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Background: The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate ([HCO.sup.-.sub.3]) secretion [...]

A fatal case of Lactobacillus rhamnosus septicaemia after prolonged oral vancomycin for recalcitrant Clostridium difficile infection is reported. The patient was immunosuppressed with cyclophosphamide and steroids for Sjogren's syndrome. The [...]

The human race is genetically programmed to consume less than 1 g of salt per day. In most human populations, the diet contains 6 to 12 g of salt per day and, in contrast to populations that consume less than 3 g of salt per day, their blood pressure rises with age. Independent of the rise in blood pressure, a high-salt diet also increases left ventricular mass, incidence of strokes, stiffness of conduit arteries, and activity of resistance arteries. In populations with high salt intake, a modest reduction in salt intake lowers blood pressure and diminishes cardiovascular disease and mortality.

Removal of fetal lung fluid at birth is crucial to survival. In vivo, a reversal in the direction of vectorial, amiloride-sensitive Na+ transport can be stimulated by ETYA, a nonmetabolizable analogue of the naturally occurring unsaturated fatty acid, arachidonate. Using the patch-clamp technique, fetal guinea pig alveolar type II pneumocyte single Na+ channel activity was robustly activated by 10 μM arachidonate, ETYA, oleate and stearate; this was unaffected by cyclooxygenase and 5′lipoxygenase inhibitors. The Na+ channel expressed in fetal guinea pig alveolar epithelial type II pneumocytes has biophysical properties compatible with species-specific coexpression of a novel variant of αENaC with βENaC. γENaC is either not expressed in this tissue or shares very little homology with the rat and human γ subunit. Thus, dramatic stimulation of this channel by arachidonate explains the in vivo observation of gestation-dependent reversal of fetal transepithelial driving force and may, therefore, be of physiological significance during the transition to breathing air at birth.

The BH3-only proteins Bim and Bad bind to the antiapoptotic Bcl-2 proteins and induce apoptosis in wild-type cells and cells from either bax(-/-) or bak(-/-) animals. In contrast, constitutively active forms of Bim and Bad failed to induce apoptosis in bax(-/-)bak(-/-) cells. Expression of Bax restored susceptibility of the cells to Bim and Bad. In addition, Bax but not Bim or Bad sensitized the bax(-/-)bak(-/-) cells to a wide variety of cell death stimuli including UV irradiation, chemotherapeutic agents, and ER stress. These results suggest that neither activation of BH3-only proteins nor suppression of pro-survival Bcl-2 proteins is sufficient to kill cells in the absence of both Bax and Bak. Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p53(-/-) MEF. Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation.

Salt-sensitive hypertension is common in people of African origin, and may be caused by increased transepithelial sodium absorption. The pH of nasal secretions is negatively correlated with the difference in Na+ concentration between nasal secretions and plasma, and may be a marker of transepithelial sodium absorption. Nasal pH was measured using a probe sited under the inferior turbinate. Measurements of nasal pH were reproducible, with a coefficient of variation of 3.3% for repeated measurements on the same day and of 2.7% between measurements on different days. Nasal pH did not correlate with nasal potential difference, a measure of transepithelial sodium absorption. Nasal pH was significantly lower in 89 black individuals (24 normotensive and 65 hypertensive) than in 51 white individuals (26 normotensive and 25 hypertensive) (black normotensive. 6.44±0.08; black hypertensive, 6.62±0.05; white normotensive, 6.91±0.06; white hypertensive, 6.98±0.06), after adjustment for age, gender, current smoking status, body mass index and 24 h urinary sodium excretion (P = 0.002), but was not significantly different between the normotensive and hypertensive individuals. Nasal pH was more acidic in black than in white individuals, which may represent generalized up-regulation of sodium transport in black people. However, the lack of correlation between nasal pH and potential difference suggests that nasal pH is, at best, only weakly related to transepithelial sodium absorption. Ethnic differences in nasal pH may be of direct relevance in the airways, as many of the functions of airway surface liquid are dependent on pH.

BackgroundWe have previously reported the use of a hospital based respiratory nurse service (Acute Respiratory Assessment Service, ARAS) to support home treatment of patients with exacerbations of chronic obstructive pulmonary disease (COPD). A controlled trial was undertaken to compare early discharge with home treatment supported by respiratory nurses with conventional hospital management of patients admitted with exacerbations of COPD.MethodsPatients with COPD admitted as emergencies were identified the next working day. They were eligible for inclusion in the study if the differential diagnosis included an exacerbation of COPD, but were excluded if other medical conditions or acidotic respiratory failure required inpatient investigation or management. Of 360 patients reviewed, 209 were being assessed for other active medical problems and were excluded, 33 potential participants were already involved in research studies and so were ineligible, and 37 did not wish to participate in the study. Eighty one patients were randomised to receive conventional inpatient care (n=40) or to planned early discharge the next working day (n=41). Those discharged early continued treatment at home under the supervision of specialist respiratory nurses. Outcome measures were readmission, additional hospital days, and deaths within 60 days of initial admission. Process measures included number of visits, duration of follow up by the respiratory nurse, and additional treatment provided to support early discharge.ResultsOn an intention to treat basis, a policy of early discharge reduced inpatient stay from a mean of 6.1 (range 1-13) days with conventional management to 3.2 (1-16) days with an early discharge policy. Twelve patients (30% conventional management, 29.3% early discharge) were readmitted in each group giving a mean difference in readmission of 0.7% (95% CI of the difference -19.2 to 20.6). In the conventional management group readmitted patients spent a mean of 8.75 additional days in hospital compared with 7.83 days in the early discharge group, giving a mean difference of 0.92 days (95% CI of the difference -6.5 to 8.3). There were two deaths (5%) in the conventional management group and one (2.4%) in the early discharge group, a mean difference of 2.6% (95% CI of the difference -5.7 to 10.8).ConclusionsPatients with acute exacerbations of COPD uncomplicated by acidotic respiratory failure or other medical problems can be discharged home earlier than is current practice with support by visiting respiratory nurses. No difference was found in the subsequent need for readmission.

Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during the pregnancy cycle. After weaning, secretory epithelial cells are removed by apoptosis. To determine whether members of the Bcl-2 gene family could be involved in regulating this process, we have examined whether changes in their expression occur during this developmental apoptotic program in vivo. Bax and Bcl-x were evenly expressed throughout development. However, expression of Bak and Bad was increased during late pregnancy and lactation, and the proteins were present during the time of maximal apoptotic involution. Thereafter, their levels declined. In contrast, Bcl-w was expressed in pregnancy and lactation but was downregulated at the onset of apoptosis. Bcl-2 was not detected in lactating or early involuting mammary gland. Thus, the pro-apoptotic proteins Bax, Bak and Bad, as well as the death-suppressors Bcl-x, Bcl-2 and Bcl-w, are synthesised in mouse mammary gland, and dynamic changes in the expression profiles of these proteins occurs during development. To determine if changes in Bak and Bcl-w expression could regulate mammary apoptosis, their effect on cultured mouse mammary epithelial cells was examined in transient transfection assays. Enforced expression of Bak induced rapid mammary apoptosis, which could be suppressed by coexpression of Bcl-w. In extracts of mammary tissue in vivo, Bak heterodimerized with Bcl-x whereas Bax associated with Bcl-w, but Bak/Bcl-w heterodimers were not detected. Thus, Bak and Bcl-w may regulate cell death through independent pathways. These results support a model in which mammary epithelial cells are primed for apoptosis during the transition from pregnancy to lactation by de novo expression of the death effectors Bak and Bad. It is suggested that these proteins are prevented from triggering apoptosis by anti-apoptotic Bcl-2 family proteins until involution, when the levels of Bcl-w decline. Our study provides evidence that regulated changes in the expression of cell death genes may contribute to the developmental control of mammary apoptosis.

1. Saralasin (Sar1-Ala8-angiotensin II), a competitive inhibitor of angiotensin II (AII), has been infused into normal subjects and patients with essential hypertension when deprived of sodium by 5 days of a 10 mmol/day sodium diet. 2. When saralasin was given by an incremental rate of infusion starting at 0·25 µg min—1 kg—1, sodium-deprived normal subjects showed a fall in standing blood pressure with no change in lying blood pressure, sodium-deprived normal-renin hypertensive patients showed no change in lying or standing blood pressure and sodium-deprived low-renin patients showed a significant sustained rise in lying and standing blood pressure. 3. These findings suggest that: (a) standing blood pressure in sodium-deprived normal subjects is angiotensin II dependent; (b) normal-renin hypertensive patients when sodium deprived by diet alone do not appear to be angiotensin II dependent (angiotensin II is unlikely therefore to be directly maintaining their blood pressure on their normal sodium intake); (c) the rise in blood pressure seen in low-renin hypertensive patients with saralasin may be a further way of distinguishing this group of patients.

1. Propranolol, saralasin and captopril changed blood pressure in normotensive as well as hypertensive subjects. 2. The percentage change in blood pressure with these three drugs for a given plasma renin activity was similar in normotensive and hypertensive subjects. 3. This suggests that when the renin-angiotensin system is maintaining blood pressure, it maintains the blood pressure to the same extent in percentage terms in normotensive and hypertensive subjects for a given plasma renin activity. 4. Saralasin has marked agonist activity, and probably underestimates the participation of the renin—angiotensin—aldosterone system in the maintenance of blood pressure. The fall in blood pressure that occurred with captopril in normal subjects on their normal sodium intake suggests that the renin—angiotensin—aldosterone system may have an important role in the control of blood pressure in normal subjects on their normal sodium intake. If it does, our results suggest that the renin—angiotensin—aldosterone system plays no greater role in maintaining blood pressure in patients with essential hypertension than normotensive subjects for a given plasma renin activity.

1. Captopril given for 5 days caused a fall in blood pressure in normotensive subjects. The percentage fall in mean supine pressure was greatest on a low sodium diet (10 mmol/day), 19.6%, least on a high sodium diet (350 mmol/day), 11%, and in between on a normal sodium diet (120 mmol/day), 16.5%. 2. Captopril caused a marked fall in plasma aldosterone in normal subjects on all three sodium intakes. 3. Captopril caused an increase in sodium excretion on the normal (120 mmol/day) and low (10 mmol/day) sodium diet but not the high sodium diet. 4. These results suggest that the renin-angiotensin-aldosterone system is a normal mechanism for maintaining blood pressure and aldosterone secretion in normotensive man. The system may also be involved in the maintenance of sodium balance. 5. These results may lead to a better understanding of the role of the renin-angiotensin-aldosterone system in the maintenance or causation of high blood pressure in essential hypertension.

