Systemic acid-base balance is tightly controlled within a narrow range of pH. Disturbances in systemic acid-base homeostasis are associated with diverse detrimental effects. The kidney is a key regulator of acid-base balance, capable of excreting HCO 3 − or H + , and chronic kidney disease invariably leads to acidosis. However, the regulatory pathways underlying the fine-tuned acid-base sensing and regulatory mechanisms are still incompletely understood. In the article published recently in Clinical Science (vol 132 (16) 1779-1796), Poulson and colleagues investigated the role of adenylyl cyclase 6 (AC6) in acid-base homeostasis. They uncovered a complex role of AC6, specifically affecting acid-base balance during HCO 3 − load, which causes pronounced alkalosis in AC6-deficient mice. However, the phenotype of AC6-deficient mice appears much more complex, involving systemic effects associated with increased energy expenditure. These observations remind us that there is much to be learned about the intricate signaling pathways involved in renal control of acid-base balance and the complex ramifications of acid-base regulation.

1. In the syndrome of inappropriate secretion of antidiuretic hormone, hyponatraemia is associated with a normal bicarbonate concentration despite dilution. This normal bicarbonate concentration is related to the development of a hyperaldosteronism, which is attributed to a direct stimulation of the zona glomerulosa by the hyponatraemic state. Some workers have suggested that, to develop this hyperaldosteronism requires the presence of a pituitary factor. To determine whether the pituitary gland plays a role in this hyponatraemia-induced hyperaldosteronism, water intoxication was performed for 24 h in normal and in panhypopituitaric rats. 2. In normal rats, hyponatraemia (108 mmol/l), induced by the administration of 1-desamino-8-D-arginine vasopressin and 2.5% D-glucose-0.45% NaCl by gavage (15% body weight) was associated with a mild increase in bicarbonate concentration, and blood acid-base equilibrium showed a mixed metabolic and respiratory alkalosis (pH 7.57, partial pressure of CO 2 29 mmHg, base excess + 5.5 mmol/l), and aldosterone concentration was increased 3-fold as compared with the control value. When hyponatraemia (110 mmol/l) was induced in a similar manner in panhypopituitaric rats, we observed a very low aldosterone concentration (< 50 pg/ml) and a compensated respiratory alkalosis (pH 7.45, partial pressure of CO 2 30 mmHg, base excess −2.6 mmol/l). The restoration of a hyperaldosteronaemic state in this group of rats was related essentially to corticosteroid intake. 3. These data suggest that corticosteroids play a critical role in the development of hyponatraemia-related hyperaldosteronism, a phenomenon not necessarily dependent on a pituitary factor.

1. To investigate mechanisms of extrarenal buffering in uraemic acidosis, we studied the effects of the carbonic anhydrase inhibitor, acetazolamide, in normal subjects and in patients with end-stage kidney disease on maintenance haemodialysis with virtually no urine output. 2. Acetazolamide (500 mg) was administered daily for 7 days, after pretreatment for 1 month with 1,25-dihydroxyvitamin D ( n = 12) or placebo ( n = 12); only placebo was administered to a third group ( n = 12) of haemodialysis patients. In addition, acetazolamide was administered to normal control subjects ( n = 12). 3. Treatment with acetazolamide resulted in a more marked metabolic acidosis in haemodialysis patients than in normal control subjects and the effect in haemodialysis patients was attenuated by prior treatment with 1,25-dihydroxyvitamin D. 4. The administration of acetazolamide to haemodialysis patients led to an increase in serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase and parathyroid hormone, and a reduction in serum calcium, whereas acetazolamide had no effect on these variables in normal subjects. In contrast, in the haemodialysis patients previously treated with 1,25-dihydroxyvitamin D, acetazolamide increased serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase, parathyroid hormone and serum calcium. 5. We hypothesize that the metabolic acidosis induced by acetazolamide in haemodialysis patients may result from interference with the mechanisms of extrarenal buffering. 6. As parathyroid hormone, 1,25-dihydroxyvitamin D and carbonic anhydrase are thought to be involved in bone buffering, we suggest that the marked acidosis seen in haemodialysis patients treated with acetazolamide may be due to impaired parathyroid hormone-mediated bone buffering.

