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PubMed1985

Effect of metabolic acidosis on the PTH receptor-adenylate cyclase system of canine kidney.

The phosphaturic action of parathyroid hormone (PTH) is blunted during metabolic acidosis. Previous studies suggest that the activation of renal cortical adenylate cyclase by PTH is decreased under this condition. However, the mechanisms underlying the defect are not completely defined. The present studies were designed to examine the interaction of PTH with its receptor-adenylate cyclase system in basolateral cortical membranes from dogs with metabolic acidosis. Chronic metabolic acidosis was induced in seven normal dogs. Venous blood pH decreased to 7.21 +/- 0.01 and serum bicarbonate to 12.58 +/- 0.32 meq/liter. In seven control dogs blood pH was 7.38 +/- 0.002 and serum bicarbonate was 20.14 +/- 0.26 meq/liter. The kidneys were surgically removed and basolateral membranes were prepared by differential centrifugation and ultracentrifugation in discontinuous sucrose density gradients for studies of adenylate cyclase activity and hormone-receptor binding. Metabolic acidosis resulted in a significant decrease in PTH-dependent adenylate cyclase activity (Vmax 2,119 +/- 150 pmol cAMP X mg prot-1 .30 min-1 vs. 3,548 +/- 116 in the controls). The PTH concentration giving half-maximal activation of adenylate cyclase was unchanged. However, PTH-receptor binding showed similar affinity and binding capacity in both groups of membranes. Basal enzyme activity was also similar. In the presence of the GTP analogue 5'-guanylylimidodiphosphate, PTH-dependent adenylate cyclase activity remained markedly decreased in the acidotic dog membranes compared with the controls. The ability of NaF to stimulate enzyme activity was also depressed in the membrane of acidotic dogs. Enzyme activity in the presence of Mn2+ was similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1986

Glucocorticoids and metabolic acidosis-induced renal transports of inorganic phosphate, calcium, and NH4.

The initial rate (5 s) of Na+-dependent inorganic phosphate (Pi) uptake in brush-border membrane vesicles isolated from rat proximal tubule was decreased in metabolic acidosis, 0.42 +/- 0.02 vs. 0.59 +/- 0.05 nmol/mg protein, in vesicles from control animals. Phosphate, ammonium, and Ca2+ excretions were increased 100, 600, and 56%, respectively. These changes in brush-border Pi transport and urinary excretion of ions were largely dependent on intact adrenal glands. After adrenalectomy there were no significant changes in brush-border Pi transport, Pi, and Ca2+ excretion, whereas ammonium excretion increased only 300% compared with controls. When the glucocorticoid dexamethasone was administered to adrenalectomized animals, it mimicked the effects of metabolic acidosis both in the presence and the absence of metabolic acidosis. The initial rate of brush-border Pi transport was decreased by dexamethasone administration to 0.37 +/- 0.04 nmol/mg protein in adrenalectomized acidotic animals and 0.39 +/- 0.03 nmol/mg protein in adrenalectomized animals. Dexamethasone administered to adrenalectomized acidotic animals increased Pi, ammonium, and Ca2+ excretion 190, 690, and 23%, respectively. Dexamethasone administered to nonacidotic adrenalectomized animals increased Pi ammonium and Ca2+ excretion 165, 240, and 31%, respectively. We conclude that changes in Pi, ammonium, and Ca2+ excretion observed during metabolic acidosis were dependent on intact adrenal glands and that glucocorticoids administered to adrenalectomized acidotic or nonacidotic animals mimicked the changes observed in acidotic animals with intact adrenal glands.

Acidosis↗
PubMed1987

Plasma glutamine and renal ammoniagenesis in dogs with chronic metabolic acidosis.