1. The aim of this study was to determine plasma levels of N-terminal atrial natriuretic peptide and atrial natriuretic peptide in normal subjects and in patients with essential hypertension, cardiac transplant and chronic renal failure, using radioimmunoassays directed towards the mid-portion pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30) of the N-terminal atrial natriuretic peptide and atrial natriuretic peptide (99-126). The circulating form(s) of the immunoreactive N-terminal atrial natriuretic peptide in plasma extracts has been investigated using all three radioimmunoassays by means of gel filtration chromatography to further clarify the major immunoreactive molecular circulating form(s) of N-terminal atrial natriuretic peptide in man. 2. The plasma level (mean ± SEM) of N-terminal pro-atrial natriuretic peptide (31-67) in the normal subjects was 547.2 ± 32.7 pg/ml (n = 36) and was significantly elevated in patients with essential hypertension (730.2 ± 72.3 pg/ml, P < 0.025, n = 39), in cardiac transplant recipients (3214.0 ± 432.2 pg/ml, P < 0.001, n = 9) and in patients with chronic renal failure (3571.8 ± 474.1 pg/ml, P < 0.001, n = 11). Plasma levels of N-terminal pro-atrial natriuretic peptide (1-30) and atrial natriuretic peptide were similarly elevated in the same patient groups when compared with the mean plasma values in the normal subjects. 3. There were positive associations between pro-atrial natriuretic peptide (31-67) and atrial natriuretic peptide, pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30) and between pro-atrial natriuretic peptide (1-30) and atrial natriuretic peptide in the normal subjects, hypertensive patients, cardiac transplant recipients and patients with chronic renal failure. The correlation coefficient for all groups taken together was 0.86 (P < 0.001. n = 95) for pro-atrial natriuretic peptide (31-67) and atrial natriuretic peptide, 0.93 (P < 0.001, n = 95) for pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30), and 0.82 (p < 0.001, n = 95) for pro-atrial natriuretic peptide (1-30) and atrial natriuretic peptide. 4. Gel filtration of extracted plasma from cardiac transplant patients and patients with chronic renal failure indicated a single peak of immunoreactivity for N-terminal atrial natriuretic peptide using both the pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30) radioimmunoassays, suggesting a major single high-molecular-mass circulating immunoreactive N-terminal atrial natriuretic peptide, probably pro-atrial natriuretic peptide (1-98). Atrial natriuretic peptide immunoreactivity, as measured by the radioimmunoassay for atrial natriuretic peptide (99-126), showed a separate and distinct peak from that of the N-terminal atrial natriuretic peptide, which co-eluted with the synthetic human standard atrial natriuretic peptide (99-126). 5. These results show that immunoreactive N-terminal atrial natriuretic peptide and atrial natriuretic peptide are elevated in patients with essential hypertension, in cardiac transplant recipients and in patients with chronic renal failure. The major immunoreactive form of N-terminal atrial natriuretic peptide cross-reacting in both the pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30) radioimmunoassays is of a high molecular mass, probably pro-atrial natriuretic peptide (1-98). Since pro-atrial natriuretic peptide (1-98) is unlikely to cross-react identically with antibodies for pro-atrial natriuretic peptide (31-67) or pro-atrial natriuretic peptide (1-30), this could account for the differences in plasma levels obtained by the assays for pro-atrial natriuretic peptide (31-67) and pro-atrial natriuretic peptide (1-30).

Platelet volume is a measure of platelet function. An increased platelet volume is found in acute vascular syndromes and may have a causative role and predict outcome. Patients with autosomal dominant polycystic kidney disease (APKD) are at increased risk of developing, and dying from, premature vascular disease. We hypothesized that platelet volume might be altered in patients with APKD. Platelet volume was measured in 16 normotensive APKD patients with normal renal function and 16 normal volunteers pair-matched for age, gender, race and body mass index.Mean platelet volume was increased by 0.4 fl (95% confidence limits 0.1 to 0.9, 2P=0.017) in patients with APKD as compared with normal subjects: median 8.4 fl (0.7) versus 8.0 fl (0.3) respectively. In contrast, platelet count was lower by 63 × 109/1 (-5 to -108, 2P = 0.031): 225 (40) × 109/1 versus 280 (35) × 109/1 while the platelet mass was not different, -0.36 ml/l (-0.81 to 0.02, 2P=0.070): 1.82 (0.30) ml/l versus 2.28 (0.38) ml/l. Platelet volume and count were inversely correlated across the two groups, rs= -0.342 (2P=0.055). Serum levels of erythropoietin, a hormone that contributes to the regulation of thrombopoeisis, were not different between the APKD patients and normal controls, 35 U/1 (-71 to 120, 2P=0.42): 107 U/I (53) versus 84 U/I (57). Although erythropoietin did not correlate with platelet volume, R., = -0.185 (2P =0.36), it was positively associated with platelet count, R., = 0.465 (2P=0.029) and platelet mass, rs = 0.466 (2P= 0.028).Since an increased platelet volume is associated with platelet hyperactivity, the increased platelet volume in APKD may be a marker, or even contribute to the development, of premature vascular disease and sudden cardiac death in patients with APKD.

The kinetics of urinary sodium excretion was studied during sodium restriction and sodium supplementation in normal subjects. Eight were studied on a normal sodium intake (24 h urinary sodium: 133.3 ± 9.6 mmol) and then during 6 days on a low sodium intake of 10 mmol/day. Six other subjects were studied after equilibration on the low sodium intake for 7 days and then during 5 days on a high sodium intake of 350 mmol/day. 24 h urinary sodium excretion during sodium restriction was consistent with a first-order exponential process with an estimated half-life of 21.8 ± 2.4 hours. During sodium supplementation there were corresponding increases in urinary sodium excretion reaching the new steady-state within 3 days but the behaviour of the urinary sodium excretion during the transition period was not consistent with a mono-exponential process. These observations support the concept that the control of sodium balance, during sodium restriction at least, is consistent with a first order proportional feed-back system. This kinetic approach should provide a useful framework for further studies on the dynamics of sodium excretion.

