The renal epithelial sodium channel: genetic heterogeneity and implications for the treatment of high blood pressure.

The renal epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium reabsorption through the distal nephron. ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium channel activity (Liddle's Syndrome and Pseudohypoaldosteronism type 1 associated with contrasting effects on blood pressure). Subtle dysregulation of ENaC however may also be important in essential hypertension - a common condition and a major cause of cardiovascular morbidity and mortality. The epithelial sodium channel is formed from three partly homologous subunits. In this review we deals firstly with current views of structural and functional features of the renal epithelial sodium channel with particular emphasis on mechanisms and processes involved in the control of sodium channel activity at the biochemical and cellular levels. We then focus on genetic aspects with reference to the significance of genetic variation in the sodium channel genes in relation to blood pressure. In particular, we review recent investigations on the potential clinical significance of mutations within the genes encoding ENaC subunits in individuals with high blood pressure. Lastly, we also examine the potential value of pharmacological targeting of the renal epithelial sodium channel with the sodium channel inhibitor amiloride for the treatment of hypertension.

Atrial natriuretic peptide mimetics and vasopeptidase inhibitors.

There is now substantial evidence supporting a role of the natriuretic peptides as a major defence mechanism against excess salt and water retention and high blood pressure. Because of this there has been considerable interest in the therapeutic potential of the natriuretic peptide system. Several approaches have been explored including the use of native peptides, the development of natriuretic peptides mimetics and targetting of endogenous clearance of natriuretic peptides. While ANP and BNP administration may be valuable in some circumstances, however, the limitations of the use of peptides especially for long-term treatment are well apparent. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides through inhibition of breakdown by neutral endopeptidase. This research has now led to the vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin converting enzyme. These agents clearly provide a novel approach to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity and may lead to an important advance in the treatment of hypertension and of conditions associated with overt salt and water overload.

A diuretic is more effective than a beta-blocker in hypertensive patients not controlled on amlodipine and lisinopril.

The combination of an angiotensin-converting enzyme inhibitor and a calcium antagonist has a synergistic effect in patients with more severe hypertension. However, when this combination fails to control blood pressure, it is not clear which drug is then additive. The aim of this work was to study in a double-blind, randomized, crossover design the effect on blood pressure of the addition of either a thiazide diuretic (bendrofluazide, 5 mg once daily) or a beta-blocker (atenolol, 100 mg once daily) or placebo each for a month in hypertensive patients who are not adequately controlled on the combined treatment of amlodipine 5 mg once daily and lisinopril 5 mg twice daily. Eighteen patients with a supine diastolic pressure of more than 90 mm Hg after at least 1 month on the combined treatment of amlodipine and lisinopril were enrolled in the study. The results show that in patients whose blood pressures are not controlled by the combination of amlodipine and lisinopril, the addition of bendrofluazide 5 mg once daily causes a significant fall in blood pressure compared with placebo and a significantly greater fall than 100 mg atenolol once daily.

Evidence for increased levels of a circulating ouabainlike factor in essential hypertension.

The effect of plasma from normotensive and hypertensive subjects on the binding of [3H]ouabain on human erythrocytes was investigated. The binding of [3H]ouabain on human erythrocytes was saturable and highly specific; linear Scatchard plots indicated the presence of a single type of binding site. Human plasma decreased the binding of [3H]ouabain on its receptor to a greater extent than could be accounted for by the plasma potassium concentration. The level of this circulating ouabainlike factor (or factors) was quantitated using a radioreceptor assay. Plasma from 22 hypertensive subjects (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 90 mm Hg) displayed higher levels than that from 24 normotensive subjects; furthermore there was a positive and significant correlation (r = 0.42, n = 46, p less than 0.004) between the ouabainlike content and the individual subject's systolic blood pressure. The receptor assay described is relatively simple and should be useful for further work on the nature and clinical importance of the endogenous ouabainlike factor.

Importance of the renin system in determining blood pressure fall with salt restriction in black and white hypertensives.