The purpose of this investigation was to determine whether the rate of glutamine metabolism in the kidneys of normal dogs and dogs with chronic metabolic acidosis was influenced by the plasma glutamine concentration. Because glutamine is a major renal energy fuel, results were examined at a constant rate of energy or ATP turnover [i.e., per 100 ml glomerular filtration rate (GFR)]. Glutamine extraction per 100 ml GFR was directly proportional to the filtered load of glutamine in normal and acidotic dogs. The slope depicting this relationship was parallel to the filtered load of glutamine; however, in normal dogs it was lower and in acidotic dogs it exceeded the filtered load by approximately 22 mumol/100 ml GFR. With respect to the fate of the nitrogens of the glutamine extracted, alanine and ammonium were produced in normal dogs at a rate nearly equivalent to that of glutamine extracted, whereas ammonium production was almost twofold greater than the rate of glutamine extraction during acidosis. There was a relatively small but constant alanine release over the entire range of plasma glutamine concentrations in these dogs. Furthermore, infusion of glutamine to raise the plasma glutamine concentration twofold during acidosis resulted in an increased rate of glutamine extraction and ammonium production equal to that predicted from the increase in filtered load of glutamine. Therefore, variations of circulating glutamine concentration within the physiological range seem to have an important influence on the steady-state rate of renal glutamine metabolism in normal dogs and in dogs with chronic metabolic acidosis.

Acid-Base Equilibrium↗
PubMed1988

Effects of respiratory acidosis on HCO3- transport by rabbit collecting tubules.

These studies were performed to determine whether in vitro elevation of bath PCO2 with associated reduction in pH (acute respiratory acidosis) affected bicarbonate transport by isolated perfused rabbit cortical collecting tubules (CCT) and collecting tubules from the outer (OMCTos) and inner (OMCTis) stripes of the outer medulla. When the PCO2 was elevated and pH reduced from approximately 7.4 to 7.0 the rate of total CO2 absorption increased to 252% of that observed at pH 7.4 in CCT, 146% in OMCTos, and 150% in OMCTis. In OMCTis, pretreatment with colchicine inhibited the stimulation of total CO2 absorption associated with respiratory acidosis, whereas lumicolchicine did not. Similar inhibition was observed in the presence of maptam and a low calcium concentration and in the presence of a calmodulin inhibitor. No differences were observed in apical or basolateral membrane morphometry of principal or intercalated cells between control tubules and those subjected to respiratory acidosis. The results indicate that acute respiratory acidosis stimulates acidification by the rabbit distal nephron in vitro through a process(es) that, at least in OMCTis, evidently involves the cell cytoskeleton and changes in cell calcium and calmodulin activities.

Acidosis, Respiratory↗
PubMed1990

Brain pH in acute isocapnic metabolic acidosis and hypoxia: a 31P-nuclear magnetic resonance study.

It is well known that brain pH changes rapidly in acute hypercapnia or hypocapnia. The effect of acute isocapnic metabolic acid-base change on brain pH is less certain. To study this problem, acute isocapnic metabolic acidosis was induced by HCl or lactic acid infusions in rats, and recovery from acidosis was accomplished by NaHCO3 infusion. Brain pH was measured by 31P-nuclear magnetic resonance. Despite decreases in blood pH of 0.34 and 0.36 units, respectively, in less than 1 h of acid infusion and rapid recovery during bicarbonate infusion, brain pH was unaffected (ranging between 7.08 and 7.11) and was uncorrelated with blood pH. The blood pH minus brain pH gradient was eliminated by the acidosis. By contrast, hypoxia-induced endogenous lactic acidosis lowered blood and brain pH equivalently, but the fall in brain pH preceded that in blood. During normoxic recovery, brain pH overshot and became alkaline when blood pH was still significantly reduced and blood lactate levels were markedly elevated. Presumably, this is due to stimulated active H+ transport. The results demonstrate that brain pH is affected differently in metabolic, respiratory, and endogenous acid-base disturbances. Thus brain pH cannot be predicted solely from blood pH values.

Acid-Base Imbalance↗
PubMed1990

NEM-sensitive ATPase activity in rat nephron: effect of metabolic acidosis and alkalosis.

