/- 200 and 730 +/- 40 fmol/ml, respectively. Topically applied isozyme-selective and nonselective inhibitors [3-isobutyl-1-methylxanthine (IBMX), theophylline, Ro 201724, dipyridamole, zaprinast, calmidazolium, and W-7] of cyclic nucleotide phosphodiesterases dilated pial arterioles with concomitant increases in cAMP and/or cGMP levels in CSF. Topical application of dibutyryl-cAMP and dibutyryl-cGMP also resulted in pial arteriolar dilation. Ten-minute hypercapnia, which results in pial arteriolar dilation, increased cAMP to 5,240 +/- 900 and cGMP to 1,350 +/- 200 fmol/ml. IBMX and zaprinast potentiated the increases in cAMP and cGMP as well as the cerebrovascular dilation in response to hypercapnia. These data suggest that cyclic nucleotides contribute to regulation of cerebral vascular tone during control conditions. Furthermore, cAMP and/or cGMP appears to be involved in arterial vasodilation in response to hypercapnia in newborn pigs.
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PMID:Cyclic nucleotides and cerebrovascular tone in newborn pigs. 828 36

1. The role of endogenous nitric oxide (NO) generated by neuronal nitric oxide synthase (NOS-1) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-1. 2. Experiments were performed on awake and anaesthetized mutant and wild-type control mice. Respiratory responses to varying levels of inspired oxygen (100, 21 and 12% O2) and carbon dioxide (3 and 5% CO2 balanced oxygen) were analysed. In awake animals, respiration was monitored by body plethysmograph along with oxygen consumption (VO2), CO2 production (VCO2) and body temperature. In anaesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Cyclic 3',5'-guanosine monophosphate (cGMP) levels in the brainstem were analysed by radioimmunoassay as an index of nitric oxide generation. 3. Unanaesthetized mutant mice exhibited greater respiratory responses during 21 and 12% O2 than the wild-type controls. Respiratory responses were associated with significant decreases in oxygen consumption in both groups of mice, and the magnitude of change was greater in mutant than wild-type mice. Changes in CO2 production and body temperature, however, were comparable between both groups of mice. 4. Similar augmentation of respiratory responses during hypoxia was also observed in anaesthetized mutant mice. In addition, five of the fourteen mutant mice displayed periodic oscillations in respiration (brief episodes of increases in respiratory rate and tidal phrenic nerve activity) while breathing 21 and 12% O2, but not during 100% O2. The time interval between the episodes decreased by reducing inspired oxygen from 21 to 12% O2. 5. Changes in arterial blood pressure and arterial blood gases were comparable at any given level of inspired oxygen between both groups of mice, indicating that changes in these variables do not account for the differences in the response to hypoxia. 6. Respiratory responses to brief hyperoxia (Dejours test) and to cyanide, a potent chemoreceptor stimulant, were more pronounced in mutant mice, suggesting augmented peripheral chemoreceptor sensitivity. 7. cGMP levels were elevated in the brainstem during 21 and 12% O2 in wild-type but not in mutant mice, indicating decreased formation of nitric oxide in mutant mice. 8. The magnitude of respiratory responses to hypercapnia (3 and 5% CO2 balanced oxygen) was comparable in both groups of mice in the awake and anaesthetized conditions. 9. These observations suggest that the hypoxic responses were selectively augmented in mutant mice deficient in NOS-1. Peripheral as well as central mechanisms contributed to the altered responses to hypoxia. These results support the idea that nitric oxide generated by NOS-1 is an important physiological modulator of respiration during hypoxia.
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PMID:Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase. 967 81

Current evidence suggests that nitric oxide (NO) and vasodilating prostanoids, possibly via the actions of cGMP and cAMP, play permissive roles in hypercapnic cerebral vasodilation. The present study examined whether cGMP and cAMP have obligatory functions in hypercapnia. Using a closed cranial window in adult rats, we measured pial arteriolar diameters and periarachnoid cerebrospinal fluid (pCSF) cyclic nucleotide levels during normo- and hypercapnia and in the presence or absence of inhibitors of neuronal NO synthase (nNOS) or cyclooxygenase (COX). Also, we measured cGMP and cAMP contents in primary neuronal and astrocyte cultures, at different levels of CO2. Hypercapnia (arterial PCO2 65 mmHg)-induced pial arteriolar dilation was accompanied by 70-80% elevations in pCSF cGMP and cAMP. Inhibition of nNOS with 7-nitroindazole (7-NI) significantly reduced both the CO2-induced arteriolar dilation (by 77%) and the pCSF cGMP and cAMP increases (by 60-70%). Inhibition of COX with indomethacin reduced arteriolar CO2 reactivity (by 83%) and pCSF cyclic nucleotide increases (by 80-100%). In neuronal cultures a transient NO-dependent increase in cGMP, but not cAMP, was seen when the CO2 level was raised from 5 to 14%. No changes were seen in astrocytes. The 7-NI and indomethacin-inhibitable increases in pial arteriolar diameter and cyclic nucleotide production during hypercapnia suggest a link between these two responses. One possible, although not exclusive, interpretation of these findings is that the cyclic nucleotides have an obligatory function in the CO2 response. The large overlap in the abilities of nNOS and COX inhibitors to elicit those effects further implies interactions ("cross talk") between the cGMP and cAMP vasodilating pathways. The in vitro data suggest that hypercapnia stimulates NO production in neurons.
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PMID:Possible obligatory functions of cyclic nucleotides in hypercapnia-induced cerebral vasodilation in adult rats. 995 Aug 48

