Gene/Protein Disease Symptom Drug Enzyme Compound
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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 carbonic anhydrase (CNA) in the dynamics of carotid body (CB) function was tested by studying the effects of the membrane-permeable CNA inhibitor methazolamide on the chemosensory responses of the cat CB, perfused and superfused in vitro with cell-free and modified Tyrode solution at 36.5 +/- 0.5 degrees C in the presence of CO2-HCO3- (PO2 = 120 Torr, PCO2 = 32 Torr, pH = 7.40). The bulk of CO2 flow to the CB from the external milieu was overwhelmingly large relative to the metabolic production of CO2 in the CB. Accordingly, the relative contribution of the endogenous CO2 to the CB responses was small. The chemosensory nerve discharges were recorded from the whole desheathed carotid sinus nerve. The responses to acidic hypercapnia (PCO2 = 50-60 Torr, pH = 7.20-7.10), hypoxia (PO2 = 25 and 50 Torr), perfusate flow interruption, and bolus injections of sodium cyanide (20-40 nmol) were tested. To contrast, we also measured the effects of nicotine (2-4 nmol), which may act at sites other than those for O2 and CO2. Methazolamide (30 mg/l) in the perfusate at constant PCO2 and pH reduced the baseline activity and delayed the responses to step changes in PCO2 (and concomitantly pH) and PO2 and to cyanide but not to nicotine. The steady-state responses to these stimuli, measured as differences from control, were reduced, but not significantly. The initial overshoots seen with step changes in both high PCO2 and low PO2 were eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dynamics of carotid body responses in vitro in the presence of CO2-HCO3-: role of carbonic anhydrase. 828 7

The electrometric [Delta]pH method and an in vitro radioisotopic HCO3- dehydration assay were used to demonstrate the presence of true extracellular carbonic anhydrase (CA) activity in the blood of the Pacific spiny dogfish Squalus acanthias. An extracorporeal circulation and stopflow technique were then used to characterise the acid­base disequilibrium in the arterial (postbranchial) blood. During the stopflow period, arterial pH (pHa) decreased by 0.028±0.003 units (mean ± s.e.m., N=27), in contrast to the increase in pHa of 0.029±0.006 units (mean ± s.e.m., N=6) observed in seawater-acclimated rainbow trout Oncorhynchus mykiss under similar conditions. The negative disequilibrium in dogfish blood was abolished by the addition of bovine CA to the circulation, while inhibition by benzolamide of extracellular and gill membrane-bound CA activities reversed the direction of the acid­base disequilibrium such that pHa increased by 0.059±0.016 units (mean ± s.e.m., N=6) during the stopflow period. When the CA activity of red blood cells (rbcs) was additionally inhibited using acetazolamide, the magnitude of the negative disequilibrium was increased significantly to -0.045±0.007 units (mean ± s.e.m., N=6). Blockage of the rbc Cl-/HCO3- exchanger using 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS) also increased the magnitude of the negative disequilibrium, in this case to -0.089±0.008 units (mean ± s.e.m., N=6). Exposure of dogfish to hypercapnia had no effect on the disequilibrium, whereas the disequilibrium was significantly larger under hypoxic conditions, at -0.049±0.008 units (mean ± s.e.m., N=6). The results are interpreted within a framework in which the absence of a positive CO2 excretion disequilibrium in the arterial blood of the spiny dogfish is attributed to the membrane-bound and extracellular CA activities. The negative disequilibrium may arise from the continuation of Cl-/HCO3- exchange in the postbranchial blood and/or the hydration of CO2 added to the plasma postbranchially. Two possible sources of this CO2 are discussed; rbc CO2 production or the admixture of blood having 'low' and 'high' CO2 tensions, i.e. the mixing of postbranchial blood with blood which has bypassed the respiratory exchange surface.
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PMID:Extracellular carbonic anhydrase and an acid-base disequilibrium in the blood of the dogfish Squalus acanthias 931 77