The present study was designed to quantitate the amount and to map the localization of N-ethylmaleimide (NEM)-sensitive adenosinetriphosphatase (ATPase) activity in microdissected segments of the rat nephron. After complete nephron mapping the effect of chronic metabolic acidosis and alkalosis on enzyme activity was determined. In control animals the highest enzyme activity was found in the early proximal convoluted tubule of juxtamedullary nephrons; superficial early proximal tubule as well as medullary and cortical thick ascending limbs and collecting ducts also contained substantial activity. Enzyme activity in the papillary collecting duct before entry into the ducts of Bellini was 329 +/- 93 pmol.mm-1.h-1 (n = 8); after entry, however, enzyme activity was approximately one-fourth that value (60 +/- 9 pmol.mm-1.h-1, n = 8, P less than 0.01). No NEM-sensitive ATPase activity was found in the thin limbs of the loop of Henle. Enzyme activity increased in both the medullary and cortical thick ascending limbs as well as in the cortical collecting tubule in response to NH4Cl-induced chronic metabolic acidosis; in the cortical collecting duct, metabolic acidosis increased maximum activity (Vmax) but did not change Michaelis-Menten constant (Km). In the proximal convoluted tubule, enzyme activity decreased with metabolic acidosis. Bicarbonate loading had no effect on enzyme activity except in the most distal portion of the collecting duct where it was stimulated. These results show that NEM-sensitive ATPase activity exists throughout much of the rat nephron. These data suggest that both the cortical collecting tubule and thick ascending limb are regulatory sites of distal urinary acidification during acid loading.

Acidosis↗
PubMed1990

Adaptation of HCO-3 and NH+4 transport in rat MTAL: effects of chronic metabolic acidosis and Na+ intake.

In vitro microperfusion experiments were performed to determine whether chronic metabolic acidosis or chronic alterations in sodium intake cause adaptive changes in bicarbonate or ammonium transport in the medullary thick ascending limb (MTAL) of the rat. In all experiments, MTAL were studied under standard conditions in vitro with 25 mM bicarbonate in perfusate and bath. Thus changes in transport rates reflect adaptive changes in the intrinsic transport properties of the tubule cells. Chronic metabolic acidosis (induced by oral NH4Cl loading) increased MTAL bicarbonate absorption by 53% and increased net ammonium absorption by 36%. Chronic administration of NaHCO3 (0.28 M NaHCO3 drinking H2O) increased MTAL bicarbonate absorption by 50% and increased net ammonium absorption by 54%, despite systemic metabolic alkalosis. Chronic administration of NaCl (0.28 M NaCl drinking H2O) also increased bicarbonate absorption by 50%. Thus an increase in sodium intake stimulated bicarbonate absorptive capacity to a similar extent when sodium was administered with either chloride or bicarbonate. Moderate dietary sodium restriction (0.5% NaCl) reduced bicarbonate absorption by 20% compared with pair-fed sodium-replete controls (2.2% NaCl). These results demonstrate that 1) the MTAL is a site of regulation of renal acid-base transport, 2) chronic metabolic acidosis is associated with adaptive increases in MTAL bicarbonate and ammonium absorption, changes that are appropriate to correct the acidosis, and 3) dietary sodium intake is an important determinant of MTAL bicarbonate and ammonium transport capacity. The response of the MTAL to changes in sodium intake suggests that this segment may play an important role in maintaining acid-base balance when NaCl intake is altered.

Acidosis↗
PubMed1990

Effect of acidosis on PTH-dependent renal adenylate cyclase in phosphorus deprivation: role of G proteins.