Previous experimental findings have led to the suggestion that guanosine 3',5'-cyclic monophosphate (cGMP) plays a permissive role in hypercapnic cerebral vasodilation. However, we recently reported that the technique used to reveal a permissive role for cGMP [cGMP repletion in the presence of nitric oxide synthase (NOS) inhibition] created a situation where CO(2) reactivity was normalized but where different mechanisms (i.e., K(+) channels) participated in the response. In the present study, we examined whether that nascent K(+)-channel dependence is related in any way to an increase in the influence of the miconazole-inhibitable cytochrome P-450 epoxygenase pathway. Using intravital microscopy and a closed cranial window system in adult rats, we measured pial arteriolar diameters during normo- and hypercapnia, first in the absence and then in the presence of a neuronal NOS (nNOS) inhibitor [7-nitroindazole (7-NI)]. This was followed by suffusion of a cGMP analog and then cGMP plus miconazole. Separate groups of rats were used to evaluate whether miconazole either alone or in the presence of 8-bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP) or its vehicle (0.1% ethanol) had any effect on CO(2) reactivity and whether miconazole affected K(+)-channel opener-induced dilations. Hypercapnic (arterial PCO(2), congruent with65 mmHg) pial arteriolar dilations, as expected, were reduced by 70-80% with 7-NI and restored with cGMP repletion. CO(2) reactivity was again attenuated after miconazole introduction. Miconazole, with and without 8-BrcGMP, and its vehicle had no influence on pial arteriolar CO(2) reactivity in the absence of nNOS inhibition combined with cGMP repletion. Miconazole alone also did not affect vasodilatory responses to K(+)-channel openers. Thus present results suggest that the nascent K(+)-channel dependence of the hypercapnic response found in our earlier study may be related to increased epoxygenase activity. The specific reasons why the pial arteriolar CO(2) reactivity gains a K(+)-channel and epoxygenase dependence only under conditions of nNOS inhibition and cGMP restoration remain to be identified. These findings again call into question the interpretations applied to data collected in studies evaluating potential permissive actions of cGMP or NO.
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PMID:Miconazole represses CO(2)-induced pial arteriolar dilation only under selected circumstances. 1051 86

We have previously shown that the cAMP signaling pathway controls major aspects of embryonic red blood cell (RBC) function in avian embryos (Glombitza et al, Am J Physiol 271:R973, 1996; and Dragon et al, Am J Physiol 271:R982, 1996) that are important for adaptation of the RBC gas transport properties to the progressive hypercapnia and hypoxia of later stages of avian embryonic development. Data about the ontogeny of receptor-mediated cAMP signaling are lacking. We have analyzed the response of primitive and definitive chick embryo RBC harvested from day 3 to 18 of development towards forskolin, beta-adrenergic, and A2 receptor agonists. The results show a strong response of immature definitive and primitive RBC to adenosine A2 and beta-adrenergic receptor agonists, which is drastically reduced in the last stage of development, coincident with the appearance of mature, transcriptionally inactive RBC. Modulation of cGMP-inhibited phosphodiesterase 3 (PDE3) has a controlling influence on cAMP accumulation in definitive RBC. Under physiological conditions, PDE3 is inhibited due to activation of soluble guanylyl cyclase (sGC). Inhibition of sGC with the specific inhibitor ODQ decreases receptor-mediated stimulation of cAMP production; this effect is reversed by the PDE3 inhibitor milrinone. sGC is acitivated by nitric oxide (NO), but we found no evidence for production of NO by erythrocyte NO-synthase. However, embryonic hemoglobin releases NO in an oxygen-linked manner that may activate guanylyl cyclase.
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PMID:Ontogeny of catecholamine and adenosine receptor-mediated cAMP signaling of embryonic red blood cells: role of cGMP-inhibited phosphodiesterase 3 and hemoglobin. 1059 76

In the present study, the role of nitric oxide (NO) generated by endothelial nitric oxide synthase (NOS-3) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-3. Experiments were performed on awake and anesthetized mutant and wild-type (WT) control mice. Respiratory responses to 100, 21, and 12% O(2) and 3 and 5% CO(2)-balance O(2) were analyzed. In awake animals, respiration was monitored by body plethysmography along with O(2) consumption (VO(2)) and CO(2) production (VCO(2)). In anesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Under both experimental conditions, WT mice responded with greater increases in respiration during 12% O(2) than mutant mice. Respiratory responses to hyperoxic hypercapnia were comparable between both groups of mice. Arterial blood gases, changes in blood pressure, VO(2), and VCO(2) during hypoxia were comparable between both groups of mice. Respiratory responses to cyanide and brief hyperoxia were attenuated in mutant compared with WT mice, indicating reduced peripheral chemoreceptor sensitivity. cGMP levels in the brain stem during 12% O(2), taken as an index of NO production, were greater in mutant compared with WT mice. These observations demonstrate that NOS-3 mutant mice exhibit selective blunting of the respiratory responses to hypoxia but not to hypercapnia, which in part is due to reduced peripheral chemosensitivity. These results support the idea that NO generated by NOS-3 is an important physiological modulator of respiration during hypoxia.
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PMID:Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3. 1074 47

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(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg x kg(-1) x 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.
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PMID:Compensatory role of NO in cerebral circulation of piglets chronically treated with indomethacin. 1179 49


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