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)

Ion channels play an important role in cellular functions, and specific cellular activity can be produced by gating them. One important gating mechanism is produced by intra- or extracellular ligands. Although the ligand-mediated channel gating is an important cellular process, the relationship between ligand binding and channel gating is not well understood. It is possible that ligands are involved in the interactions of different protein domains of the channel leading to opening or closing. To test this hypothesis, we studied the gating of Kir2.3 (HIR) by intracellular protons. Our results showed that hypercapnia or intracellular acidification strongly inhibited these channels. This effect relied on both the N and C termini. The CO(2)/pH sensitivities were abolished or compromised when one of the intracellular termini was replaced. Using purified N- and C-terminal peptides, we found that the N and C termini bound to each other in vitro. Although their binding was weak at pH 7.4, stronger binding was seen at pH 6.6. Two short sequences in the N and C termini were found to be critical for the N/C-terminal interaction. Interestingly, there was no titratable residue in these motifs. To identify the potential protonation sites, we systematically mutated most histidine residues in the intracellular N and C termini. We found that mutations of several histidine residues in the C but not the N terminus had a major effect on channel sensitivities to CO(2) and pH(i). These results suggest that at acidic pH, protons appear to interact with the C-terminal histidine residues and present the C terminus to the N terminus. Consequentially, these two intracellular termini bound to each other through two short motifs and closed the channel. Thus, a novel mechanism for K(+) channel gating is demonstrated, which involves the N- and C-terminal interaction with protons as the mediator.
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PMID:Gating of inward rectifier K+ channels by proton-mediated interactions of N- and C-terminal domains. 1089 60

Kir1.1 (ROMK1) is inhibited by hypercapnia and intracellular acidosis with midpoint pH for channel inhibition (pK(a)) of approximately 6.7. Another close relative, Kir4.1 (BIR10), is also pH sensitive with much lower pH sensitivity (pK(a) approximately 6. 0), although it shares a high sequence homology with Kir1.1. To find the molecular determinants for the distinct pH sensitivity, we studied the structure-functional relationship using site-directed mutagenesis. An NH(2)-terminal residue (Lys-53) was found to be responsible for the low pH sensitivity in Kir4.1. Mutation of this lysine to valine (K53V), a residue seen at the same position in Kir1. 1, markedly increased channel sensitivity to CO(2)/pH. Reverse mutation on Kir1.1 (V66K) decreased the CO(2)/pH sensitivities. Interestingly, mutation of these residues to glutamate greatly enhanced the pH sensitivity in both channels. Other contributors to the distinct pH sensitivity were histidine residues in the COOH terminus, whose numbers are fewer in Kir4.1 than Kir1.1. Mutation of two of these histidine residues in Kir1.1 (H342Q/H354N) reduced CO(2)/pH sensitivities, whereas the creation of two histidines (S328H/G340H) in Kir4.1 increased the CO(2)/pH sensitivities. Combined mutations of the lysine and histidine residues in Kir4.1 (K53V/S328H/G340H) gave rise to a channel that had CO(2)/pH sensitivities almost identical to those of the wild-type Kir1.1. Thus the residues demonstrated in our current studies are likely the molecular basis for the distinct pH sensitivity between Kir1.1 and Kir4.1.
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PMID:Molecular determinants for the distinct pH sensitivity of Kir1.1 and Kir4.1 channels. 1102 94

ATP-sensitive K(+) (K(ATP)) channels may be regulated by protons in addition to ATP, phospholipids, and other nucleotides. Such regulation allows a control of cellular excitability in conditions when pH is low but ATP concentration is normal. However, whether the K(ATP) changes its activity with pH alterations remains uncertain. In this study we showed that the reconstituted K(ATP) was strongly activated during hypercapnia and intracellular acidosis using whole-cell recordings. Further characterizations in excised patches indicated that channel activity increased with a moderate drop in intracellular pH and decreased with strong acidification. The channel activation was produced by a direct action of protons on the Kir6 subunit and relied on a histidine residue that is conserved in all K(ATP). The inhibition appeared to be a result of channel rundown and was not seen in whole-cell recordings. The biphasic response may explain the contradictory pH sensitivity observed in cell-endogenous K(ATP) in excised patches. Site-specific mutations of two residues showed that pH and ATP sensitivities were independent of each other. Thus, these results demonstrate that the proton is a potent activator of the K(ATP). The pH-dependent activation may enable the K(ATP) to control vascular tones, insulin secretion, and neuronal excitability in several pathophysiologic conditions.
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PMID:Direct activation of cloned K(atp) channels by intracellular acidosis. 1127 32

A-19-year old male patient complained of shortness of breath. Aspiration of the pleural fluid revealed chylothorax. Right chest tube was inserted. His ABG showed hypoxaemia with relative hypercarbia. He underwent right thoracotomy and thoracic duct ligation under general anaesthesia and double lumen endobroncheal intubation. During surgery he lost 1.5 L of blood and 4 L chyle. He was transferred to the SICU intubated and on mechanical ventilation. On the subsequent days chyle leak was reduced to a minimum of 10 ml/hr. On the 9th postoperative day the patient was extubated. He was receiving TPN 2600 kcal/day. He was transferred to the normal floor on the 15th day. After 7 day he was readmitted, his chest showed severe lung fibrosis and consolidation. His ABG showed severe hypercarbia (PaCO2 = 126 mmHg). The patient was intubated. His condition deteriorated and he was considered for lung transplantation. No donor was available. Later he arrested and died. Anaesthesia and surgical management of spontaneous chylothorax is challenging. The mortality rate is high.
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PMID:Spontaneous chylothorax--case report. 1133 Feb 18