1. To test the hypothesis that NaCl increases blood pressure, while NaHCO 3 does not, we measured the effect of an NaHCO 3 -containing mineral water on blood pressure in stroke-prone spontaneously hypertensive (SHR-SP) and Wistar–Kyoto (WKY) rats. We compared mineral water with equimolar amounts of NaCl and demineralized drinking water in six groups of 20 rats each over 24 weeks. 2. NaCl consistently increased blood pressure in both SHR-SP and WKY compared with demineralized water, while mineral water did not. 3. We studied the possible role of sodium-regulating hormones. Sodium, potassium-dependent adenosine triphosphatase activity was decreased by NaCl and by age, but not by mineral water. The concentration of atrial natriuretic peptide was greater in SHR-SP, but was not influenced by the two regimens. Components of the renin–angiotensin–aldosterone system and 18-hydroxy-deoxycorticosterone tended to decrease with NaCl, but not with mineral water. 4. Plasma pH values in the six groups of rats were not different; however, SHR-SP had consistently lower P co 2 and HCO − 3 values and higher anion gap values than WKY rats. These values were not influence by the two regimens. 5. NaCl elevates blood pressure in SHR-SP while NaHCO 3 does not. The changes in hormones regulating sodium homoeostasis suggest that NaCl induces volume expansion while NaHCO 3 does not. The effect may be related to influences on renal sodium reabsorption by chloride and bicarbonate. The possible role of increased proton excretory activity in SHR-SP remains to be determined.

1. The acid–base status of young spontaneously hypertensive rats (SHR) was compared with that of Wistar–Kyoto rats (WKY) in the steady state, after acid loading and after blood pressure had been maintained at normal levels from weaning. Whole blood ionized calcium was measured simultaneously. 2. In the prehypertensive stage (4 weeks of age), plasma bicarbonate was significantly lower in SHR than in WKY, while blood pH did not differ significantly. 3. After 6 weeks of age, blood pH and plasma bicarbonate were significantly lower in both anaesthetized and conscious SHR than in corresponding WKY. After 7 days administration of NH 4 Cl in the drinking fluid, both parameters decreased significantly in both strains and the difference in pH remained constant (0.05 pH unit, P < 0.01). 4. In none of the groups investigated did non-pH-adjusted ionized calcium differ significantly between the SHR and WKY. 5. Prevention of the development of hypertension in SHR by hydralazine treatment from weaning did not increase pH or bicarbonate compared with untreated SHR, indicating that the metabolic acidosis in the SHR was not a consequence of raised blood pressure. 6. Disturbance in acid–base balance may be involved in the pathogenesis of raised blood pressure in this animal model of genetic hypertension.

1. Quadriceps femoris muscle needle biopsies were performed in 21 patients with chronic obstructive lung disease (COLD) and acute respiratory failure (ARF) and in 21 age-matched healthy control subjects. 2. Muscle samples were analysed to obtain intracellular bicarbonate and pH values from total acid-labile carbon dioxide content. Muscle potassium, magnesium and sodium content were also determined, as well as water compartments. 3. Skeletal muscle of COLD patients with ARF showed intracellular acidosis and reduced potassium and magnesium content. Total muscle water increase was linked to extracellular water increment. 4. It was concluded that in COLD patients with ARF an overall derangement of skeletal muscle metabolism is present.

1. There is evidence that both β-adrenergic stimulation and insulin are of importance in controlling intracellular pH. Therefore we have investigated the influence of intravenous infusion of adrenaline or insulin glucose (euglycaemic clamp) on pH and electrolyte composition in resting skeletal muscle (m. quadriceps femoris) and arterial blood in six healthy subjects. 2. A decrease in the arterial potassium concentration was observed during infusion of adrenaline and is in conformity with previous studies. Both adrenaline and insulin infusions resulted in an increased lactate content of muscle and blood, indicating an enhanced glycolysis. The intracellular concentrations of K + , Na + , Mg 2+ and H + , however, remained unchanged during the adrenaline infusions as well as during infusions of insulin. 3. It is concluded that increasing the plasma adrenaline and insulin concentrations to levels well above the physiological range (adrenaline) or in the upper physiological range (insulin) does not affect the concentrations of electrolytes and hydrogen ions in resting human muscle to any appreciable extent.

1. To assess the non-respiratory acid—base disturbance which results from cardiorespiratory arrest experiments were performed on anaesthetized dogs, and circulatory arrest was established either by inducing ventricular fibrillation or by complete occlusion of the great veins. 2. In the first series of experiments (group A) the period of cardiorespiratory arrest was limited to 2·0–3·5 min. It was shown that the non-respiratory component of the ensuing acid—base disturbance as expressed by the non-respiratory pH was small: in nine episodes of circulatory arrest after occlusion of the great veins there was a mean reduction in the non-respiratory pH of 0·04 pH unit (range 0·025–0·055), and in seven episodes of ventricular fibrillation the mean reduction was 0·024 pH unit (range 0–0·055). 3. In the second series of experiments (group B) the period of cardiorespiratory arrest was varied from 3·0 to 11·0 min. It was found that the degree of non-respiratory acidaemia was correlated with the duration of arrest but the magnitude of these changes was not large.