In order to test the hypothesis that carotid body (CB) chemoreception depends on the functions of anion channels and HCO3-/Cl- exchangers, we studied the effects of the anion channel blocker anthracene-9-carboxylic acid (9-ANC), the carbonic anhydrase inhibitor methazolamide, and the HCO3-/Cl- exchanger blocker 4,4 diisothiocyanatostilbene-2-2'disulfonic acid (DIDS) on the chemosensory discharges of cat CB, perfused-superfused in vitro at 36.5 +/- 0.5 degrees C, with a modified Tyrode solution. The chemosensory responses to hypoxia (PO2 approximately 50 Torr), hypercapnia (PCO2 approximately 60 Torr, pH = 7.10), nicotine (2-4 nmol) and NaCN (20-40 nmol) were recorded. 9-ANC (2 microM) and DIDS (10 microM) decreased the chemosensory baseline activity, and eliminated the initial peak responses to hypercapnia and hypoxia and increased the time to achieve it. Methazolamide (0.13 mM) did not alter the effect of 9-ANC. The steady state responses to hypoxia and hypercapnia were not diminished after 9-ANC but DIDS lowered the responses. Responses to NaCN effects were all diminished but those to nicotine were not affected. The results suggest that the functions of anion channels and HCO3-/Cl- exchangers are important for the resting dischargers and for the fast responses to hypoxia and hypercapnia.
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PMID:Anion exchanger and chloride channel in cat carotid body chemotransduction. 968

Acetazolamide, a carbonic anhydrase inhibitor, is used in patients with chronic obstructive pulmonary diseases and central sleep apnoea syndrome and in the prevention and treatment of the symptoms of acute mountain sickness. In these patients, the drug increases minute ventilation (V'E), resulting in an improvement in arterial oxygen saturation. However, the mechanism by which it stimulates ventilation is still under debate. Since hypoxaemia is a frequently observed phenomenon in these patients, the effect of 4 mg x kg(-1) acetazolamide (i.v.) on the ventilatory response to hypercapnia during hypoxaemia (arterial oxygen tension (Pa,O2)=6.8+/-0.8 kPa, mean+/-SD) was investigated in seven anaesthetized cats. The dynamic end-tidal forcing (DEF) technique was used, enabling the relative contributions of the peripheral and central chemoreflex loops to the ventilatory response to a step change in end-tidal carbon dioxide tension, (PET,CO2) to be separated. Acetazolamide reduced the CO2 sensitivities of the peripheral (Sp) and central (Sc) chemoreflex loops from 0.22+/-0.08 to 0.11+/-0.03 L x min(-1) x kPa(-1) (mean+/-SD) (p<0.01) and from 0.74+/-0.32 to 0.40+/-0.10 L x min(-1) x kPa(-1) (p<0.01), respectively. The apnoeic threshold B (x-intercept of the ventilatory CO2 response curve) decreased from 2.88+/-0.97 to 0.95+/-0.92 kPa (p<0.01). The net result was a stimulation of ventilation at PET,CO2 <5 kPa. The effect of acetazolamide is possibly due to a direct effect on the peripheral chemoreceptors as well as to an effect on the cerebral blood flow regulation. Possible clinical implications of these results are discussed.
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PMID:Effect of low-dose acetazolamide on the ventilatory CO2 response during hypoxia in the anaesthetized cat. 987 70

1. At present, CO2 is considered to be the most important factor in regulating cerebral blood flow by modification of the interstitial fluid and extracellular pH, but the mechanism by which hypercapnia produces vasodilation is still controversial. In the present paper we investigated the effect of hypercapnia on carbonic anhydrase (CA) activity. We also studied the combined effects of CO2 with either indomethacin or an L-arginine analogue on CA activity. 2. Nine groups of 12 rabbits each were established. Groups 1-4 were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 20, 60, 120 and 180 min. Group 5 rabbits received 15 mg/kg bodyweight, i.v., indomethacin and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 6 animals were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h and then received indomethacin. Group 7 rabbits received 100 mg/kg bodyweight, i.v., NG-monomethyl-L-arginine (L-NMMA) and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 8 rabbits were ventilated for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2 and were then administered L-NMMA. Group 9 rabbits received L-NMMA treatment concomitant with ventilation for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2. In all groups, the erythrocyte CA activity was measured, as well as PaCO2 before and after ventilation or treatment. 3. The present study shows that CO2 reduces CA I activity down to complete inhibition and antagonizes the activating effects of indomethacin and L-NMMA on this isozyme. Our data prove that nitric oxide- and prostaglandin-induced CA I inhibition is involved in the vasodilation produced by hypercapnia. These results suggest that, due to subsequent pH changes, CA I is directly implicated in the modulation of vascular processes in the organism.
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PMID:Carbonic anhydrase I inhibition by nitric oxide: implications for mediation of the hypercapnia-induced vasodilator response. 1069 35