These studies examine the regulation of adenylate cyclase in renal cortical membranes from phosphate-deprived and phosphate-deprived acidotic dogs. Enzyme stimulation by parathyroid hormone (PTH) was decreased in phosphate deprivation [Vmax 1,578 +/- 169 vs. 2,581 +/- 219 pmol adenosine 3',5'-cyclic monophosphate (cAMP).mg protein-1 x 30 min-1 in controls, P less than 0.01]. Metabolic acidosis further decreased PTH-stimulated activity. Membranes from phosphate-deprived dogs showed a decrease in Gs alpha-content by cholera toxin-dependent ADP-ribosylation (174 +/- 18 arbitrary units vs. 266.4 +/- 13.6 in controls, P less than 0.01). Metabolic acidosis further decreased Gs alpha-content, P less than 0.01. Gi content by pertussis-dependent ADP-ribosylation was also lower in phosphate-deprived and phosphate-deprived acidotic animals. Gs function was examined by its property to protect the catalytic unit from inactivation by N-ethylmaleimide when preincubated with GTP gamma S. In controls, protection of inactivation was 80% of the maximal activity, whereas in phosphate deprivation protection was less than 50%. In conclusion, metabolic acidosis enhances adenylate cyclase resistance to PTH in phosphate deprivation. These alterations are associated with a decrease in the content and function of Gs alpha, suggesting a role of Gs in the renal adaptation to phosphate depletion and acidosis.

Acidosis↗
PubMed1998

Effect of metabolic acidosis on NaCl transport in the proximal tubule.

In metabolic acidosis, the capacity of the proximal tubule for bicarbonate absorption is enhanced, whereas NaCl reabsorption is inhibited. Recent evidence indicates that transcellular NaCl absorption in the proximal tubule is mediated by apical membrane Cl/formate exchange and Cl/oxalate exchange, in parallel with recycling of these organic anions. We evaluated whether the effect of metabolic acidosis to inhibit NaCl reabsorption in the proximal tubule is due at least in part to inhibition of organic anion-dependent NaCl transport in this nephron segment. Absorption rates of bicarbonate (JHCO3), chloride (JCl), and fluid (Jv) were measured in rat proximal tubule segments microperfused in situ. We confirmed that metabolic acidosis stimulates JHCO3 in tubules microperfused with 25 mM HCO3, pH 7.4. For measurements of JCl, tubules were microperfused with a low-bicarbonate (5 mM), high-chloride solution, simulating conditions in the late proximal tubule. Under these conditions, baseline JCl and Jv measured in the absence of formate and oxalate were not significantly different between control and acidotic rats. However, whereas addition of 50 ¿M formate or 1 ¿M oxalate to luminal and capillary perfusates markedly stimulated JCl and Jv in control rats, formate and oxalate failed to stimulate JCl and Jv in acidotic rats. We conclude that metabolic acidosis markedly downregulates organic anion-stimulated NaCl absorption, thereby allowing differential regulation of proximal tubule NaHCO3 and NaCl transport.

Absorption↗
PubMed1998

Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts.

Chronic metabolic acidosis induces net calcium efflux from bone mineral through an increase in osteoclastic resorption and a decrease in osteoblastic matrix deposition and mineralization. To determine the effects of chronic metabolic acidosis on the expression of genes necessary for mineralization, we grew primary bone cells, which are principally osteoblasts, to confluence in neutral pH (7.5) medium and then switched the cells either to a neutral pH or to an acidic pH (7.1) differentiation medium. Cells were harvested for RNA at 4- to 7-day intervals for up to 44 days. By 36 days, there was extensive bone nodule formation and mineralization in cells cultured in neutral medium; however, there was a substantial decrease in nodule formation and mineralization in cells cultured in acidic medium. There was a marked increase in matrix Gla protein RNA and an increase in osteopontin RNA in neutral cultures; however, acidic medium almost completely prevented any increase. In contrast, RNA levels for osteonectin and transforming growth factor-beta1 were not altered by chronic acidosis. Additional cells were incubated in acid differentiation medium for 1, 2, or 3 wk and then transferred to neutral medium; in each case, there was recovery of matrix Gla protein RNA and osteopontin RNA expression. Still other cells were incubated in neutral differentiation medium for 1, 2, or 3 wk and then transferred to acid medium; in each case there was inhibition of matrix Gla protein RNA and osteopontin RNA expression. Thus metabolic acidosis appears to specifically inhibit RNA accumulation of certain genes whose products may be essential for formation of mature bone matrix.