1. Plasma and urine free dopamine (3,4-dihydroxyphenethylamine) were measured in six normal male volunteer subjects and the urinary clearance of dopamine was calculated for each subject. 2. The excretion rates for free dopamine in man were greater than could be explained by simple renal clearance. It was concluded that free dopamine must, therefore, be formed in the kidney. 3. Changes in urinary dopamine excretion were studied in four groups of rats initially maintained on a low sodium diet and then given equimolar dietary supplements of NaCl, NaHCO 3 , KCl or NH 4 Cl, to study the specificity of the previously observed increase in dopamine excretion after increased dietary NaCl. 4. The mean dopamine excretion increased significantly in rats given NaCl, KCl and NH 4 Cl, whereas dopamine excretion decreased in those given NaHCO 3 . 5. The failure of dopamine excretion to rise in response to loading with NaHCO 3 was unexpected, and argues against a simple effect of volume expansion by the sodium ion. The increase in dopamine excretion with KCl and NH 4 Cl showed that this response was not specific to the sodium ion.

1. Human leucocytes were isolated from venous blood and resuspended in the subject's plasma. 2. Intracellular pH measurements were made in vitro by the dimethyloxazolidinedione technique in 13 healthy subjects and in 11 subjects with renal failure and metabolic acidosis. 3. The intracellular pH of the healthy subjects was found to be 7·07 (sd 0·04), significantly lower than that of the patients, which was 7·11 (sd 0·03). For all estimations plasma P co 2 was maintained at approximately 5·5 kPa. The methodological and possible metabolic reasons for this difference in intracellular pH are discussed.

1. Carbon dioxide titration curves were determined in vivo in dog and man at various degrees of acute non-respiratory acidaemia and alkalaemia. 2. The slope of the CO 2 titration curve (Δlog Pco 2 /ΔpH) was found to increase with the severity of the acute non-respiratory acidaemia. In states of acute non-respiratory alkalaemia the slope (Δlog Pco 2 /ΔpH) tended towards unity. 3. A simple scheme based on the CO 2 titration curves determined in vivo has been proposed for the assessment of acute acid-base disturbances in man. 4. Carbon dioxide titration curves were also determined in vivo in patients with chronic respiratory and non-respiratory acidaemia and it was found that these curves were not significantly different from those obtained in states of acute acid-base disturbances. It is therefore suggested that the scheme described in this paper is applicable to all acid-base disturbances.

1. The respiratory response to chronic metabolic alkalosis was defined on the basis of 182 determinations of the arterial blood pH, P co 2 , HCO 3 − concentration and P o 2 obtained in thirty uraemic patients undergoing chronic haemodialysis. Plasma bicarbonate concentrations, [HCO 3 − ], ranged from 20 to 38 mmol/l before dialysis, and were elevated by increasing the acetate content of the dialysate. 2. The calculated arterial carbon dioxide tension ( P a,co 2 ) was linearly related to HCO 3 − , P a,co 2 reaching 50 mmHg at a [HCO 3 − ] of 37.5 mmol/l. This response was virtually identical with that previously reported in chronic metabolic acidosis. The 95% confidence limits of the respiratory adaptation to chronic metabolic acid-base disorders were calculated for [HCO 3 − ] ranging from 11 to 38 mmol/l. 3. Analysis of the individual response lines of thirteen patients revealed no difference among their slopes but significant differences among their elevations. Each subject appears thus to have his own threshold to acid-base stimuli. 4. Hypoxaemia developed with increasing [HCO 3 − ], P a,o 2 falling in a curvilinear fashion to reach 70 mmHg at a [HCO 3 − ] of 37.5 mmol/l.

1. The non-respiratory pH, which is based upon in vivo carbon dioxide titration curves, was compared with empirical corrections to the base excess values derived from in vitro carbon dioxide titration curves. 2. These two indices were highly correlated in thirty-two measurements made at between-sample intervals of less than 12 h in four patients with acute exacerbations of chronic bronchitis and in two patients with ketoacidosis. 3. These observations confirm that the acute whole body CO 2 titration curves established in anaesthetized man by others can be applied to acute clinical situations, so that either index can adequately describe these disturbances.