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)

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.
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PMID:Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans. 1084 37

We report a 55-year-old woman with typical clinical, biochemical and radiological features of Cushing's disease, who developed a severe respiratory insufficiency as the main symptom. She also complained of proximal muscle weakness over the last year and progressive dyspnea over the last four months. Bronchospasm, respiratory infection or cardiologic dysfunction were excluded. Arterial blood gas analysis showed severe respiratory insufficiency with hypoxemia and hypercapnia, respiratory acidosis and a normal alveolar-arterial oxygen gradient. Spirometry and plethysmography showed a restrictive ventilatory failure and maximum inspiratory and expiratory pressures were reduced. These findings were strongly suggestive of neuromuscular disease. Serum creatine kinase, aldolase, sodium, potassium and thyroid function tests were normal. An electromyogram and a muscle biopsy confirmed myopathic disease. Ketoconazole therapy improved her symptoms and respiratory function tests. In conclusion although proximal myopathy is a frequent presenting symptom of Cushing's syndrome, involvement of respiratory muscles with severe restrictive ventilatory dysfunction has not been previously reported as the main initial feature of Cushing's disease. Medical treatment of hypercortisolism improves muscle strength and resolves the respiratory insufficiency.
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PMID:Severe respiratory failure secondary to Cushing's myopathy. 1168 45

Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.
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PMID:Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2+-activated potassium channels. 1452 33

It is not clear whether activation of ATP-sensitive potassium channels (K(ATP)) with pinacidil in advance of ischemia and reperfusion promotes or suppresses arrhythmias. This study determines the effects of pinacidil pretreatment on arrhythmias and the changes in cellular electrophysiological parameters in segments of guinea pig right ventricular free walls exposed to simulated ischemia and reperfusion. Microelectrode recordings were made from endo- and epicardium during endocardial pacing. Preparations were superfused with Tyrode's solution and then exposed for 5 min to either 100 muM pinacidil or its solvent. After a 5-min washout, preparations were exposed to 15 min of ischemic conditions (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, and glucose-free) followed by reperfusion with Tyrode's solution. Pinacidil pretreatment increased ischemia-induced abbreviation of endo- and epicardial action potential durations and effective refractory periods. Pinacidil had no effect on endocardial conduction times but greatly prolonged transmural conduction during ischemia and early reperfusion, and it increased the incidence of transmural conduction block. Pinacidil pretreatment caused a significant increase in the incidence of arrhythmias in ischemia and reperfusion. Reperfusion arrhythmias in control preparations had electrophysiological characteristics of activity initiated by afterpotentials; however, arrhythmias with these characteristics were absent in pinacidil-pretreated preparations, and all reperfusion arrhythmias exhibited characteristics of reentry. The increased incidence of re-entrant arrhythmias is likely explained by pinacidil-induced reduction in effective refractory periods in combination with prolonged transmural conduction times. Thus, pinacidil pretreatment enhanced the effects of ischemia and reperfusion on action potential duration, effective refractory period, and transmural conduction, and it promoted re-entrant arrhythmias.
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PMID:Pretreatment with pinacidil promotes arrhythmias in an isolated tissue model of cardiac ischemia and reperfusion. 1567 Dec 2

A considerable volume of evidence implicates the purine adenosine in the regulation of cerebral blood flow during states such as hypotension, neural activation, hypoxia/ischemia, and hypercapnia/acidosis. The aim of this review is to describe developments in our understanding of the roles that adenosine and the adenine nucleotides play in cerebral blood flow control, with some comparisons to coronary blood flow. The first part of the review focuses on the categorization of receptors for adenosine (A1, A2A, A2B, and A3) and the adenine nucleotides, ATP and ADP (P2X and P2Y). Frequently used agonists and antagonists for these different receptors are mentioned. A description follows of the distribution of these different receptors in cerebral arterioles. The second part of the review initially deals with the literature on the release of adenosine and adenine nucleotides into the extracellular space of the brain, describing the various techniques used to make these measurements and assessing the pitfalls associated with their use. This is followed by a discussion of the factors affecting purine release, which include cell swelling and acidosis. The third section evaluates the role of smooth muscle potassium channels in controlling arteriolar diameter. There is evidence for an important role of KATP and KCa channels, but less is known about the contributions of voltage-dependent (KV) and inwardly rectifying (KIR) channels. This section ends with a discussion on the reported inhibitory effect of nitric oxide synthase inhibitors on the KATP channel and the consequences of such an action for the interpretation of much of the published work on nitric oxide as a regulator of cerebral blood flow. The fourth section evaluates the data supporting a role of adenosine and ATP in the regulation of cerebral blood flow during autoregulation, hypotension, neural activity, hypoxia/ ischemia, and hypercapnia. Studies using antagonists and potentiators of adenosine's actions have led to the conclusion that adenosine is involved in vascular flow control, matching metabolic activity to blood flow in all of these conditions, possibly with the exceptions of autoregulation at mean arterial blood pressures above approximately 60 mmHg. Evidence is presented for a major role of A2A, and a more limited role of A2B receptors, in balancing blood flow with metabolism. The primary effect of receptor occupancy is activation of KATP and KCa channels with smooth muscle relaxation and elevated blood flow rates. There are presently fewer data on ATP's participation in flow control, but recent evidence regarding glial cell control of cerebral arteriolar diameter suggests that this may be an important mechanism. The semi-final section, which briefly describes the evidence for a comparable role of adenosine in regulating coronary blood flow, is followed by a concluding statement reaffirming the importance of adenosine as a cerebral blood flow regulator.
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PMID:Adenosine and adenine nucleotides as regulators of cerebral blood flow: roles of acidosis, cell swelling, and KATP channels. 1586 8