There is controversy about the relationship between sodium intake and the prevalence of high blood pressure. Part of this controversy relates to how an increase in sodium intake could cause an increase in peripheral resistance. We have put forward the following hypothesis. In essential hypertension there is an inherited defect of the kidney's ability to excrete sodium which becomes increasingly obvious the greater the sodium intake. This difficulty in sodium excretion by the kidney increases the concentration of a circulating sodium transport inhibitor that affects sodium transport across many cell membranes. In the kidney the inhibitor adjusts urinary sodium excretion back towards normal sc that sodium balance is near that of normal subjects on the same intake of sodium. In the arteriolar smooth muscle the inhibition of sodium transport across the cell wall causes a rise in intracellular sodium concentration which, in turn, raises the intracellular calcium concentration and thus increases vascular reactivity. This hypothesis also proposes that the abnormalities of sodium transport in circulating cells in vivo are directly due to the increased secretion of the circulating sodium transport inhibitor. Evidence supporting this hypothesis is discussed. Firstly, it is pointed out that there is much evidence which suggests that there is a circulating inhibitor of Na+ -K+ -ATPase, the level of which is related to sodium intake and that the level of this inhibitor appears to be increased in many hypertensives. Secondly, the finding that normotensive white cells incubated in the plasma of hypertensive patients develop the same decrease in the Na+ -K+ -ATPase dependent sodium transport as the hypertensives own white cells also suggests that hypertensives have an increase in a circulating Na+-K+ -ATPase inhibitor.

The proportion of hexokinase (HK; EC 2.7.1.1) isozyme 1 (HK1) that is bound to the outer mitochondrial membrane is tissue specific and developmentally regulated. HK activity is known to be markedly elevated in many cancer cells and a significant fraction is mitochondrial bound. This study examined the role of the 15-amino acid N-terminal domain of HK1 in binding to liver and hepatoma mitochondria. A chimeric reporter construct, pCMVHKCAT, encoding this HK1 domain coupled to the chloramphenicol acetyltransferase (CAT) gene was electroporated into mouse Hepa 1-6 hepatoma cells. After digitonin treatment, cell fractions were assayed for HK, lactate dehydrogenase, and CAT activities. Digitonin (75 micrograms/mg of protein) caused cytosolic leak but 70% of HK remained with the pellet. HKCAT, like HK, remained predominantly with the pellet; CAT form the control, pCMVCAT, remained mostly unbound. Binding of membrane-free cell extracts to rat liver mitochondria in vitro showed 91% of the HKCAT bound, whereas only 12% of CAT bound. Specificity of HKCAT binding to mitochondria was demonstrated by competition of HK1 for HKCAT binding sites on rat liver mitochondria as well as by blockage of HKCAT binding by N,N'-dicyclohexylcarbodiimide, which covalently binds to porin and blocks HK1 binding. Deletional mutant constructs of HKCAT showed reduced binding with increasing deletion size. In summary, these studies demonstrate that the 15-amino acid N-terminal domain of HK1 is necessary and sufficient to confer mitochondrial binding properties to CAT and that there is specificity for this binding to the mitochondria.

1. The possible natriuretic and kaliuretic effects of a single dose of lithium, as used in lithium clearance studies, were investigated in 15 healthy subjects on fixed sodium (100 mmol/24 h) and potassium (70 mmol/24 h) intakes. Lithium carbonate (300 mg or 600 mg) or placebo tablets were administered, double-blind and in random order, midway through a 48 h urine collection (divided into six 8 h periods), at 23.00 hours. 2. During the three 24 h periods which preceded the administration of lithium or placebo (control days), rates of sodium and potassium excretion followed normal circadian patterns, but no differences in excretion rates between the 3 control days were observed. Placebo tablets did not affect excretion rates. 3. After the 300 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 17 mmol (P < 0.05); almost all of the natriuretic effect occurred during the first two 8 h periods. No effect on potassium excretion was observed. 4. After the 600 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 48 mmol (P < 0.001) and 24 h potassium excretion increased by approximately 19 mmol (P < 0.01). These effects were confined to the first two 8 h periods and thus occurred before and during the usual lithium clearance period. 5. Plasma renin activity, measured in 10 subjects, increased after the 600 mg dose of lithium carbonate (P < 0.005), but plasma concentrations of aldosterone and atrial natriuretic peptide were not significantly affected. Neither the 300 mg dose of lithium carbonate nor the placebo tablets affected hormone levels. 6. It is recommended that the test dose of lithium carbonate for use in lithium clearance studies should not exceed 300 mg.

1. Aldosterone is suppressed by sodium loading. We studied the contribution of this decrease in plasma aldosterone to the natriuresis after acute sodium loading in healthy volunteers. 2. Two litres of saline [0.9% (w/v) NaCl] were infused during the second hour of a 6 h infusion of aldosterone (3 pmol min−1 kg−1) or placebo in eight healthy young men. On the placebo day, plasma aldosterone decreased by 30 min after the start of saline infusion and remained suppressed. During aldosterone infusion, plasma aldosterone was maintained at around 400 pmol/l. 3. Urinary sodium excretion, lithium clearance and plasma atrial natriuretic peptide increased and plasma renin activity decreased after saline infusion, whether or not aldosterone was infused. However, from 60 to 240 min after saline infusion, natriuresis was significantly less during aldosterone infusion than on the placebo day. In addition, saline loading led to a progressive increase in the ratio of sodium clearance to lithium clearance, used as an index of the fractional distal tubular rejection of sodium, and in the ratio of urinary sodium to potassium. These increases were prevented by the infusion of aldosterone. 4. This study suggests that there are differences in the mechanisms determining the early and the later responses to an acute sodium load. Suppression of aldosterone may explain much of the later increase in natriuresis after saline infusion. In addition, the results are consistent with a role for atrial natriuretic peptide in the immediate increase in sodium excretion after saline loading.

