Genetic risk markers for coronary artery disease and associated phenotypes, such as restenosis after angioplasty, have the potential to be valuable to the individual, but even more so in facilitating an understanding of causal factors in the disease, and thereby the development of novel preventative and therapeutic strategies. In this issue of Clinical Science , Völzke and co-workers were unable to show association of a panel of candidate polymorphisms with restenosis, but their study has highlighted the need for even larger studies, as well as the potential benefits of finding causal genetic variation.

Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved–for reasons that remain to be established–that asthma occurs.

1. The possible role of autonomic neurotransmitters in atrial natriuretic peptide secretion was investigated using spontaneously beating guinea-pig atria in vitro. Dose responses were determined for adrenaline, noradrenaline and acetylcholine and the selective α- and β-adrenoceptor agonists phenylephrine and isoprenaline, respectively. Adrenoceptor effects were further studied using the selective α- and β-adrenoceptor antagonists prazosin and propranolol, respectively, in conjunction with maximal adrenaline challenge. Results for rate and force of contraction and atrial natriuretic peptide secretion are expressed as a ratio (mean ± SEM) of a 15 min treatment period (stage 2) to a corresponding pretreatment period (stage 1). 2. Adrenaline and noradrenaline caused dose-dependent increases in the rate and force of contraction and in atrial natriuretic peptide secretion with a peak secretory response at 2 × 10 −6 mol/l of 1.54 ± 0.08 ( P <0.01) and 1.34 ± 0.08 ( P <0.01) for adrenaline and noradrenaline, respectively. Acetylcholine decreased the rate and force of contraction, and ANP secretion was reduced to 0.47 ± 0.06 at 3 × 10 −5 mol/l ( P <0.01). Isoprenaline increased the rate and force of contraction and atrial natriuretic peptide secretion with a peak secretory response of 152 ± 0.22 at 2 × 10 −6 mol/l ( P <0.01). Phenylephrine increased the force but had no effect on the rate of contraction, and stimulated atrial natriuretic peptide secretion to 1.13 ± 0.09 at 2 × 10 −5 mol/l ( P <0.05). After both α- and β-adrenoceptor blockade, adrenaline was still able to significantly stimulate atrial natriuretic peptide secretion and positive inotropy. There was no chronotropic effect of adrenaline in the presence of propranolol. Simultaneous α- and β-adrenoceptor blockade inhibited all the effects of adrenaline. 3. A significant correlation was observed between the absolute change in rate of contraction and the absolute change in atrial natriuretic peptide secretion upon stimulation with each of the drugs ( r = 0.63, P < 0.001). A similar relationship between developed tension and atrial natriuretic peptide secretion could not be demonstrated. 4. In conclusion, secretion of atrial natriuretic peptide from guinea-pig atria was stimulated by adrenergic and inhibited by cholinergic agonists. The adrenergic response was mediated by both α- and β-adrenoceptor stimulation. The observed changes in the rate of contraction showed a significant correlation with atrial natriuretic peptide secretion.

1. A new tracer method is described for the noninvasive measurement of bone formation in the proximal femur. The method is based on our previously described whole-body method using 85 Sr as the tracer (Reeve, J., Hesp, R. & Wootton, R. Calcif. Tissue Res. 1976; 22, 191–206). It allows correction to be made for long-term exchange processes within the skeleton. 2. The method has been applied in a study of regional and whole-body bone formation in 12 rehabilitated patients who had previously suffered a fracture of the proximal femur. Twelve healthy control subjects were studied, who were selected for their good health and continued physical activity. The aim was to explore the relationship between bone formation and physical activity. 3. Bone formation was similar in the two groups, both regionally and in the whole body. Based on analyses of four cadaver specimens, bone formation in the proximal femur was about one and two-thirds times that in the whole skeleton when related to mass of calcium in the region of interest. 4. Whole-body bone resorption, estimated from five measurements per subject of hydroxyproline excretion in relation to creatinine excretion, was significantly higher in the fracture patients ( P <0.01, Wilcoxon's test). 5. Estimates of current physical activity (and immediate pre-fracture physical activity) were made with a newly devised questionnaire. Historical levels of physical activity (at ages 15–45 years) were determined with Astrom's questionnaire. No bone formation index correlated with any index of physical activity. Urinary hydroxyproline excretion correlated inversely both with current physical activity and historical physical activity (for both regression coefficients P <0.01). 6. The results are discussed in the light of our current understanding of the control of bone remodelling by the discrete basic multicellular units of bone. The opportunity to study regional bone resorption by the additional use of serial dual X-ray absorptiometry of the same region will in future allow the direct monitoring of the effects of therapeutic interventions which have been designed to prevent contralateral hip fracture.