Modified Hb solutions have been developed as O(2) carrier transfusion fluids, but of concern is the possibility that increased scavenging of nitric oxide (NO) within the plasma will alter vascular reactivity even if the Hb does not readily extravasate. The effect of decreasing hematocrit from approximately 30% to 18% by an exchange transfusion of a 6% sebacyl cross-linked tetrameric Hb solution on the diameter of pial arterioles possessing tight endothelial junctions was examined through a cranial window in anesthetized cats with and without a NO synthase (NOS) inhibitor. Superfusion of a NOS inhibitor decreased diameter, and subsequent Hb transfusion produced additional constriction that was not different from Hb transfusion alone but was different from the dilation observed by exchange transfusion of an albumin solution after NOS inhibition. In contrast, abluminal application of the cross-linked Hb produced constriction that was attenuated by the NOS inhibitor. Neither abluminal nor intraluminal cross-linked Hb interfered with pial arteriolar dilation to cromakalim, an activator of ATP-sensitive potassium channels. Pial vascular reactivity to hypocapnia and hypercapnia was unaffected by Hb transfusion. Microsphere-determined regional blood flow indicated selective decreases in perfusion after Hb transfusion in the kidney, small intestine, and neurohypophysis, which does not have tight endothelial junctions. Administration of a NOS inhibitor to reduce the basal level of NO available for scavenging before Hb transfusion prevented further decreases in blood flow to these regions compared with NOS inhibition alone. In contrast, blood flow to skeletal and left ventricular muscle increased, and cerebral blood flow was unchanged after Hb transfusion. This cross-linked Hb tetramer is known to appear in renal lymph but not in urine. We conclude that cell-free tetrameric Hb does not scavenge sufficient NO in the plasma space to significantly affect baseline tone in vascular beds with tight endothelial junctions but does produce substantial constriction in beds with porous endothelium. The data support increasing the molecular size of Hb by polymerization or conjugation to limit extravasation in all vascular beds to preserve normal vascular reactivity.
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PMID:Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion. 1589 76

In the present study we investigated the involvement of the hypothalamic paraventricular nucleus (PVN) in the modulation of sympathoexcitatory reflex activated by peripheral and central chemoreceptors. We measured mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) before and after blocking neurotransmission within the PVN by bilateral microinjection of 2% lidocaine (100 nl) during specific stimulation of peripheral chemoreceptors by potassium cyanide (KCN, 75 microg/kg iv, bolus dose) or stimulation of central chemoreceptors with hypercapnia (10% CO(2)). Typically stimulation of peripheral chemoreceptors evoked a reflex response characterized by an increase in MAP, RSNA, and PNA and a decrease in HR. Bilateral microinjection of 2% lidocaine into the PVN had no effect on basal sympathetic and cardiorespiratory variables; however, the RSNA and PNA responses evoked by peripheral chemoreceptor stimulation were attenuated (P < 0.05). Bilateral microinjection of bicuculline (50 pmol/50 nl, n = 5) into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation (P < 0.05). Conversely, the GABA agonist muscimol (0.2 nmol/50 nl, n = 5) injected into the PVN attenuated these reflex responses (P < 0.05). Blocking neurotransmission within the PVN had no effect on the hypercapnia-induced central chemoreflex responses in carotid body denervated animals. These results suggest a selective role of the PVN in processing the sympathoexcitatory and ventilatory component of the peripheral, but not central, chemoreflex.
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PMID:Differential role of the paraventricular nucleus of the hypothalamus in modulating the sympathoexcitatory component of peripheral and central chemoreflexes. 1610 20