1. Pressure was measured within 28 capillaries of the nailfolds of nine patients with essential hypertension and in 33 capillaries of nine age- and sex-matched normotensive control subjects, using direct micropuncture, a dynamic servo-nulling system and computerized analysis. 2. Average pressure at the apex of the capillary was found to be elevated in the patients with hypertension (21.1 ± 4.9 mmHg compared with 13.0 ± 2.0 mmHg in the control subjects; mean ± SD, P < 0.01). If the two groups were combined, there was an overall correlation between average capillary pressure and mean blood pressure (r = 0.68, P < 0.01, n = 18), but within each group separately there was no significant relation between these parameters. 3. There were also abnormalities in the waveforms of pulsations in capillary pressure in the group with hypertension, with an increased attenuation of high-frequency harmonics. Pulses appeared to be conducted more rapidly along the vascular tree in the patients with hypertension. 4. The elevation of capillary pressure in essential hypertension demonstrated in this study is in agreement with indirect evidence of capillary hyperfiltration provided by other studies which showed a reduced plasma volume and increased transcapillary escape rate of plasma proteins. 5. The finding of elevated capillary pressure demands the inclusion of the postcapillary segment (and possibly vascular density) in the resistance equation in essential hypertension.

1. To study the importance of cardiac innervation in the regulation of atrial natriuretic peptide, plasma atrial natriuretic peptide levels were measured during symptom-limited, graded exercise on a cycle ergometer in seven male orthotopic cardiac transplant recipients. 2. Resting plasma atrial natriuretic peptide was significantly higher in the transplant recipients than in two control groups, one matched to the transplant recipients (group 1) and the other to the age of the donor heart (group II). 3. The response to exercise of the cardiac transplant recipients was compared with the response of control group II. Mean maximal work load achieved with exercise was around 40% lower in the cardiac transplant recipients. During exercise, plasma atrial natriuretic peptide levels increased in both the cardiac transplant recipients and the control subjects. The increase in plasma atrial natriuretic peptide with exercise was greater in absolute, but less in percentage, terms in transplant recipients than in the control subjects. 4. The increase in mean arterial pressure with exercise was similar in patients and in control subjects; however, heart rate increased in the patients by only 33% compared with a rise of 151% in the control group. 5. These results provide insight into the control of the sodium regulatory hormone atrial natriuretic peptide. First, factors other than a change in heart rate appear of importance in the regulation of atrial natriuretic peptide. Secondly, these findings suggest that cardiac innervation is not of dominant importance in the modulation of atrial natriuretic peptide secretion.

1. The effects of synthetic human and rat atrial peptides on sodium and potassium ion transport has been investigated in intact human erythrocytes. 2. The effects of these peptides have been tested on the active, sodium pump-dependent (ouabain-sensitive) and on the sodium-potassium cotransport system (bumetanide-sensitive) with 86Rb used as a tracer. 3. Human (α-ANP, 28 amino acids) or rat (atriopeptin III) atrial peptides, over a wide range of concentrations, did not influence the uptake of 86Rb in either the ouabain-sensitive or the bumetanide-sensitive transport system. 4. These results suggest that the natriuretic effect of the atrial peptides is not mediated through inhibition of the sodium pump or the loop-diuretic-sensitive Na-K cotransport.

The acute effects on urinary electrolyte excretion and plasma potassium were compared of the anti-hypertensive dihydrofuropyridine cicletanine with the thiazide bendrofluazide in 6 patients with uncomplicated essential hypertension.

Multiple replication-defective retrovirus vectors were tested for their ability to transfer and express human adenosine deaminase in vitro and in vivo in a mouse bone marrow transplantation model. High-titer virus production was obtained from vectors by using both a retrovirus long terminal repeat promoter and internal transcriptional units with human c-fos and herpes virus thymidine kinase promoters. After infection of primary murine bone marrow with one of these vectors, human adenosine deaminase was detected in 60 to 85% of spleen colony-forming units and in the blood of 14 of 14 syngeneic marrow transplant recipients. This system offers the opportunity to assess methods for increasing efficiency of gene transfer, for regulation of expression of foreign genes in hematopoietic progenitors, and for long-term measurement of the stability of expression in these cells.

Renovascular disease is the most frequently encountered secondary cause of hypertension and is one of the few potentially reversible causes of chronic renal failure. These patients are at increased risk of having cerebrovascular events following operative management for atheromatous renal-artery stenosis. We studied the prevalence of carotid-artery disease in patients with atheromatous renal-artery stenosis.

Mouse primordial germ cells express tissue non-specific alkaline phosphatase (TNAP) during development, but the widespread expression of another alkaline phosphatase gene in the early embryo limits the potential use of this marker to trace germ cells. To attempt to identify germ cells at all stages during embryonic development and to understand the role of TNAP in germ cell ontogeny, mice carrying a beta geo (lacZ/neor) disrupted allele of the TNAP gene were generated by homologous recombination in embryonic stem cells. Using beta-galactosidase activity, the embryonic pattern of TNAP expression was examined from the blastocyst stage to embryonic day 14. Results indicate that primordial germ cell progenitors do not express TNAP prior to gastrulation although at earlier times TNAP expression is found in an extraembryonic lineage destined to form the chorion. In homozygous mutants, primordial germ cells appear unaffected indicating that TNAP is not essential for their development or migration.