Acidosis↗
PubMed2001

Mechanism of increased renal gene expression during metabolic acidosis.

Increased renal catabolism of plasma glutamine during metabolic acidosis generates two ammonium ions that are predominantly excreted in the urine. They function as expendable cations that facilitate the excretion of acids. Further catabolism of alpha-ketoglutarate yields two bicarbonate ions that are transported into the venous blood to partially compensate for the acidosis. In rat kidney, this adaptation is sustained, in part, by the induction of multiple enzymes and various transport systems. The pH-responsive increases in glutaminase (GA) and phosphoenolpyruvate carboxykinase (PEPCK) mRNAs are reproduced in LLC-PK(1)-fructose 1,6-bisphosphatase (FBPase) cells. The increase in GA activity results from stabilization of the GA mRNA. The 3'-untranslated region of the GA mRNA contains a direct repeat of an eight-base AU sequence that functions as a pH-response element. This sequence binds zeta-crystallin/NADPH:quinone reductase with high affinity and specificity. Increased binding of this protein during acidosis may initiate the pH-responsive stabilization of the GA mRNA. In contrast, induction of PEPCK occurs at the transcriptional level. In LLC-PK(1)-FBPase(+) kidney cells, a decrease in intracellular pH leads to activation of the p38 stress-activated protein kinase and subsequent phosphorylation of transcription factor ATF-2. This transcription factor binds to cAMP-response element 1 within the PEPCK promoter and may enhance its transcription during metabolic acidosis.

Acidosis↗
PubMed1975

CSF bicarbonate regulation in respiratory acidosis and alkalosis.

CSF bicarbonate regulation was studied in respiratory acidosis and alkalosis of 4h duration in antsthetized dogs. PCO2, pH, HCO3, ammonia, and lactate in CSF and arterial and safittal sinus bloof were measured when equal volumes of saline or acetazolamide (8 mg) were injected into lateral cerebral ventricles. The brain CO2 dissociation curve was determined at the end of all experiments. CSF and arterial bicarbonate increased 11.8 and 5.9 meg/l, respectively, in acidosis. Acetazolamide limited the rise in CSF bicarbonate to 4.2 meg/l, and prevented the CSF bicarbonate increase associated with hyperammonemia. During alkalosis CSF bicarbonate fell 6.5 meg/l and CSF lactate increased almost 2 meg/l while arterial bicarbonate fell 5.7 meg/l and lactate remained unchanged. Thus plasma bicarbonate changes account for some of the CSF unchanged. Thus plasma bicarbonate changes account for some of the CSF bicarbonate alterations in respiratory acid-base-disturbances. In acidosis additional CSF bicarbonate is formed by the choroid plexus and glial cells on the inner and outer surfaces of the brain--a reaction catalyzed by the locally present carbonic anhydrase. In alkalosis the greater fall in CSF bicarbonate than blood is due to selective brain and CSF lactic acidosis.

Acetazolamide↗
PubMed1977

Effect of respiratory acidosis and activity on airway smooth muscle intracellular pH.

Previous work in our laboratory has shown that respiratory acidosis (RA) impaired mechanical function in canine tracheal smooth muscle (TSM). Since an intracellular acidosis could be brought on by the increased CO2 content of the bathing medium and alter the Km's of rate-limiting glycolytic enzymes in the pathway of energy production for contractile function, we have investigated the effects of RA on the intracellular pH (pHi) of TSM. Using the DMO method, paired unstimulated or resting TSM strips were incubated under normocapnic conditions (PO2 600 Torr, PCO2 40 Torr, pH 7.40) and RA (PO2 550 Torr, PCO2 110 Torr, pH 6.95) with 14C-labeled DMO and 3H-labeled inulin or PEG-4000. In another set of paired experiments, TSM strips were tetanized electrically every 5 min or pharmacologically throughout the incubation period ("active" muscle strips). The tissue and an aliquot of bathing medium were counted for 3H and 14C content and the values entered into the Wadell and Butler equation. The pHi's of "resting" normocapnic and acidotic strips were 7.041 +/- 0.017 (SE) and 6.752 +/- 0.012, respectively. However, the pHi's of "active" normocapnic and acidotic strips were 7.275 +/- 0.017 and 7.017 +/- 0.015, respectively. We conclude that respiratory acidosis lowers intracellular pH in both resting and mechanically active TSM's; however, "active" preparations whether exposed to normocapnia or acidosis were unexpectedly more alkaline than their "resting" counterparts.