Seventy-one white and 33 black patients with essential hypertension were studied while on a high sodium intake of 350 mmol/d for 5 days and low sodium intake of 10 mmol/d for 5 days. The fall in blood pressure on changing from the high sodium to the low sodium diet was 17/6 mm Hg in whites and 22/10 mm Hg in blacks. Compared with whites, black patients had a 7-mm Hg greater fall (P<0.05) in systolic blood pressure and 4-mm Hg greater fall (P=0.068) in diastolic blood pressure (adjusted for age and blood pressure on the normal diet) with similar changes in urinary sodium excretion. With sodium restriction, plasma renin activity rose from 0.65 to 3.03 ng. mL-1. h-1 in whites, whereas in blacks it rose only from 0.3 to 1.28 ng. mL-1. h-1 (P<0.001 between blacks and whites). From the high to the low salt diet, plasma angiotensin II increased by 31 pmol/L in whites and by 12 pmol/L in blacks (P<0.05 compared with whites), and plasma aldosterone rose by 499 pmol/L in whites and by 256 pmol/L in blacks (P<0.01). Significant inverse correlations were obtained for all patients between the fall in systolic blood pressure from the high to low salt diet and the rise in plasma renin activity and angiotensin II, as well as the absolute level on the low salt diet. These results demonstrate that the larger fall in blood pressure with a reduction in salt intake in blacks is due at least in part to a less responsive renin-angiotensin-aldosterone system in blacks.

Evidence using human arterial tissue for a circulating vascular sensitizing agent in essential hypertension.

We studied the effect of plasma from 12 patients with essential hypertension and 12 normotensive subjects on the contractile response to norepinephrine in human isolated arterial spiral strips. Human mesenteric and uterine arteries were obtained during abdominal surgery; they were cut into spiral strips and set up in isolated organ baths. After the equilibration period, arterial strips were incubated for 20 min in plasma from either normotensive subjects or hypertensive patients, and the contractile responses to norepinephrine (2.96 X 10(-7) M) were recorded. Plasma from hypertensive subjects significantly increased the contractile response to norepinephrine by 25.8% (P less than 0.02). Plasma from normotensive subjects did not increase the contractile response to the pressor agent (-3.2%; P = NS). The mean change in contractile response to norepinephrine in the presence of plasma from hypertensive patients was significantly higher than that after incubation of the human arterial strips in plasma from normotensive subjects (P less than 0.02). When both groups were considered as a whole, there was a significant correlation between diastolic pressure and the change in the contractile response to norepinephrine (r = 0.52; P less than 0.01). These results suggest the existence of a circulating vascular sensitizing substance in patients with essential hypertension.

Reduction of salt intake during converting enzyme inhibitor treatment compared with addition of a thiazide.

A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor. However, it is unclear how effective reduction of salt intake is compared with addition of other drugs, in particular, thiazide diuretics. We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the pressure of a converting enzyme inhibitor in a double-blind, randomized, crossover study. We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month. In the double-blind study, after 1 month of captopril alone, supine blood pressure was 151 +/- 5/95 +/- 4 (SEM) mm Hg. With the addition of 25 mg hydrochlorothiazide once daily for 1 month, blood pressure fell to 137 +/- 5/87 +/- 3 mm Hg. When a moderate reduction in salt intake (from 206 +/- 26 to 109 +/- 20 mmol urinary sodium/24 h) was added to captopril for 1 month, blood pressure was reduced by a similar amount (to 137 +/- 4/90 +/- 3 mm Hg). Plasma potassium fell during the diuretic treatment (3.9 +/- 0.1 to 3.7 +/- 0.1 mmol/L, P < .05) but increased nonsignificantly during salt reduction (3.9 +/- 0.1 to 4.1 +/- 0.2 mmol/L). These results clearly demonstrate that moderate salt reduction, which can be easily achieved, is as effective as a thiazide diuretic in lowering blood pressure in the presence of a converting enzyme inhibitor and has the particular advantage that plasma potassium does not decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension.

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.

Characteristics of a (Na+-K+)-ATPase inhibitor in extracts of tea.

Extracts of tea were examined for inhibitors of the sodium-potassium pump by investigating the effect of the extracts on 1) isolated preparations of (Na+-K+)-ATPase from hog brain and human blood cells; 2) the displacement of radioactive ouabain from its specific receptor on red blood cells, and 3) the uptake of radioactive rubidium in intact red blood cells. It has been found that extracts of tea were potent inhibitors of the purified hog brain (Na+-K+)-ATPase. However, the inhibition was not specific for the (Na+-K+)-ATPase and the extract of tea did not displace 3H-ouabain in a specific ouabain-receptor assay. Additionally, the tea extracts displayed only a small inhibitory effect on the uptake of 86Rb in intact red blood cells. These observations suggest that the material is not like digitalis and that, unlike cardiac glycosides, it may inhibit the activity of the (Na+-K+)-ATPase by interacting with the enzyme at intracellular sites.