A line of transgenic mice that carries an insertional mutation in a gene essential for spermatogenesis is described. Males homozygous for the transgenic insert are sterile, while female homozygotes and both male and female heterozygotes exhibit normal fertility. Developing spermatids in homozygous males form prominent abnormal multinucleated syncytia (symplasts) and do not complete maturation. In addition, abnormal cytoplasmic vacuolation is commonly seen in Sertoli cells. One flank of the transgenic integration site within the genome has been cloned and used to show linkage between homozygosity for the transgene and the mutant phenotype. The flank maps to mouse chromosome 14 approximately 4 centimorgans proximal to the gene encoding esterase-10 (Es-10). As no other gene that is known to be essential for spermatogenesis has been mapped to this region of the genome and as the mutant phenotype is unique, the transgenic insert appears to affect a previously unidentified gene. We have named the mutation "symplastic spermatids" (sys).

Abnormalities of calcium binding and calcium transport in cells from hypertensive subjects or animals have been previously described. Total cell sodium is reported to be increased in white blood cells from hypertensive subjects; thus by analogy with Blaustein's proposal for the vascular smooth muscle cell, mononuclear leucocyte cytosolic calcium might be increased via a reduction of the Na-Ca exchange. Using the fluorescent calcium indicator, quin 2, cytosolic calcium was measured in mononuclear leucocytes from 22 hypertensive and 19 normotensive subjects. There was no significant difference between the mononuclear leucocyte cytosolic calcium level in the two groups. Incubation of the cells with 104M ouabain reduced 86rubidium (86Rb) uptake by 80 of the control value but failed to alter cytosolic calcium. These findings are consistent with a minimal role of the Na-Ca exchange in the mononuclear leucocyte and may explain why the cytosolic calcium was not increased in hypertension despite the previous reports of increased total cell sodium in white blood cells.

1. The plasma's ability to stimulate guinea-pig renal glucose 6-phosphate dehydrogenase (G6PD) in vitro was measured by a cytochemical technique in 23 normotensive subjects and 19 patients with hypertension, all of whom were studied on their normal sodium intake. The ability of plasma to stimulate renal G6PD was significantly (P < 0.001) increased in the hypertensive patients (mean 195 ± 52 units/ml) compared with the normotensive subjects (mean 22.2 ± 5.8 units/ml). In all 42 individuals, there was a significant correlation between diastolic pressure and the ability of plasma to stimulate G6PD (r = 0.69 P < 0.001). 2. The ability of plasma to stimulate G6PD was greatest in the hypertensive patients with values of plasma renin activity below the normal range. In the normotensive subjects the ability of plasma to stimulate G6PD was significantly greater in the older subjects. 3. As the ability of plasma to stimulate G6PD reflects its ability to inhibit Na+,K+-dependent ATPase, these results suggest that patients with essential hypertension have an increase in a circulating inhibitor of Na+,K+-ATPase. The results support the hypothesis that a rise in a circulating sodium transport inhibitor may, in part, be responsible for the rise in blood pressure in essential hypertension, and may form the link between salt intake, abnormalities of sodium transport and a rise in blood pressure.

1. Seventy-seven patients with essential hypertension and 28 normotensive subjects were studied on their normal diet (ND), on the fifth day of a high sodium diet (HS) (350 mmol/day) and on the fifth day of a low sodium diet (LS) (10 mmol/day). 2. With an increase in sodium intake, there was no change in mean blood pressure either in the normotensive subjects (ND, 120/75 ± 2.4/1.7 mmHg—HS, 119/75 ± 2.7/1.7 mmHg) or in the hypertensive subjects (ND, 173/110 ± 2.5/1.3 mmHg—HS, 174/110 ± 2.5/1.4 mmHg). 3. On the fifth day of the low sodium diet there was no change in mean blood pressure in the normotensive subjects (ND, 120/75 ± 2.5/1.7 mmHg—LS, 116/76 ± 2.7/2.0 mmHg). In contrast, the hypertensive group on the fifth day of the low salt diet had a significant fall in supine mean blood pressure compared with those on the normal diet (ND, 173/110 ± 2.5/1.3—LS, 155/102 ± 2.2/1.3 mmHg; P < 0.001). The fall in mean blood pressure was 10.8 ± 1.1 mmHg (8.4%). 4. There was a significant correlation between the fall in blood pressure with the low sodium diet and the level of blood pressure on the normal diet (r = 0.52; P < 0.001) and a significant inverse correlation with the fall in blood pressure on the low sodium diet and the rise in plasma renin activity from the normal to low sodium diet (r = -0.36; P < 0.001). 5. Nineteen patients with mild to moderate essential hypertension were studied in a double-blind randomized crossover study of moderate dietary sodium restriction using slow sodium and placebo for 1 month each. On the fourth week of placebo (mean 24 h UNa 86 ± 9 mmol), mean supine blood pressure was 7.1 mmHg lower (6.1%), P < 0.001 compared with the fourth week of slow sodium (mean 24 h UNa 162 ± 9 mmol). 6. Moderate dietary sodium restriction over 1 month caused a fall in blood pressure in patients with essential hypertension. A more severe reduction in sodium intake for a shorter period of time lowered blood pressure in hypertensive but not normotensive subjects. Part of the mechanism of this blood pressure reduction with sodium restriction appeared to be related to the severity of the hypertension and to suppression of the renin-angiotensin system.