Acidosis, Respiratory↗
PubMed1980

CSF bicarbonate regulation in metabolic acidosis: role of HCO3- formation in CNS.

In metabolic acidosis, cerebrospinal fluid bicarbonate content (CSF [HCO3-]) falls in parallel with reductions in CSF CO2 tension (PCO2), and the fall is minimal with isocapnia. Regulation of CSF HCO3- was therefore investigated during 6 h of isocapnic metabolic acidosis in dogs. One group received intraventricular injections of acetazolamide to inhibit the centrally located carbonic anhydrase, essential in central nervous system (CNS) HCO3- formation, while the control group received intraventricular saline. Plasma [HCO3-] was reduced by 10 meq/l with iv infusion of 0.2 N HCl. CSF [HCO3-] fell in the control group from 22.8 to 17.7 meq/l at 6 h, whereas in the acetazolamide group it fell from 22.9 to 13.0 meq/l. Brain ammonia content was 1,286 +/- 153 microgram/100 g in the controls and 666.2 +/- 103 microgram/100 g in the acetazolamide-treated group at 6 h. Therefore, some reduction in CSF [HCO3-] occurred during 6 h of isocapnic metabolic acidosis along the chemical concentration gradient between CSF and blood, but further falls, in CSF [HCO3-] were minimized by de novo, carbonic anhydrase-dependent HCO3- formation within the CNS. Some of H+ formed were buffered by the increase in brain ammonia. These central mechanisms contribute to local CNS H+ homeostasis in metabolic acidosis.

Acetazolamide↗
PubMed1983

Ventilation and CSF ions during hypocapnic HCl and HNO3 acidosis in conscious rabbits.

In conscious rabbits with preimplanted arterial, central venous, and cisterna magna catheters, we infused HNO3 or HCl to lower and maintain arterial PCO2, pH, and plasma HCO-3 at the same mean values in both groups over 9 h. The hypothesis was that greater entry into cerebrospinal fluid (CSF) of the strong anion NO-3 vs. Cl- would result in a greater decrease in CSF [HCO-3] in the HNO3 vs. the HCl experiment, even though the acid-base stress as measured by arterial PCO2 and plasma [HCO-3] was the same. The results did not support the hypothesis. With HCl acidosis, delta CSF [HCO-3] was equal to delta CSF [Cl-]. With HNO3 acidosis, delta CSF [HCO-3] was equal to delta CSF [NO-3] + delta CSF [Cl-], as both CSF Cl- and HCO-3 decreased with NO-3 entry into CSF. The change in CSF [HCO-3] appeared tightly linked to the PCO2 or the plasma [HCO-3], it did not depend on the type of acid used. The ionic mechanisms that determine the CSF [HCO-3] in metabolic acidosis appear able to utilize changes in the strong anions NO-3 and Cl- to bring about CSF acid-base regulation. The change in alveolar ventilation per unit CO2 production as reflected by the arterial PCO2 was the same in both groups, although the expired minute ventilation and respiratory frequency responses were diminished in the HNO3 vs. the HCl groups. In both groups with acidosis, tidal volume increased, whereas respiratory frequency decreased.

Acidosis↗
PubMed1984

CSF and plasma ions and blood gases during organic metabolic acidosis in conscious rabbits.

