Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure-associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the gamma-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg-1). 2. Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg-1), arterial O2 partial pressure (PaO2) significantly dropped from 17.49 +/- 1.20 kPa to 7.51 +/- 2.21 kPa (P < 0.01) and arterial CO2 partial pressure (PaCO2) significantly increased from 4.64 +/- 0.56 kPa to 8.15 +/- 0.99 kPa (P < 0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end-inspiratory airway pressure (Paw) rapidly increased. 3. Concomitantly there was a time-dependent increase of big ET-1 and ET-1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicuculline injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not contain detectable amounts of ET. 4. Pretreatment with the endothelin-converting enzyme inhibitor, phosphoramidon (5.4 mg kg-1, i.v.) for 5 min significantly (P < 0.001) reduced peak ET-1 levels in BAL fluid by 65.4 +/- 9.9% at 8 min after bicuculline injection. Simultaneously it afforded protection from hypoxia. PaCO2 did not increase and PaO2 decreased only slightly from 14.63 +/- 1.00 kPa to 12.97 +/- 0.61 kPa (P > 0.05) after phosphoramidon pretreatment. In contrast, vehicle-treated animals that received bicuculline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in Paw by 76.7 +/- 12.4% (P <0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.5. Pretreatment with the ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.), for 5 min did not affect the levels of ET-1 in the BAL fluid at 8 min after bicuculline injection but did ameliorate the development of hypoxia. No hypercapnia developed and Pa02 decreased only moderately from 16.65 +/-0.25 kPa to 14.19 +/-2.15 kPa (P>0.05) in BQ-123-treated animals. In contrast, vehicle-treated animals that received bicuculline exhibited significant hypercapnia as well as profound hypoxia. BQ-123 significantly reduced the increase in Paw by 51.3 +/- 12.8% (P < 0.01). It affected MABP only slightly and had no effect on the acidosis.6. These results suggest that ET peptides play a significant role in this model of neurogenic pulmonary oedema and may act as mediators of respiratory distress. The deleterious effects of endogenous ET in this model are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, BQ-123. ETA receptor antagonists may therefore be of potential therapeutic value in respiratory distress.
 ...
PMID:A role for endothelin in bicuculline-induced neurogenic pulmonary oedema in rats. 854 73

1. Exogenously administered endothelin (ET) modulates the activity of cardiovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a physiological role(s) for endogenous ET in the CNS has not been elucidated. To address this question, we examined ABP and ventilation in mutant mice deficient in ET-1, ETA and ETB receptors and endothelin-converting enzyme-1, which were made by gene targeting. 2. Respiratory frequency and volume was measured in mice by whole body plethysmography when animals breathed normal room air and hypoxic and hypercapnic gas mixtures. A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia. On the following day, the ABP of awake mice was measured through the indwelling catheter and heart rate was calculated from the ABP signal. After 2 h ABP measurement, arterial blood was collected through the catheter and pH and the partial pressures of O2 and CO2 were measured by a blood gas analyser. 3. Compared with corresponding controls, the mean (+/- SEM) ABP in ET-1+/- and ETB-deficient mice was significantly higher (118 +/- 2 vs 106 +/- 3 mmHg for ET-1+/- (n = 22) and ET-1+/+ (n = 17) mice, respectively; 127 +/- 3 vs 109 +/- 4 mmHg for ETB-/s (n = 9) and ETB+/s (n = 9) mice, respectively; P < 0.05 for both). In ET-1+/- mice, PCO2 tended to be higher and PO2 was significantly lower than corresponding values in ET-1+/+ mice. Under resting conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increases of ventilation to hypoxia and hypercapnia were significantly attenuated in ET-1+/-, ET-1-/- and ETA-/- mice. 4. In another series of experiments in ET-1+/- mice, we found that sympathetic nerve activity (SNA) was augmented and reflex excitation of phrenic nerve activity (PNA) in response to hypoxia and hypercapnia was blunted. Attenuation of the reflex PNA response to hypercapnia was also observed in the medulla-spinal cord preparation from ET-1-/- mice. 5. Elevation of ABP in ETB-deficient mice was most likely due to a peripheral mechanism, because SNA and respiratory reflexes were not different from those in control animals. 6. We conclude that endogenous ET-1 plays an important role in the central neural control of circulation and respiration and that ETA receptors mediate this mechanism.
 ...
PMID:Endothelin in the central control of cardiovascular and respiratory functions. 1062 68

Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to mature endothelin-1. Most homozygous ECE-1-/- embryos die in utero and show severe craniofacial, enteric, and cardiac malformations precluding ventilatory function assessment. In contrast, heterozygous ECE-1+/- embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations in mice with endothelin-1 gene disruption, we hypothesized that ECE-1-deficient mice may have impaired ventilatory control. We analyzed ventilatory responses to hypercapnia (8% CO(2)) and hypoxia (10% O(2)) in newborn and adult mice heterozygous for ECE-1 deficiency (ECE-1+/-) and in their wild-type littermates (ECE-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypoxia were significantly weaker in ECE-1+/- than in ECE-1+/+ newborn mice (percentage ventilation increase: 1 +/- 25% versus 33 +/- 29%, p = 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal in the ECE-1+/- newborn mice. No differences were observed between adult ECE-1+/- and ECE-1+/+ mice. We conclude that ECE-1 is required for normal ventilatory response to hypoxia at birth.
 ...
PMID:Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1. 1132 56

We recently concluded that constriction of basilar artery due to respiration-induced hypocapnia in rabbits with acute metabolic alkalosis and accompanying compensatory hypercapnia was independent of NO and K(ATP) channels. Based on reports that endothelin-1-mediated hypocapnic constriction of the rabbit basilar artery in vitro, we further investigated whether the respiration-induced hypocapnic constriction was endothelin-1 mediated. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. The ET(A) plus ET(B) receptor antagonist, PD145065 (1 microM), and the selective ET(A) receptor antagonist, BQ610 (3 microM), completely relaxed the hypocapnic constriction, as determined in a cranial window. Unexpectedly, the ET(B) receptor antagonists, BQ788 and RES-701-1 (3 microM), relaxed the constriction by 72.1+/-2.8% (4) and 77.2+/-8.7% (5), respectively (means+/-S.E. (n)). To investigate whether the large magnitudes of relaxation to both ET(A) and ET(B) receptor antagonists were due to nonselectivity of the antagonists, the effects of the antagonists on the constriction to exogenous endothelin-1 were evaluated. BQ610, BQ788, and RES-701-1 relaxed the 3-5 nM endothelin-1 constriction by only 64.3+/-7.6% (4), 43.5+/-8.5% (5), and 26.7+/-4.8% (3) (means+/-S.E. (n)), respectively, consistent with the selective blocking action of these antagonists. To investigate whether the greater magnitude of BQ610, BQ788, and RES-701-1 relaxation of hypocapnic constricted versus exogenous endothelin-1-constricted vessels was due to differences between constriction elicited by endogenous versus exogenous endothelin-1, the effects of the endothelin receptor antagonists on constriction to isocapnic alkaline suffusate were evaluated. PD145065 (1 microM) and 0.1 mM phosphoramidon, an endothelin-converting enzyme inhibitor, inhibited the constriction to isocapnic alkaline suffusate by 83.8+/-7.8% (6) and 74.3+/-9.7% (8) (means+/-S.E. (n)), respectively, consistent with the endothelin-1 dependency of the constriction. BQ610, BQ788, and RES-701-1 relaxed the isocapnic alkaline suffusate constriction by 74.9+/-6.7% (5), 65.5+/-6.4% (5), and 78.0+/-6.5% (4) (means+/-S.E. (n)), respectively. Thus, the relaxation profile to the selective endothelin receptor antagonists in isocapnic alkaline constricted vessels more closely approximated the relaxation profile observed in hypocapnic constricted as compared to endothelin-1-constricted vessels. Hypocapnia did not alter the 5 nM endothelin-1 constriction. These results suggest that, under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent hypocapnic constriction is endothelin mediated. Both ET(A) and ET(B) receptor activation may mediate the hypocapnic constriction. The hypocapnic constriction is not due to enhanced endothelin-1 constriction and, thus, is due to the release of endothelin-1 and/or additional endothelins.
 ...
PMID:Reversal of hypercapnia induces endothelin-dependent constriction of basilar artery in rabbits with acute metabolic alkalosis. 1192 64