1. Brain natriuretic peptide, closely related to atrial natriuretic peptide in structure, may be an important circulating hormone. Its physiological role is unclear. First, we studied the effects of incremental infusions of brain natriuretic peptide in six healthy men on plasma brain natriuretic peptide levels and the pharmacokinetics of brain natriuretic peptide. Synthetic human brain natriuretic peptide-32 was infused intravenously, at an initial rate of 0.4 pmol min −1 kg −1 , doubling every 15 min until the dose rate reached 6.4 pmol min −1 kg −1 , at which rate the infusion was maintained for 30 min. 2. The brain natriuretic peptide infusion raised the brain natriuretic peptide-like immunoreactivity from 1.4 ± 0.5 pmol/l to 21.4 ± 7.6 pmol/l. Brain natriuretic peptide-like immunoreactivity after the end of infusion was consistent with a bi-exponential decay, with half-lives of 2.1 min and 37 min. 3. Next, we studied the effects of low-dose infusion of brain natriuretic peptide to mimic physiological increments in the circulating levels in comparison with atrial natriuretic peptide. Six dehydrated male subjects received intravenous infusions of atrial natriuretic peptide and brain natriuretic peptide, separately and in combination, in a randomized double-blind, placebo-controlled, four-part cross-over design. Atrial natriuretic peptide and brain natriuretic peptide were given at the rate of 0.75 and 0.4 pmol min −1 kg −1 , respectively, for 3 h. The control infusion consisted of the vehicle. 4. Analysis of variance showed that atrial natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide, but not brain natriuretic peptide alone, increased urinary flow and decreased urinary osmolality significantly. However, urinary sodium excretion was significantly increased by atrial natriuretic peptide, brain natriuretic peptide and atrial natriuretic peptide plus brain natriuretic peptide. 5. None of the four infusates significantly altered the blood pressure, heart rate or glomerular filtration rate. 6. This study showed, for the first time, that physiological increments in brain natriuretic peptide, like those in atrial natriuretic peptide, are natriuretic. Although atrial natriuretic peptide and brain natriuretic peptide do not appear to interact synergistically, they are likely to act in concert in the physiological regulation of sodium balance.

1. Guanine nucleotide-binding proteins (G-proteins) play a central role in signal transduction between a wide variety of cell-surface receptors and intracellular second messenger systems. Recently, we and others have demonstrated that cross-regulation can occur between a variety of G-protein-linked receptors in human heart. Chronic β 1 -adrenoceptor blockade gives rise to sensitization of β 2 -adrenoceptor and of 5HT 4 -receptor responses, both of which are mediated via stimulation of adenylate cyclase through stimulatory G-proteins (G s ), and also gives rise to desensit-ization of muscarinic M 2 -receptor responses, which inhibit adenylate cyclase through inhibitory G-proteins (G i ). 2. In order to investigate whether these effects are due to quantitative changes in cardiac G-protein isoforms, we measured their abundance in right atrial appendage from patients taking or not taking β 1 -adrenoceptor antagonists, by immunoblotting. 3. Samples of right atrial appendage homogenate were subjected to SDS/PAGE, and proteins were electroblotted on to nitrocellulose membranes. These were then probed with specific anti-G protein anti-sera, and binding was revealed by means of a secondary antibody labelled with alkaline phosphatase and using a chromogenic substrate. The resulting bands were quantified by laser densitometry. 4. No quantitative differences were detected, between these two groups of patients, in the amounts of α-subunit of ‘long’ or ‘short’ G s isoforms (G s αL and G s αS), or in the amounts of G i 1 + 2 α-subunit (G i α1 + 2). Nor was any difference found in the abundance of the β-subunit of G-proteins. No ‘other’ G-protein (G o ) was detectable in these samples by immunoblotting. 5. We conclude that the phenomenon of receptor cross-regulation which we have previously observed in human right atrial appendage is unlikely to be explained by quantitative changes at the G-protein level.