A 41-year-old man fell into type II respiratory failure after catching a cold, and became dependent on a respirator. Chest radiography showed no abnormalities and the hyperventilation test showed improved arterial blood gas findings. His sleep study showed marked nocturnal desaturation due to hypopnea and apnea with a decrease of thoracic and abdominal movement during sleep. Therefore, we diagnosed him as primary alveolar hypoventilation syndrome (PAH). Seven years previously, his 2-year elder sister had suffered from similar respiratory failure during her second pregnancy and had been diagnosed as PAH. While myopathy was suspected in both cases, attenuation of muscle strength was slight and it appeared not to be the main cause of alveolar hypoventilation. Since medication was not effective in each case, they underwent non-invasive positive pressure ventilation (NIPPV). While sustained mild hypercapnia remained during the daytime, it improved their respiratory failure. To our knowledge, this is the first study of familial adult onset PAH.
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PMID:Familial adult onset primary alveolar hypoventilation syndrome. 1144 65

A case of dramatic improvement of respiratory function after lobectomy for bullous emphysema with severe hyperinflation of the left lower lobe was reported. A 72-year-old gentleman was admitted to our hospital due to increasing dyspnea with Hugh-Johns class V. His chest X-ray and computed tomography revealed a hyperinflation of the left lower lobe. Despite medication and respiratory rehabilitation, blood gas analysis showed hypercapnia and his symptoms had been progressing. Bronchofiberscopy revealed that the left lower lobe bronchi opened on inspiration and closed on expiration. Since complete destruction of the lower lobe due to air trapping was thought to be the cause of localized hyperinflation and the compression of left upper lobe, left lower lobectomy was performed. His dyspnea immediately disappeared and the respiratory function improved dramatically. We concluded that lobectomy could be considered as one of surgical options in case of complete lobar destruction in emphysema patients.
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PMID:Dramatic improvement of respiratory condition after lobectomy for localized bullous emphysema. 1556 65

This article reports the case of a 10-year-old child with an exacerbation of asthma requiring mechanical ventilation. His immediate course was complicated by significantly elevated arterial CO(2) tensions and a unilateral dilated pupil. A computed tomography scan of his brain failed to demonstrate any evidence of intracranial hypertension or cerebral edema, and he went on to make an uncomplicated recovery, with no evidence of neurological sequelae. The most likely diagnosis appeared to be local contamination with ipratropium when he was receiving frequent nebulizers prior to mechanical ventilation. Similar cases reported in the literature are reviewed, with a discussion of clinical management, implications of permissive hypercapnia and neurological complications in ventilating asthmatic patients and the importance of safe drug handling by staff members.
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PMID:A 10-year-old child with status asthmaticus, hypercapnia and a unilateral dilated pupil. 1632 36

John T. (Jack) Reeves' science is reviewed across the 37 years of his research career at the University of Colorado Health Sciences Center, a period which occupied approximately half his remarkable life. His contributions centered on understanding the inter-relatedness as well as the underlying mechanisms controlling the various components of the O(2) transport system. We review here his studies on exercise performance; these encompassed about half his scientific output with the other half being devoted to the study of hypoxic pulmonary hypertension. Early studies concerned cardiac output, showing how it was a balance between O(2) uptake and O(2) extraction, and that cardiac output during exercise at high altitude was reduced, most likely because of decreased plasma volume and left ventricular filling. Jack's many studies addressed virtually every aspect of the O(2) transport system -- adding significantly to our understanding of the syndromes of altitude illness, the mechanisms by which ventilatory sensitivity to hypoxia and hypercapnia influenced ventilatory acclimatization, and the contributions of the various limbs of the autonomic nervous system on systemic blood pressure, vascular resistance and substrate utilization. His scientific career ended abruptly in 2004 when struck by a car while biking to work, but his legacy remains in his more than 385+ research articles or chapters, the 40+ fellows he trained, and the countless number of younger (and older) scientists for whom he served as a role model for learning how to scrutinize their data and present their findings in clear and sometimes bold prose. An integral man, he is sorely missed.
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PMID:Jack Reeves and his science. 1638 71

Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be caused by lactic acidosis.
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PMID:[A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin]. 1675 49

Here we report two cases of congenital myopathy visited our hospital with respiratory failure. Case 1 was a 31-year-old woman, who had muscular weakness from birth but had never been diagnosed. She had an onset of pneumonia followed by severe type 2 respiratory failure. Even after the healing of pneumonia, hypercapnia remained. A diagnosis of nemaline myopathy was made after muscle biopsy. Case 2 is a 62-year-old man, who had slowly progressing respiratory failure accompanied with severe hypercapnea. His respiratory failure was improved by NIPPV. He also under went muscle biopsy and nemaline myopathy was diagnosed. Nemaline myopathy is one of congenital myopathy and is known to be a nonprogressive or slowly progressive disorder. However, some patients are diagnosed appropriately only when adult onset acute respiratory failure occurs.
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PMID:[Two cases of nemaline myopathy diagnosed after episodes of respiratory failure]. 1684 21


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