Role of acidosis-induced increases in calcium on PTH secretion in acute metabolic and respiratory acidosis in the dog.
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Recently, we showed that both acute metabolic acidosis and respiratory acidosis stimulate parathyroid hormone (PTH) secretion in the dog. To evaluate the specific effect of acidosis, ionized calcium (iCa) was clamped at a normal value. Because iCa values normally increase during acute acidosis, we now have studied the PTH response to acute metabolic and respiratory acidosis in dogs in which the iCa concentration was allowed to increase (nonclamped) compared with dogs with a normal iCa concentration (clamped). Five groups of dogs were studied: control, metabolic (clamped and nonclamped), and respiratory (clamped and nonclamped) acidosis. Metabolic (HCl infusion) and respiratory (hypoventilation) acidosis was progressively induced during 60 min. In the two clamped groups, iCa was maintained at a normal value with an EDTA infusion. Both metabolic and respiratory acidosis increased (P < 0.05) iCa values in nonclamped groups. In metabolic acidosis, the increase in iCa was progressive and greater (P < 0.05) than in respiratory acidosis, in which iCa increased by 0.04 mM and then remained constant despite further pH reductions. The increase in PTH values was greater (P < 0.05) in clamped than in nonclamped groups (metabolic and respiratory acidosis). In the nonclamped metabolic acidosis group, PTH values first increased and then decreased from peak values when iCa increased by > 0.1 mM. In the nonclamped respiratory acidosis group, PTH values exceeded (P < 0.05) baseline values only after iCa values stopped increasing at a pH of 7.30. For the same increase in iCa in the nonclamped groups, PTH values increased more in metabolic acidosis. In conclusion, 1) both metabolic acidosis and respiratory acidosis stimulate PTH secretion; 2) the physiological increase in the iCa concentration during the induction of metabolic and respiratory acidosis reduces the magnitude of the PTH increase; 3) in metabolic acidosis, the increase in the iCa concentration can be of sufficient magnitude to reverse the increase in PTH values; and 4) for the same degree of acidosis-induced hypercalcemia, the increase in PTH values is greater in metabolic than in respiratory acidosis. (+info)
Integrated responses of Na+/HCO3- cotransporters and V-type H+-ATPases in the fish gill and kidney during respiratory acidosis.
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Using degenerate primers, followed by 3' and 5' RACE and "long" PCR, a continuous 4050-bp cDNA was obtained and sequenced from rainbow trout (Oncorhynchus mykiss) gill. The cDNA included an open reading frame encoding a deduced protein of 1088 amino acids. A BLAST search of the GenBank protein database demonstrated that the trout gene shared high sequence similarity with several vertebrate Na(+)/HCO(3)(-) cotransporters (NBCs) and in particular, NBC1. Protein alignment revealed that the trout NBC is >80% identical to vertebrate NBC1s and phylogenetic analysis provided additional evidence that the trout NBC is indeed a homolog of NBC1. Using the same degenerate primers, a partial cDNA (404 bp) for NBC was obtained from eel (Anguilla rostrata) kidney. Analysis of the tissue distribution of trout NBC, as determined by Northern blot analysis and real-time PCR, indicated high transcript levels in several absorptive/secretory epithelia including gill, kidney and intestine and significant levels in liver. NBC mRNA was undetectable in eel gill by real-time PCR. In trout, the levels of gill NBC1 mRNA were increased markedly during respiratory acidosis induced by exposure to hypercarbia; this response was accompanied by a transient increase in branchial V-type H(+)-ATPase mRNA levels. Assuming that the branchial NBC1 is localised to basolateral membranes of gill cells and operates in the influx mode (HCO(3)(-) and Na(+) entry into the cell), it would appear that in trout, the expression of branchial NBC1 is transcriptionally regulated to match the requirements of gill pHi regulation rather than to match trans-epithelial HCO(3)(-) efflux requirements for systemic acid-base balance. By analogy with mammalian systems, NBC1 in the kidney probably plays a role in the tubular reabsorption of both Na(+) and HCO(3)(-). During periods of respiratory acidosis, levels of renal NBC1 mRNA increased (after a transient reduction) in both trout and eel, presumably to increase HCO(3)(-) reabsorption. This strategy, when coupled with increased urinary acidification associated with increased vacuolar H(+)-ATPase activity, ensures that HCO(3)(-) levels accumulate in the body fluids to restore pH. (+info)
Indirect sensing of insulin-induced hypoglycaemia by the carotid body in the rat.