1. The effects of the infusion of a low dose (2 pmol min −1 kg −1 for 3 h) of human atrial natriuretic peptide (hANP) were studied in seven healthy volunteers undergoing a water diuresis. Lithium clearance was used to monitor proximal tubular function. 2. hANP increased urine flow rate, sodium, calcium and magnesium excretion without significant changes in potassium and phosphate excretion, heart rate or blood pressure. 3. hANP caused a small change in fractional lithium clearance, and larger changes in distal nephron handling of sodium and water. 4. Plasma renin activity tended to decrease during the infusion of hANP, while plasma aldosterone concentration decreased during and increased after stopping the infusion of hANP. 5. The data suggest that hANP inhibits the reabsorption of sodium and water by an action on distal segments of the nephron and perhaps the proximal tubule. Inhibition of renin and aldosterone secretion may contribute to the natriuresis.

1. The effect of meals with a high and low protein content and of the fasting state on renal function and plasma atrial natriuretic peptide was studied in water-loaded normal volunteers. 2. Creatinine clearance increased after the high protein meal, but did not change after the low protein meal or while fasting. Observations of similar increases in urine sodium and potassium excretion and a transient decrease in urine flow after both meals suggest that the protein content of the meal is not an important contributory factor in these responses to feeding. 3. Absolute delivery of sodium and water out of the proximal tubules (assessed by the lithium clearance method) was higher after both meals than while fasting; fractional lithium clearance was higher after the low protein meal than the high protein meal and while fasting. Absolute reabsorption from proximal tubules was increased after only the high protein meal. 4. A transient decrease in the fraction of water delivered to distal nephron segments that appeared in the urine (fractional distal water excretion) was observed after both meals. Fractional distal sodium excretion and absolute distal sodium and water reabsorption increased after both meals. 5. Since plasma atrial natriuretic peptide either decreased (high protein meal) or remained unchanged (low protein meal and fasting), it is unlikely that this hormone is involved in the hyperfiltration after the high protein meal and the natriuresis after both high and low protein meals.

1. The effects of amiloride and frusemide on lithium clearance were studied during changes in dietary sodium chloride intake and during infusion of 0.9% NaCl in normal human volunteers. 2. Lithium and fractional lithium clearances were less on the low than on the high salt diet. Values for the medium salt diet were intermediate. Acute extracellular fluid volume expansion with 0.9% NaCl infusion and extracellular fluid volume contraction 3–4 h after intravenous frusemide caused lithium and fractional lithium clearances to increase and decrease respectively. 3. Amiloride caused small changes in lithium and fractional lithium clearances on a low salt diet, but was without effect when salt intake was medium or high. 4. Increases in lithium clearance occurred immediately after frusemide irrespective of dietary salt intake and in subjects infused with 0.9% NaCl. Only in salt-depleted subjects did frusemide cause a substantial increase in fractional lithium clearance. Changes induced under other circumstances were small. 5. It is concluded that the lithium clearance method for assessment of proximal tubule salt and water re-absorption can be used with some degree of confidence in certain circumstances (medium and high salt intake as well as in acute volume expansion) but may not be reliable when dietary salt intake is low.

1. The effect of changes of dietary sodium chloride intake and posture on plasma atrial natriuretic peptide concentration and renal function was studied in 11 normal human volunteers. 2. Plasma atrial natriuretic peptide concentration was higher in the upright posture on a high than it was on a medium or low salt diet. On the medium and high but not on the low salt diet the concentration increased significantly on adoption of the supine posture. 3. Creatinine, sodium, lithium and fractional lithium clearances, fractional distal sodium excretion and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, were significantly higher on the high than on the low salt diet. The medium salt intake gave intermediate values. 4. Heart rate while upright was significantly higher on the low than on either the medium or the high salt diets. Systolic blood pressure was unaffected by salt intake. Diastolic blood pressure in the supine position was significantly higher on the low than on the medium or high salt diets. 5. Both plasma noradrenaline concentrations and plasma renin activity were significantly higher on the low than on the high salt diet. Values on the medium salt intake were intermediate. Plasma concentrations of both hormones were higher in the upright than in the supine posture on all three salt intakes. 6. The data are consistent with the hypothesis that atrial natriuretic peptide contributes to the cardiovascular and renal adjustments to changes in dietary sodium chloride, and the possible role of the peptide is discussed.