In conscious rabbits with arterial, central venous, and cisterna magna catheters, we infused HCl, Hlactate, and Hacetate so as to lower and maintain plasma [HCO3-] at the same mean values in all three groups over 6 h. The hypothesis was that the cerebrospinal fluid (CSF) [HCO3-] will depend on the changes in CO2 partial pressure (PCO2) and be determined by the net increase in the CSF concentration of the strong anion of the acid. The delta CSF [HCO3-] did correlate strongly with the delta PCO2, with the largest decrease in CSF [HCO3-] and PCO2 being in the Hacetate group, a response we attribute to a greater stimulatory effect of Hacetate on the alveolar ventilation relative to CO2 production. However, the delta CSF [HCO3-] was not simply determined in all cases by the increase in the CSF concentration of the strong anion of the acid. In HCl acidosis, statistically delta CSF [HCO3-] was equal to delta CSF [Cl-]. In H lactate acidosis delta CSF [HCO3-] was equal to the sum of a small positive delta CSF [lactate] and a small positive delta CSF [Cl-]. In Hacetate acidosis, delta CSF [HCO3-] was equal to the sum of a large positive delta CSF [acetate] and a small negative delta CSF [Cl-]. We hypothesize that in metabolic acidosis the changes in large cavity CSF [HCO3-] depend on changes in the PCO2. The strong anion regulated by the PCO2 changes is Cl-.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1992

Failure of pulmonary acidosis to increase respiratory drive.

Experiments were performed to determine whether increases in acidity isolated to the pulmonary circulation would stimulate hypothesized pulmonary chemoreceptors and increase respiratory drive in the anesthetized paralyzed mechanically ventilated cat (n = 9). Respiratory drive was assessed by measuring the frequency and amplitude of the integrated phrenic neurogram. To create an isolated pulmonary acidosis, blood returning to the lung was acidified by infusion of 0.3 M lactic acid (1.91 ml/min) into the inferior vena cava, while systemic arterial pH was restored to near normal levels by simultaneous infusion of base (0.3 M NaOH) into the left atrium. Six minutes after the start of this dual infusion of acid and base, right ventricular (pulmonary) pH decreased from 7.286 to 7.179 and PCO2 increased 7 Torr. Systemic arterial pH and PCO2 were unchanged from measurements immediately before the infusion. This level of pulmonary acidosis failed to increase respiratory drive as assessed by phrenic activity. To test the sensitivity of the preparation to known systemic arterial chemical stimuli, a combined pulmonary and systemic acidosis was elicited by infusion of 0.3 M lactic acid into the inferior vena cava and 0.3 M NaCl into the left atrium. This infusion significantly lowered both systemic arterial and pulmonary arterial pH (7.343 to 7.155 for systemic arterial pH and 7.286 to 7.067 for pulmonary pH) and increased phrenic efferent activity 45%. We conclude that phrenic efferent activity is unaffected by moderate reductions in the pH of the pulmonary circulation in the absence of a significant systemic arterial acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Respiratory↗
PubMed1994

Interactive effects of K+, acidosis, and catecholamines on isolated rabbit heart: implications for exercise.

Intense exercise can double arterial K+ concentration, decrease pH by 0.4 units, and increase catecholamines 15-fold. Any one of these changes may be cardiotoxic in a subject at rest, yet these changes are well tolerated in exercise. We tested the interactive effects of extracellular K+ concentration ([K+]o), metabolic acidosis (pH 7.0), and raised catecholamines in the isolated working rabbit heart when they were changed with similar kinetics and concentrations to those seen in exercise. Raised [K+]o (8 and 12 mM) significantly decreased aortic flow (AF) by 23 and 76%, respectively (P < 0.01). Acidosis decreased AF by 19% (P < 0.05) and by 38% in combination with 8 mM [K+]o (P < 0.05), making their combined effect additive. Either epinephrine (80 nM), norepinephrine (80 nM) or extracellular Ca2+ concentration (5 mM) offset the negative effects of 8 and 12 mM [K+]o on AF. Norepinephrine also improved AF in 8 mM [K+]o with acidosis. Thus, there may be a beneficial interaction among changes in K+, catecholamines, and acidosis during exercise such that each could offset the others' potentially harmful effects.

Acidosis↗