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The most physiologically important sensors for systemic glucoregulation are located in extra-cranial sites. Recent evidence suggests that the carotid body may be one such site. We assessed rat carotid body afferent neural output in response to lowered glucose, indirectly by measurement of ventilation, and directly by recording single or few-fibre chemoafferent discharge, in vitro. Insulin (0.4 Ukg(-1)min(-1))-induced hypoglycaemia (blood glucose reduced by ca 50% to 3.4 +/- 0.1 mmoll(-1)) significantly increased spontaneous ventilation in sham-operated animals but not in bilateral carotid sinus nerve sectioned (CSNX) animals. In both groups, metabolic rate (measured as ) was almost doubled during hypoglycaemia. The ventilatory equivalent was unchanged in the sham group leading to a maintained control level of P(a, CO(2)), but was significantly reduced in the CSNX group, giving rise to an elevation of 6.0 +/- 1.3 mmHg in P(a, CO(2)). When pulmonary ventilation in sham animals was controlled and maintained, phrenic neural activity increased during hypoglycaemia and was associated with a significant increase in P(a, CO(2)) of 5.1 +/- 0.5 mmHg. Baseline chemoreceptor discharge frequency, recorded in vitro, was not affected, and did not increase when the superfusate [glucose] was lowered from 10 mm to 2 mm by substitution with sucrose: 0.40 +/- 0.20 Hz to 0.27 +/- 0.15 Hz, respectively (P > 0.20). We suggest therefore that any potential role of the carotid bodies in glucose homeostasis in vivo is mediated through its transduction of some other metabolically derived blood-borne factor rather than glucose per se and that this may also provide the link between exercise, metabolic rate and ventilation. (+info)
Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria.
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AIMS: To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether. METHODS: Following a single intramuscular (i.m.) injection of 3.2 mg kg-1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration-time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin. RESULTS: A total of 100 children with a median age of 36.4 (range 5-108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h-1 with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays "flip-flop" kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h-1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited. CONCLUSIONS: Administration of a single 3.2 mg kg-1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered. (+info)
Effect of extracellular acid-base disturbances on the intracellular pH of neurones cultured from rat medullary raphe or hippocampus.
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Previous reports suggest that an important characteristic of chemosensitive neurones is an unusually large change of steady-state intracellular pH in response to a change in extracellular pH (DeltapH(i)/DeltapH(o)). To determine whether such a correlation exists between neurones from the medullary raphe (a chemosensitive brain region) and hippocampus (a non-chemosensitive region), we used BCECF to monitor pH(i) in cultured neurones subjected to extracellular acid-base disturbances. In medullary raphe neurones, respiratory acidosis (5%--> 9% CO(2)) caused a rapid fall in pH(i) (DeltapH(i) approximately 0.2) with no recovery and a large DeltapH(i)/DeltapH(o) of 0.71. Hippocampal neurones had a similar response, but with a slightly lower DeltapH(i)/DeltapH(o) (0.59). We further investigated a possible link between pH(i) regulation and chemosensitivity by following the pH(i) measurements on medullary raphe neurones with an immunocytochemistry for tryptophan hydroxylase (a marker of serotonergic neurones). We found that the DeltapH(i)/DeltapH(o) of 0.69 for serotonergic neurones (which are stimulated by acidosis) was not different from either the DeltapH(i)/DeltapH(o) of 0.75 for non-serotonergic neurones (most of which are not chemosensitive), or from the DeltapH(i)/DeltapH(o) of hippocampal neurones. For both respiratory alkalosis (5%--> 3% CO(2)) and metabolic alkalosis (22 mm--> 35 mm HCO(3)(-)), DeltapH(i)/DeltapH(o) was 0.42-0.53 for all groups of neurones studied. The only notable difference between medullary raphe and hippocampal neurones was in response to metabolic acidosis (22 mm--> 14 mm HCO(3)(-)), which caused a large pH(i) decrease in approximately 80% of medullary raphe neurones (DeltapH(i)/DeltapH(o)= 0.71), but relatively little pH(i) decrease in 70% of the hippocampal neurones (DeltapH(i)/DeltapH(o)= 0.09). Our comparison of medullary raphe and hippocampal neurones indicates that, except in response to metabolic acidosis, the neurones from the chemosensitive region do not have a uniquely high DeltapH(i)/DeltapH(o). Moreover, regardless of whether neurones were cultured from the chemosensitive or the non-chemosensitive region, pH(i) did not recover during any of the acid-base stresses. (+info)
Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats.