1. Microperfusion of tubules in situ was used to study the direct effect of sodium taurocholate on reabsorption of fluid by the proximal tubule of the rat. 2. Sodium taurocholate (0.1 mmol/l) in the tubular perfusate reduced proximal tubular fluid reabsorption by approximately 30%. 3. Thus, the proximal tubule appears to be a major site at which bile salts cause a natriuresis in the rat, and possibly in obstructive jaundice in man.

1. The effect of changes of posture on plasma atrial natriuretic peptide concentrations and renal function was studied in normal human volunteers. 2. Plasma atrial natriuretic peptide concentrations increased in the supine posture, reached a maximum value after 30–60 min, remained elevated for 4 h and decreased to baseline values on return to the upright posture. Inflation of antishock trousers, which apply positive pressure to the legs and lower abdomen, attenuated the fall in plasma atrial natriuretic peptide concentration in the upright position. 3. In the supine posture there were increases in urine flow rate, sodium, lithium, fractional sodium and fractional lithium clearances. Fractional distal water and sodium excretion, and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, also increased. 4. Heart rate and systolic and diastolic blood pressures decreased in the supine and increased on return to the upright posture. Inflation of antishock trousers prevented the increase in heart rate in the upright posture. 5. The contribution of haemodynamic factors to the increase in plasma atrial natriuretic peptide concentrations in the supine position and the relationship between this increase and the associated changes in renal function are discussed. However, the contribution of atrial natriuretic peptide to these changes is uncertain.

Although our understanding of many renal mechanisms has been advancing rapidly over the past few years, there is still a dearth of information about changes that occur in renal function during pregnancy — surely one of the greatest physiological disturbances possible. It is difficult in many instances to find a description of the changes that occur quite apart from the underlying alterations in mechanisms that are responsible for them. Part of the difficulty has arisen because of the ethical and methodological problems that arise when women are used as ‘experimental animals’ until recently there has not been a suitably documented animal model, though whether this was because of technical difficulties or lack of interest on the part of investigators is not known. Recently, however, it has become apparent that many changes in renal function in the rat are similar to those occurring in women and some aspects of renal function in the rat have been investigated in detail. Since not all aspects of renal function can be covered in this review we shall concentrate on three of the more important areas, namely haemodynamics, sodium and water handling and glucose excretion, and discuss how these are changed during pregnancy; comments on the possible mechanisms involved in these changes are presented where appropriate.

1. Calcium balances and formation rates of new bone measured with an improved tracer technique using 85 Sr have been determined simultaneously in 21 patients with idiopathic osteoporosis and vertebral crush fractures. 2. A weak positive association was found between calcium balance and the kinetically measured calcium accretion rate, which is the sum of the true rate of bone formation and various long-term exchange processes. 3. The more negative balances were associated with significantly greater early loss of tracer taken up into bone by ‘accretion’, so that long-term (> 200 day) uptake was reduced. 4. This indicates that patients actively losing bone mineral have lower true rates of bone formation and higher rates of long-term exchange than their fellow patients who are more nearly in calcium equilibrium. 5. No statistically significant association was found between measured rates of bone resorption and calcium balance.

1. Hydrolysis of N -benzoyl-l-tyrosyl- p -aminobenzoic acid (PABA-peptide) has been measured in soluble and particulate fractions of human small intestinal mucosa. 2. Both soluble and particulate fractions contained enzymic activity capable of splitting the PABA-peptide. In the paniculate fractions this activity increased threefold towards the distal small intestine. 3. Neither soluble nor paniculate activity was inhibited by the chymotrypsin inhibitor 1-chloro-4-phenyl-3-l-toluene- p -sulphonamidobutan-2-one (TPCK). 4. Column chromatography on Sephacryl S-300 resolved a peak of PABA-peptide hydrolase activity that was clearly distinct from other known brush-border peptide hydrolases and from added chymotrypsin standard. 5. This PABA-peptide hydrolase thus represents a distinct intestinal enzyme, possibly bound to the brush-border membrane, which could account for the residual urinary PABA recovery observed in patients and animal models with exocrine pancreatic insufficiency.