1. The present study was designed to investigate the relationships between circulating atrial natriuretic peptide, plasma and urinary cyclic GMP and sodium excretion under basal conditions and in response to changes in dietary sodium intake. 2. Measurements of plasma atrial natriuretic peptide and plasma and urinary (24 h collections) cyclic GMP, sodium and creatinine were made in (i) 30 normotensive subjects on their normal sodium intake and (ii) 12 subjects on the 5th day of a low and on the 5th day of a high sodium intake. 3. Plasma cyclic GMP, urinary cyclic GMP and fractional excretion of cyclic GMP in 30 normotensive subjects on their normal sodium intake were (means ± SEM) 5.4 ± 0.5 pmol/ml, 434.5 ± 31.8 pmol/min and 86.9 ± 8.6%, respectively. There were significant correlations between urinary cyclic GMP and its corresponding filtered load (r = 0.55) and between the renal clearance of cyclic GMP and that of creatinine (r = 0.44), but there were no significant associations between circulating atrial natriuretic peptide and plasma cyclic GMP or the fractional excretion of cyclic GMP or between urinary sodium and the fractional excretion of cyclic GMP. 5. Plasma atrial natriuretic peptide was significantly raised on the 5th day of the high sodium intake compared with the low sodium intake (10.6 ± 1.6 versus 4.2 ± 0.9 pg/ml; P <0.05). Similarly, there were increases in urinary cyclic GMP excretion (692.3 ± 43.4 versus 427.4 ± 41.9 pmol/min, P <0.05), but there were no significant differences in the fractional excretion of cyclic GMP. 6. As neither plasma nor urinary cyclic GMP was strongly associated with circulating levels of atrial natriuretic peptide, the present study suggests that other factors may be more important than circulating atrial natriuretic peptide as determinants of extracellular cyclic GMP.

1. We have developed a radioimmunoassay for the measurement of immunoreactive brain natriuretic peptide (1–32) in human plasma. Simultaneous measurements of atrial natriuretic peptide have also been carried out to allow for direct comparison between circulating brain natriuretic peptide and atrial natriuretic peptide. Plasma levels of immunoreactive brain natriuretic peptide (means ± sem) were 1.1 ± 0.1 pmol/l in 36 normal healthy subjects and were significantly elevated in cardiac transplant recipients (18.8 ± 3.9 pmol/l, n = 12) and in patients with dialysis-independent (8.8 ± 1.5 pmol/l, n = 11) or dialysis-dependent (41.6 ± 8.8 pmol/l, n = 14) chronic renal failure. Similarly, in these groups of patients plasma levels of atrial natriuretic peptide were also significantly raised when compared with those in the group of normal healthy subjects. 2. The plasma level of atrial natriuretic peptide was significantly higher than that of brain natriuretic peptide in normal subjects and in patients with dialysis-independent chronic renal failure, with ratios (atrial natriuretic peptide/brain natriuretic peptide) of 2.8 ± 0.2 and 2.2 ± 0.3, respectively. However, in both cardiac transplant recipients and patients on dialysis plasma levels of atrial natriuretic peptide and brain natriuretic peptide were similar, with ratios of 1.3 ± 0.2 and 1.0 ± 0.1, respectively, in these two groups. 3. Plasma levels of brain natriuretic peptide and atrial natriuretic peptide were significantly correlated in the healthy subjects and within each group of patients. When all groups were taken together, there was an overall correlation of 0.90 (P<0.001, n = 73). 4. Patients on dialysis had the highest plasma levels of both brain natriuretic peptide (41.6 ± 8.8 pmol/l, n = 14) and atrial natriuretic peptide (41.3 ± 9.4 pmol/l, n = 14) and the levels of both peptides declined significantly after maintenance haemodialysis. However, the overall percentage decrease in the plasma level of atrial natriuretic peptide (43.6 ± 7.5%) after dialysis was significantly greater than that observed for brain natriuretic peptide (15.9 ± 5.3%, P<0.005). 5. Displacement curves of iodinated atrial natriuretic peptide from bovine adrenal membranes by human atrial natriuretic peptide (99–126) and human brain natriuretic peptide (1–32) gave a median inhibitory concentration of 144 pmol/l for atrial natriuretic peptide and 724.4 pmol/l for brain natriuretic peptide. The cross-reactivity of human brain natriuretic peptide with the atrial natriuretic peptide receptor preparation was 19.5% of that of atrial natriuretic peptide, indicating that human brain natriuretic peptide has a lower binding affinity for the atrial natriuretic peptide receptor/binding site on bovine adrenal membranes. 6. These results suggest that brain natriuretic peptide is co-secreted with atrial natriuretic peptide and may also be an important factor in the adaptive mechanisms to impairment of renal function. However, whether brain natriuretic peptide has an independent and fundamentally important role in man remains to be investigated.

1. Plasma levels of immunoreactive N-terminal pro-atrial natriuretic peptide (N-terminal ANP) have been measured in 25 normal subjects, 29 patients with essential hypertension, six cardiac transplant recipients, seven patients with dialysis-independent chronic renal failure and 11 patients with haemodialysis-dependent chronic renal failure. Plasma was extracted on Sep-Pak cartridges and N-terminal ANP immunoreactivity was measured using an antibody directed against pro-ANP (1–30). 2. Plasma levels of TV-terminal ANP (means ± sem) were 235.3 ± 19.2 pg/ml in normal subjects and were significantly raised in patients with essential hypertension (363.6 ± 36.3 pg/ml), in cardiac transplant recipients (1240.0 ± 196.2 pg/ml), in patients with chronic renal failure not requiring dialysis (1636.6 ± 488.4 pg/ml) and patients with chronic renal failure on maintenance haemodialysis (10 336.1 ± 2043.7 pg/ml). 3. There were positive and significant correlations between the plasma levels of TV-terminal ANP and α-human ANP (α-hANP) with individual correlation coefficients of 0.68 within the normal subjects, 0.47 in patients with essential hypertension, 0.78 in patients with dialysis-independent chronic renal failure and 0.68 in patients with haemodialysis-dependent chronic renal failure (P < 0.05 in every case). 4. Gel filtration behaviour on Sephadex G-50 of the immunoreactive N-terminal ANP from Sep-Pak extracts of plasma from normal subjects or patients was consistent with a single peak having an elution volume corresponding to that of human pro-ANP (1–67) standard. 5. These studies demonstrate that the N-terminal pro-ANP peptide is co-secreted with α-hANP in both normal subjects and patients with cardiovascular/renal disease. The higher levels of the N-terminal ANP may reflect differences in the rate of elimination from the circulation but the exact structure and functional significance of the circulating N-terminal ANP remains to be established.