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To gain insight into why there are chemoreceptors at widespread sites in the brain, mircrotubules were chronically implanted at two or three sites in the medullary raphe nuclei of adult goats (n = 7). After >2 wk, microdialysis (MD) probes were inserted into the microtubules to create focal acidosis (FA) in the awake state using mock cerebral spinal fluid (mCSF) equilibrated with 6.4% (pH = 7.3), 50% (pH = 6.5), or 80% CO(2) (pH = 6.3), where MD with 50 and 80% CO(2) reduces tissue pH by 0.1 and 0.18 pH unit, respectively. There were no changes in all measured variables with MD with 6.4% at single or multiple raphe sites (P > 0.05). During FA at single raphe sites, only 80% CO(2) elicited physiological changes as inspiratory flow was 16.9% above (P < 0.05) control. However, FA with 50 and 80% CO(2) at multiple sites increased (P < 0.05) inspiratory flow by 18.4 and 30.1%, respectively, where 80% CO(2) also increased (P < 0.05) tidal volume, heart rate, CO(2) production, and O(2) consumption. FA with 80% CO(2) at multiple raphe sites also led to hyperventilation (-2 mmHg), indicating that FA had effects on breathing independent of an increased metabolic rate. We believe these findings suggest that the large ventilatory response to a global respiratory brain acidosis reflects the cumulative effect of stimulation at widespread chemoreceptor sites rather than a large stimulation at a single site. Additionally, focal acidification of raphe chemoreceptors appears to activate an established thermogenic response needed to offset the increased heat loss associated with the CO(2) hyperpnea. (+info)
Limited extracellular but complete intracellular acid-base regulation during short-term environmental hypercapnia in the armoured catfish, Liposarcus pardalis.
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Environmental hypercapnia induces a respiratory acidosis that is usually compensated within 24-96 h in freshwater fish. Water ionic composition has a large influence on both the rate and degree of pH recovery during hypercapnia. Waters of the Amazon are characteristically dilute in ions, which may have consequences for acid-base regulation during environmental hypercapnia in endemic fishes. The armoured catfish Liposarcus pardalis, from the Amazon, was exposed to a water P(CO(2)) of 7, 14 or 42 mmHg in soft water (in micromol l(-1): Na(+), 15, Cl(-), 16, K(+), 9, Ca(2+), 9, Mg(2+), 2). Blood pH fell within 2 h from a normocapnic value of 7.90+/-0.03 to 7.56+/-0.04, 7.34+/-0.05 and 6.99+/-0.02, respectively. Only minor extracellular pH (pH(e)) recovery was observed in the subsequent 24-96 h. Despite the pronounced extracellular acidosis, intracellular pH (pH(i)) of the heart, liver and white muscle was tightly regulated within 6 h (the earliest time at which these parameters were measured) via a rapid accumulation of intracellular HCO(3)(-). While most fish regulate pH(i) during exposure to environmental hypercapnia, the time course for this is usually similar to that for pH(e) regulation. The degree of extracellular acidosis tolerated by L. pardalis, and the ability to regulate pH(i) in the face of an extracellular acidosis, are the greatest reported to date in a teleost fish. The preferential regulation of pH(i) in the face of a largely uncompensated extracellular acidosis in L. pardalis is rare among vertebrates, and it is not known whether this is associated with the ability to air-breathe and tolerate aerial exposure, or living in water dilute in counter ions, or with other environmental or evolutionary selective pressures. The ubiquity of this strategy among Amazonian fishes and the mechanisms employed by L. pardalis are clearly worthy of further study. (+info)
Acidosis in a patient with cholera: a need to redefine concepts.
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A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal. A detailed analysis emphasizing principles of physiology and a quantitative approach provided new insights and eventually better definitions of metabolic and respiratory acidosis. A shift in focus from HCO3- concentration to HCO3- content in the extracellular fluid (ECF) compartment revealed the presence of metabolic acidosis. Central to this analysis was an emphasis on the haematocrit to enable a more accurate estimate of the degree of ECF volume contraction. The latter also revealed 'contraction' metabolic alkalosis, which masked the underlying metabolic acidosis. The presence of a respiratory acidosis of the tissue type was evident from the raised venous PCO2, which was not surprising once the magnitude of the ECF contraction had been appreciated. 'Bad buffering', as defined by Professor McCance, was the immediate danger and prompted swift action to restore an effective circulation. The haematocrit and the venous PCO2 also contribute valuable information to monitor the response to therapy. Nevertheless, there were still dangers to be discovered when an in-depth analysis suggested that the administration of isotonic saline would introduce an unanticipated danger for the patient. (+info)