In situ and in vivo experiments were performed on rainbow trout (Oncorhynchus mykiss) to examine (i) the direct effect of CO(2) on the systemic vasculature and (ii) the influence of internal versus external hypercapnic acidosis on cardiovascular variables including blood pressure, cardiac output and systemic vascular resistance. Results from in situ saline-perfused trunk preparations indicated that CO(2) (0.6, 1.0 or 2.0% CO(2)) elicited a significant vasodilation, but only in the presence of pre-existing humoral adrenergic tone. In the absence of pre-existing vascular tone, CO(2) was without effect on systemic resistance. In contrast, hypercarbia in vivo triggered a statistically significant increase in systemic resistance (approximately 70 %) that was associated with elevated ventral aortic (approximately 42 %) and dorsal aortic (approximately 43 %) blood pressures and with a significant bradycardia (approximately 12 %); cardiac output was not significantly affected. To determine the potential roles of internal versus external chemoreceptors in mediating the cardiovascular responses to hypercarbia, experiments were performed to elevate the endogenous arterial partial pressure of CO(2) (Pa(CO2)) without an accompanying increase in external P(CO2) (Pw(CO2)). In one series, trout were given a bolus injection of the carbonic anhydrase inhibitor acetazolamide (30 mg kg(-1)) to inhibit CO(2) excretion, and thus raise Pa(CO2), 5-7 h prior to being exposed to an acute increase in Pw(CO2) (maximum Pw(CO2)=6.3+/-0.4 mmHg; 1 mmHg=0.133 kPa). Despite a marked increase in Pa(CO2) (approximately 7 mmHg) after injection of acetazolamide, there was no increase in dorsal aortic blood pressure (P(DA)) or systemic resistance (R(S)). The ensuing exposure to hypercarbia, however, significantly increased P(DA) (by approximately 20 %) and R(S) (by approximately 35 %). A second series of experiments used a 5-7 h period of exposure to hyperoxia (Pw(O2)=643+/-16 mmHg) to establish a new, elevated baseline Pa(CO2) (7.8+/-1.1 mmHg) without any change in Pw(CO2). Despite a steadily increasing Pa(CO2) during the 5-7 h of hyperoxia, there was no associated increase in P(DA) or R(S). Ensuing exposure to hypercarbia, however, significantly increased P(DA) (by approximately 20 %) and R(S) (by approximately 150 %). Plasma adrenaline levels were increased significantly during exposure to hypercarbia and, therefore, probably contributed to the accompanying cardiovascular effects. These findings demonstrate that the cardiovascular effects associated with hypercarbia in rainbow trout are unrelated to any direct constrictory effects of CO(2) on the systemic vasculature and are unlikely to be triggered by activation of internally oriented receptors. Instead, the data suggest that the cardiovascular responses associated with hypercarbia are mediated exclusively by externally oriented chemoreceptors.
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PMID:Cardiovascular effects of hypercarbia in rainbow trout (Oncorhynchus mykiss): a role for externally oriented chemoreceptors. 1110 15

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg(-1) I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 +/- 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2 in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 +/- 0.66 vs. 4.07 +/- 1.03 l x min(-1) (mmHg CO2)(-1), P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 +/- 0.92 vs. 1.33 +/- 0.46 l x min(-1) (mmHg CO2)(-1), P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.
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PMID:Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest. 1118 79

When carbonic anhydrase activity decreases, the regional blood flow (rBF) in organs increases as hypercapnia develops. However, the effects of acetazolamide (AZ)-induced vasodilation have not been estimated with respect to vessel size and organs. The aim of this study was to determine the diameter of the capillaries in various organs that respond to inhibition of carbonic anhydrase activity by AZ. White rabbits were anesthetized with urethane and ketamine and infused with AZ. While the systolic blood pressure (SBP), pH, hemoglobin concentration, and base excess did not change, the partial pressure of arterial oxygen (PaO2) increased significantly and the partial pressure of arterial carbon dioxide (PaCO2) decreased significantly with AZ. The rBF was calculated by using 3 different sizes (15, 25, and 50 microm) of colored microspheres (CM). The rBF measured with 15 microm CM in the brain, kidneys, and liver increased in response to AZ, and the rBF in these organs was different with the different sizes of CM. However, the rBF calculated by using the different sizes of CM in the stomach and abdominal muscle did not change after the administration of AZ. The AZ-induced vasodilation occurred in all sizes of vessels in the liver, in the small and medium-sized vessels in kidneys, and in the larger capillaries in the brain.
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PMID:Preferential acetazolamide-induced vasodilation based on vessel size and organ: confirmation of peripheral vasodilation with use of colored microspheres. 1151 88