1. To study the anti-hypertensive effects of atrial natriuretic peptide (ANP), eight patients with mild to moderate essential hypertension, on no treatment, were infused with α-human ANP (102–126) (37 pmol min−1 kg−1) or placebo for 60 min and observed for a further 4 h on the fifth day of low and high sodium diets in a randomized, cross-over study. 2. Plasma ANP levels increased over 30-fold into the high pathophysiological range during ANP infusion, but had returned to control values by 60 min after the end of infusion. With ANP infusion, there was a large decrease in supine blood pressure which was similar on both the low and high sodium intakes and was maximal 20–40 min after completion of the infusion. These reductions in blood pressure were sustained for a further 4 h after the end of ANP infusion and for 3 h after plasma ANP levels had returned to control values. 3. Maximal urinary sodium excretion increased 10-fold on the low sodium diet (negative sodium balance 20 mmol) and threefold on the high sodium diet (negative sodium balance 30 mmol) during ANP infusion; however, during the 4 h after infusion, urinary sodium excretion was below placebo values. During ANP infusion, packed cell volume increased significantly on both diets but returned to control values by 4 h after the end of infusion. 4. There were no significant changes in plasma renin activity compared with placebo during or after ANP infusion. However, plasma aldosterone was significantly greater than placebo values after the end of ANP infusion on both low and high sodium diets. 5. The sustained fall in blood pressure after ANP infusion appears to be unexplained by changes in sodium balance, packed cell volume and plasma ANP levels. These findings suggest that ANP may have a prolonged action on a pressor mechanism which remains to be defined.

Because captopril alone does not control blood pressure in all patients with essential hypertension, studies were performed to assess the effect of sodium intake and of captopril combined with hydrochlorothiazide, propranolol, and nifedipine. Captopril given for 5 days to normotensive subjects having high, normal, and low sodium intakes reduced blood pressure the most in those on the lowest intake the fall correlated with that in plasma angiotensin II. When 12 patients with moderate hypertension had hydrochlorothiazide added to captopril their blood pressure fell significantly. When propranolol was added to captopril, however, there was no further fall in blood pressure. When propranolol was added to captopril and a diuretic, pressures measured 4 and 6 h after the last dose of captopril showed reduced values compared with placebo pressures measured 2 and 12 h after did not. Nifedipine added to captopril reduced blood pressure more than either drug alone. When renin and angiotensin are low, as they may be in essential hypertension, captopril is less effective its effectiveness should increase if sodium is restricted. Both diuretics and nifedipine increase the effectiveness of captopril propranolol does not, although it may prolong captopril's action. Experience in patients with resistant hypertension suggests that adding nifedipine to captopril may reduce the need for diuretics, while adding captopril to nifedipine may reduce the need for betablockers.

The effects of alterations in dietary potassium (40, 80 and 160 mmol day-1) on endocrine status and on renal lithium clearance were assessed in 10 healthy subjects on a fixed sodium intake; measurements were made on the fifth day of each dietary regimen. Plasma aldosterone concentration was found to increase with potassium intake, whereas plasma renin activity and the plasma concentration of atrial natriuretic peptide did not change significantly. Neither absolute lithium clearance nor fractional lithium excretion was affected measurably by changes in dietary potassium, suggesting that provided the potassium intake remains within the normal range it is unnecessary to control this factor during lithium clearance studies in man.

1. The pattern of urinary acid excretion during mannitol diuresis was studied in five normal adult subjects. 2. At peak diuresis (osmolal clearance 19·3–27·9 ml/min), the urinary pH approached 6·9 irrespective of the initial pH. 3. Total hydrogen ion excretion fell sharply during mannitol diuresis. Changes in the excretion of ammonium and titratable acid were small and variable, but in each subject bicarbonate excretion increased markedly. 4. Despite previous conflicting published results urinary acid excretion during mannitol diuresis in man resembles that in the dog and is dominated by a bicarbonate diuresis.

Plasma levels of atrial natriuretic peptides (ANP) were significantly higher in 7 patients with treated Addison’s disease (15.8 ± 8.8 pg/ml, mean ± SD) than in 7 control subjects (6.1 ± 3.8 pg/ml) matched for sex, age, body weight and blood pressure. All subjects were studied on their usual sodium intake and had similar urinary sodium excretions. These findings indicate inappropriately high leveles of plasma ANP in patients with treated Addison’s disease and are possibly due to the lack of adrenal control on ANP synthesis and/or secretion in these patients.

Twelve patients with essential hypertension on no other drug treatment were entered into a randomised crossover study of 5, 10 and 20 mg capsules of nifedipine given 3 times a day and 20 mg tablets given twice a day. Each dose was given for 2 weeks in a random order. All forms of nifedipine were effective in lowering blood pressure.