1. To examine the metabolic effects of increases in circulating endogenous plasma catecholamines, we measured plasma glucose, potassium and magnesium in 14 patients undergoing elective coronary artery bypass grafting. The patients were randomized into two groups and received either sodium nitroprusside (a direct-acting vasodilator) or trimetaphan camsylate (a ganglion-blocking agent) for routine control of blood pressure during the operation. 2. There were significant differences between the two groups in the levels of all three metabolic variables studied. Plasma glucose levels rose in both groups, but were significantly higher in the sodium nitroprusside group [peak levels 9.14 ( sem 0.72)mmol/l compared with 6.71 (0.88) mmol/l, P < 0.001, analysis of variance]. The cardioplegia solution caused a large increase in plasma magnesium in both groups but in the sodium nitroprusside group the level rose higher [to 1.59 (0.12)mmol/l compared with 1.34 (0.06)mmol/l] and fell faster ( P < 0.05, analysis of variance). In the group receiving sodium nitroprusside, plasma potassium fell, by a mean of 0.34 mmol/l, as plasma catecholamine levels rose; no such fall was seen in the group receiving trimetaphan camsylate ( P < 0.05, analysis of variance). 3. It is concluded that the sympathoadrenal system is important in causing metabolic changes during cardiopulmonary bypass and may be relevant in other conditions such as acute myocardial infarction.

From this issue, Clinical Science will increase its page numbers from an average of 112 to 128 per monthly issue. This welcome change — equivalent to at least two manuscripts — has been ‘forced’ on us by the increasing pressure on space; this has led to an undesirable increase in the delay between acceptance and publication, and to a fall in the proportion of submitted manuscripts we have been able to accept. The change in page numbers will instead permit us now to return to our exceptionally short interval between acceptance and publication of 3–4 months; and at the same time we shall be able not only to accept (as now) those papers requiring little or no revision, but also to offer hope to some of those papers which have raised our interest but come to grief in review because of a major but remediable problem. Our view, doubtless unoriginal, has been that the review process, which is unusually thorough for Clinical Science , involving a specialist editor and two external referees, is most constructive when it helps the evolution of a good paper from an interesting piece of research. Traditionally, the papers in Clinical Science have represented some areas of research more than others. However, this has reflected entirely the pattern of papers submitted to us, rather than any selective interest of the Editorial Board, which numbers up to 35 scientists covering most areas of medical research. Arguably, after the explosion during the last decade of specialist journals, the general journal can look forward to a renaissance in the 1990s, as scientists in apparently different specialities discover that they are interested in the same substances, asking similar questions and developing techniques of mutual benefit to answer these questions. This situation arises from the trend, even among clinical scientists, to recognize the power of research based at the cellular and molecular level to achieve real progress, and at this level the concept of organ-based specialism breaks down. It is perhaps ironic that this journal, for a short while at the end of the 1970s, adopted — and then discarded — the name of Clinical Science and Molecular Medicine , since this title perfectly represents the direction in which clinical science, and therefore Clinical Science , is now progressing.

1. The game of squash has recently been associated with a high incidence of ventricular arrhythmias and sudden death. To investigate this further, plasma catecholamines and potassium (K + ) were monitored during a game of squash in six normal volunteers. 2. No cardiac arrhythmias were seen in this study despite the subjects reaching maximum heart rates of 181 ± 5 beats/min (mean ± sem ). 3. During exercise, plasma K + rose from 3.82 ± 0.16 to 4.29 ± 0.2 mmol/l, but after 90 s rest this fell to 3.68 ± 0.28 mmol/l and after 180 s to 3.44 ± 0.17 mmol/l. This rapid K + shift could not be accounted for by generalized changes in venous acid-base status or by changes in venous plasma catecholamines. Although pre-treatment with a β 2 -antagonist caused the overall plasma K + levels to be higher, it had no significant effect on the fall in plasma K + after exercise. 4. Such rapid K + shifts after exercise might contribute to arrhythmogenesis in susceptible individuals. The precise mechanism of the fall in K + after exercise remains undetermined, but it seems not to involve catecholamines stimulating β 2 -adrenoceptors and is more likely to be due to increased skeletal muscle blood flow and/or intracellular acidosis.