Although neutrophils are a critical component of the inflammatory process, their functional regulation is incompletely understood. Of note, although pCO2 varies physiologically and pathologically in the neutrophilic milieu, its affect on neutrophil biological processes is unresolved. We demonstrate here that neutrophils respond to hypo- and hypercarbia, (0.04% and 10%) by increasing and decreasing, respectively, intracellular oxidant production (basally and in response to opsonized Escherichia coli and phorbol esters). Further, hypo- and hypercarbia increase and decrease, respectively, the release of IL-8 from LPS-stimulated cells; both effects are attenuated by the carbonic anhydrase inhibitor, acetazolamide. Anion exchange did not restore pH(i) under hypocarbic conditions, however partial restoration of pH(i) under hypercarbic conditions was achieved by Na+/H+ exchange and vacuolar ATPases. Abrogation of pCO2-induced changes in pH(i) prevented hypocarbia-induced generation of reactive oxidant species. These observations suggest that CO2 modifies neutrophil activity significantly by altering pH(i).
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PMID:Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. 1192 46

The medullary raphe nuclei contain putative central respiratory chemoreceptor neurones that are highly sensitive to acidosis. To define the primary stimulus for chemosensitivity in these neurones, the response to hypercapnic acidosis was quantified and compared with the response to independent changes in P(CO2) and extracellular pH (pH(o)). Neurones from the ventromedial medulla of neonatal rats (P0-P2) were dissociated and maintained in tissue culture for long enough to develop a mature response (up to 70 days). Perforated patch clamp recordings were used to record membrane potential and firing rate while changes were made in pH(o), P(CO2) and/or [NaHCO(3)](o) from baseline values of 7.4, 5 % and 26 mM, respectively. Hypercapnic acidosis (P(CO2) 9 %; pH(o) 7.17) induced an increase in firing rate to 285 % of control in one subset of neurones ('stimulated neurones') and induced a decrease in firing rate to 21 % of control in a different subset of neurones ('inhibited neurones'). Isocapnic acidosis (pH(o) 7.16; [NaHCO(3)](o) 15 mM) induced an increase in firing rate of stimulated neurones to 309 % of control, and a decrease in firing rate of inhibited neurones to 38 % of control. In a different group of neurones, isohydric hypercapnia (9 % P(CO2); [NaHCO(3)](o) 40 mM) induced an increase in firing rate of stimulated neurones by the same amount (to 384 % of control) as in response to hypercapnic acidosis (to 327 % of control). Inhibited neurones also responded to isohydric hypercapnia in the same way as they did to hypercapnic acidosis. In Hepes-buffered solution, both types of neurone responded to changes in pH(o) in the same way as they responded to changes in pH(o) in bicarbonate-buffered Ringer solution. It has previously been shown that all acidosis-stimulated neurones in the medullary raphe are immunoreactive for tryptophan hydroxylase (TpOH-ir). Here it was found that TpOH-ir neurones in the medullary raphe were immunoreactive for carbonic anhydrase type II and type IV (CA II and CA IV). However, CA immunoreactivity was also common in neurones of the hypoglossal motor nucleus, inferior olive, hippocampus and cerebellum, indicating that its presence is not uniquely associated with chemosensitive neurones. In addition, under the conditions used here, acetazolamide (100 microM) did not have a significant effect on the response to hypercapnic acidosis. We conclude that chemosensitivity of raphe neurones can occur independently of changes in pH(o), P(CO2) or bicarbonate. The results suggest that a change in intracellular pH (pH(i)) may be the primary stimulus for chemosensitivity in these putative central respiratory chemoreceptor neurones.
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PMID:Quantification of the response of rat medullary raphe neurones to independent changes in pH(o) and P(CO2). 1198 82


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