The carbonic anhydrase inhibitor acetazolamide may have both inhibitory and stimulatory effects on breathing. In this placebo-controlled double-blind study we measured the effect of an intravenous dose (4 mg kg(-1)) of this agent on the acute isocapnic hypoxic ventilatory response in 16 healthy volunteers (haemoglobin oxygen saturation 83-85%) and examined whether its inhibitory effects on this response could be reversed by antioxidants (1 g ascorbic acid i.v. and 200 mg alpha-tocopherol p.o.). The subjects were randomly divided into an antioxidant (Aox) and placebo group. In the Aox group, acetazolamide reduced the mean normocapnic and hypercapnic hypoxic responses by 37% (P < 0.01) and 55% (P < 0.01), respectively, and abolished the O2-CO2 interaction, i.e. the increase in O2 sensitivity with rising Pco2. Antioxidants completely reversed this inhibiting effect on the normocapnic hypoxic response, while in hypercapnia the reversal was partial. In the placebo group, acetazolamide reduced the normo- and hypercapnic hypoxic responses by 33 and 47%, respectively (P < 0.01 versus control in both cases), and also abolished the O2-CO2 interaction. Placebo failed to reverse these inhibitory effects of acetazolamide in this group. We hypothesize that either an isoform of carbonic anhydrase may be involved in the regulation of the redox state in the carotid bodies or that acetazolamide and antioxidants exert independent effects on oxygen-sensing cells, in which both carbonic anhydrase and potassium channels may be involved. The novel findings of this study may have clinical implications, for example with regard to a combined use of acetazolamide and antioxidants at high altitude.
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PMID:Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man. 1643 32

We created a single-compartment computer model of a CO(2) chemosensory neuron using differential equations adapted from the Hodgkin-Huxley model and measurements of currents in CO(2) chemosensory neurons from Helix aspersa. We incorporated into the model two inward currents, a sodium current and a calcium current, three outward potassium currents, an A-type current (I(KA)), a delayed rectifier current (I(KDR)), a calcium-activated potassium current (I(KCa)), and a proton conductance found in invertebrate cells. All of the potassium channels were inhibited by reduced pH. We also included the pH regulatory process to mimic the effect of the sodium-hydrogen exchanger (NHE) described in these cells during hypercapnic stimulation. The model displayed chemosensory behavior (increased spike frequency during acid stimulation), and all three potassium channels participated in the chemosensory response and shaped the temporal characteristics of the response to acid stimulation. pH-dependent inhibition of I(KA) initiated the response to CO(2), but hypercapnic inhibition of I(KDR) and I(KCa) affected the duration of the excitatory response to hypercapnia. The presence or absence of NHE activity altered the chemosensory response over time and demonstrated the inadvisability of effective intracellular pH (pH(i)) regulation in cells designed to act as chemostats for acid-base regulation. The results of the model indicate that multiple channels contribute to CO(2) chemosensitivity, but the primary sensor is probably I(KA). pH(i) may be a sufficient chemosensory stimulus, but it may not be a necessary stimulus: either pH(i) or extracellular pH can be an effective stimuli if chemosensory neurons express appropriate pH-sensitive channels. The lack of pH(i) regulation is a key feature determining the neuronal activity of chemosensory cells over time, and the balanced lack of pH(i) regulation during hypercapnia probably depends on intracellular activation of pH(i) regulation but extracellular inhibition of pH(i) regulation. These general principles are applicable to all CO(2) chemosensory cells in vertebrate and invertebrate neurons.
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PMID:A computational analysis of central CO2 chemosensitivity in Helix aspersa. 1692 73

Elevated levels of carbon dioxide increase lung ventilation in Helix aspersa. The hypercapnic response originates from a discrete respiratory chemosensory region in the dorsal subesophageal ganglia that contains CO(2)-sensitive neurons. We tested the hypothesis that pH-dependent inhibition of potassium channels in neurons in this region mediated the chemosensory response to CO(2). Cells isolated from the dorsal subesophageal ganglia retained CO(2) chemosensitivity and exhibited membrane depolarization and/or an increase in input resistance during an acid challenge. Isolated somata expressed two voltage-dependent potassium channels, an A-type and a delayed-rectifier-type channel (I(KA) and I(KDR)). Both conductances were inhibited during hypercapnia. The pattern of voltage dependence indicated that I(KA) was affected by extracellular or intracellular pH, but the activity of I(KDR) was modulated by extracellular pH only. Application of inhibitors of either channel mimicked many of the effects of acidification in isolated cells and neurons in situ. We also detected evidence of a pH-sensitive calcium-activated potassium channel (I(KCa)) in neurons in situ. The results of these studies support the hypothesis that I(KA) initiates the chemosensory response, and I(KDR) and I(KCa) prolong the period of activation of CO(2)-sensitive neurons. Thus multiple potassium channels are inhibited by acidosis, and the combined effect of pH-dependent inhibition of these channels enhances neuronal excitability and mediates CO(2) chemosensory responses in H. aspersa. We did not find a single "chemosensory channel," and the chemosensitive channels that we did find were not unique in any way that we could detect. The protein "machinery" of CO(2) chemosensitivity is probably widespread among neurons, and the selection process whereby a neuron acts or does not act as a respiratory CO(2) chemosensor probably depends on the resting membrane potential and synaptic connectivity.
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PMID:CO2 chemosensitivity in Helix aspersa: three potassium currents mediate pH-sensitive neuronal spike timing. 1692 74


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