1. In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. 2. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 ± 5 to 55 ± 7mmHg ( P < 0.05), the heart rate to increase from 61 ± 7 to 87 ± 5 beats/min ( P < 0.05) and the skin temperature to increase from 33.7 ± 0.9 to 34.9 ± 0.5°C. Plasma noradrenaline increased from 481 ± 126 to 835 ± 65 pg/ml ( P < 0.05) and plasma adrenaline from 57 ± 17 to 82 ± 12 pg/ml ( P < 0.05). There were no significant changes in the albumin-corrected plasma calcium. 3. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

1. Six healthy volunteers received a 60 min infusion of guanfacine (α 2 -agonist) on two occasions, preceded by either idazoxan (α 2 -antagonist) or vehicle. 2. Idazoxan elevated blood pressure by 8/7 mmHg, but there was no change on either day during guanfacine infusion. 3. Guanfacine reduced plasma noradrenaline by approximately 30%, and this was not antagonized by idazoxan. By contrast, the 30-fold increase in plasma growth hormone caused by guanfacine was almost completely blocked by idazoxan. 4. Guanfacine caused a two- to three-fold increase in plasma glucagon and a similar reduction in plasma insulin. Only the latter was antagonized by idazoxan. No consistent changes in plasma ACTH were observed after either idazoxan or guanfacine. 5. Idazoxan itself elevated plasma noradrenaline up to twice baseline values, but did not affect the other metabolic measurements. 6. α 2 -Adrenoceptor stimulation plays a minor role in control of hormone release but has a greater physiological role in regulating release of the neurotransmitter, noradrenaline.

1. Ventral noradrenergic projections (VNAB) from lateral tegmental (A 1 , A 2 ) and dorsal noradrenergic projections (DNAB) from the coeruleal (A 6 ) as well as A 1 cell groups in the brain-stem of the rat were lesioned by intracerebral injection of 6-hydroxydopamine. 2. A marked increase in plasma renin activity and adrenaline concentrations followed haemorrhage (0.5 ml/100 g body weight) in the sham-operated rats. VNAB-lesioned rats showed a similar response to the sham-operated controls, but in DNAB-lesioned animals the rise of plasma renin was markedly attenuated.

1. Venous plasma histamine and catecholamines were measured in stable asthmatic subjects by a recently developed specific and sensitive radioenzymatic assay. 2. Plasma histamine concentrations were significantly elevated in both extrinsic and intrinsic asthmatic subjects, compared with both normal controls and patients with chronic obstructive airways disease. There was no correlation between histamine concentration and severity of airways obstruction, however. 3. Elevated plasma histamine concentrations at rest-5-indicate increased release of mediators from ‘leaky’ mast cells in asthma. 4. Plasma catecholamine concentrations in asthmatic subjects did not differ from normal and there was no correlation with severity of broncho- constriction or with plasma histamine concentration.

1. A novel use of a double-isotope method is described which allows radioenzymatic assays to combine precision and sensitivity. 2. In the catechol O -methyltransferase assay separate portions of each plasma sample are incubated with either S -[ 3 H]- or S -[ 14 C]-adenosyl- l -methionine. Standards of noradrenaline and adrenaline are added to the latter portions and are thus converted into standards of [ 14 C]metadrenalines. These are added to the 3 H-labelled portions after the incubation, where they function as tracers. 3. The final recovery of 14 C radioactivity corrects for (a) the efficiency of methylation in the plasma sample concerned and (b) the recovery of metadrenalines during the extraction procedures. 4. The 3 H/ 14 C ratio is constant in each assay for a given catecholamine concentration and is determined for samples to which standards of noradrenaline and adrenaline are added to the 3 H- (as well as the I4 C-) labelled portions before the initial incubation. 5. The sensitivity of the assay is increased by using high specific radioactivity S -[ 3 H]adenosyl- l -methionine (60-85 Ci/mmol), and low backgrounds are maintained by catecholamine depletion in vivo in the rats used for enzyme preparation. 6. Both catecholamines (1.5 pg/ml; 10 pmol/l) may be detected; the coefficients of variation are 3.0 and 3.2% for noradrenaline and adrenaline respectively (intra-assay) and 4.6 and 5.0% (inter-assay).

1. The validity of plasma noradrenaline as an index of sympathetic nervous activity was assessed by estimating variation in individual organ contribution to circulating concentrations. 2. Arteriovenous (A—V) differences in noradrenaline and adrenaline concentration were measured across several organs in nine patients with mild essential hypertension, in five with renal artery stenosis and 15 phaeochromocytoma patients. 3. In patients with phaeochromocytomas the percentage extraction of noradrenaline and adrenaline (estimated from the A—V differences) was similar across all organs, suggesting that adrenaline extraction could be used as a marker for noradrenaline extraction. 4. In the non-tumour patients the A—V difference for noradrenaline was less than that for adrenaline across most organs studied, reflecting the net result of noradrenaline release and extraction. The estimated contribution of various organs to the noradrenaline concentrations in their venous effluent was: heart. 21%; kidney 47%; legs 68%. 5. This pattern of A—V difference proved a positive diagnostic feature for non-tumour patients since it was not found even in the patients with small phaeochromocytomas, whose peripheral venous noradrenaline concentration alone did not distinguish them. 6. The venous-arterial difference across the adrenal glands of non-tumour patients was more than 10-fold greater for adrenaline than that for noradrenaline. Since the mean arterial concentration of noradrenaline was more than fivefold higher than that of adrenaline, the normal adrenal contribution to circulating noradrenaline is likely to be less than 2%. 7. In the patients with renal artery stenosis renal venous concentrations of noradrenaline (from the ischaemic kidney) were higher than arterial values, but mean arterial values were no higher than in the essential hypertensive patients. 8. Local variations in sympathetic activity may occur without altering the plasma noradrenaline concentration measured in peripheral plasma.

1. Venous plasma histamine was measured by a specific and sensitive radioenzymatic assay in seven male extrinsic asthmatic and six age-matched non-atopic non-asthmatic male subjects during exercise and voluntary isocapnic hyperventilation. 2. There was no change in peak expiratory flow in normal subjects with exercise or hyperventilation, but asthmatic subjects showed a 29.4 ± sem 5.8% fall after exercise and a 29.0 ± 5.4% fall after matched hyperventilation. 3. Plasma histamine was significantly higher ( P < 0.05) in asthmatic (6.2 ± 0.95 nmol/l) than that in normal subjects (3.4 ± 0.61 mmol/l) and showed a significant ( P < 0.01) rise (to 14.4 ± 1.83 nmol/l) during exercise in asthmatic, but not in normal subjects. This suggests that discharge of mast-cell mediators may occur during exercise in asthmatic subjects who develop exercise-induced asthma. 4. With hyperventilation there was no change in plasma histamine in either asthmatic or normal subjects, but this does not exclude the possibility that mediators may be released locally in the airways.

1. The importance of central vasomotor effects of endogenously generated angiotensin in the acute hypertensive response to renal artery constriction has been investigated in the anaesthetized greyhound. 2. When the central cardiovascular action of angiotensin was abolished by thermocoagulation of the areas postrema, the hypertensive response to renal artery constriction was reduced by half while the increase in plasma renin activity was unchanged. 3. It is concluded that central vasomotor effects of angiotensin play a significant role in renin-dependent hypertension.