Acute and sustained changes in sodium balance during nifedipine treatment in essential hypertension.

PURPOSE: To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine. PATIENTS: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days' duration. METHODS: Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake, patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter, patients continued to receive nifedipine GITS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied. RESULTS: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal. CONCLUSION: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Serum ionized calcium and pH: effects of blood storage, some physiological influences and a comparison between normotensive and hypertensive subjects.

The effects on serum ionized calcium (ICa) and pH of different storage conditions of blood or serum, and of physiological influences such as over-ventilation, food intake and dietary sodium intake have been investigated. Temperature and time-related changes in ICa occurred with storage and were minimized by immediate separation of serum and storage at 4 degrees C, (6 h or less). Elevation of serum ICa and a fall in pH accompanied increased salt intake; over-ventilation induced an elevation of serum pH and a reduction in ICa. Day-to-day intra-individual variation of ICa was 0.93%. We proceeded to examine a group of age-, sex- and race-matched hypertensive and normotensive subjects under standardized conditions designed to minimize such technical and physiological artefacts. ICa was not significantly different in the two groups; however, serum pH was significantly elevated in the hypertensive group. In the combined group of normotensive and hypertensive subjects, serum pH was significantly correlated with blood pressure. Exclusion of the black subjects from the analysis did not alter the findings.

Sodium restriction lowers high blood pressure through a decreased response of the renin system--direct evidence using saralasin.

Twenty-nine patients with essential hypertension were studied while on their normal diets, on the 5th day of a high sodium diet (around 350 mmol/day) and on the 5th day of a low sodium diet (10 mmol/day). The fall in mean arterial pressure on changing from the high sodium to the low sodium diet was 9.0 +/- 1.6 mmHg and the rise in the plasma renin activity in the same period was 2.52 +/- 0.41 ng/ml/h, these two variables being significantly correlated (r = -0.45; P less than 0.02). An infusion of saralasin was given on the 5th day of the low sodium diet. A highly significant negative correlation was found between the fall in blood pressure on sodium restriction and the change in blood pressure with saralasin (r = -0.52; P less than 0.005); this correlation was still significant when corrected for the severity of the hypertension (r = -0.41; P = 0.03) while it became non-significant if controlled for plasma renin activity on the low sodium diet (r = -033; NS). These results provide direct evidence that the fall in blood pressure which is seen on reducing sodium intake in many patients with essential hypertension is, at least in part, directly mediated by the reactivity of the renin angiotensin system.

Brain and atrial natriuretic peptides: a dual peptide system of potential importance in sodium balance and blood pressure regulation in patients with essential hypertension.

OBJECTIVE: To examine the changes in plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and blood pressure in patients with essential hypertension on a low, normal and high sodium intake. DESIGN AND METHODS: Twelve patients with mild-to-moderate essential hypertension were studied. Plasma, urinary and blood pressure measurements were made with the patients on their usual sodium intake, then on the fifth day of a low (10 mmol/day) and on the fifth day of a high (350 mmol/day) sodium intake, the sequence being allocated randomly. RESULTS: Plasma levels of BNP and ANP increased significantly on the high sodium intake compared with when the patients were on their normal diet. The mean blood pressure on the high sodium intake was not significantly different from that with the patients on their normal diet. In contrast, plasma BNP and ANP decreased on the low sodium intake, but were not significantly different compared with when the patients were on their normal diet. However, there was a significant reduction in the mean blood pressure on the low sodium intake compared with when the patients were on their normal diet. Compared with the normal diet, BNP and ANP plasma levels showed similar percentage decreases on the low sodium intake and similar percentage increases on the high sodium intake. CONCLUSIONS: These findings suggest that BNP and ANP are released in response to a common stimulus during changes in dietary sodium intake. The changes in plasma BNP and ANP observed with sodium restriction and sodium loading indicate the potential importance of BNP and ANP as a dual peptide system contributing to the maintenance of sodium balance and blood pressure regulation in patients with essential hypertension, during changes in dietary sodium intake.

Comparison of calcium, magnesium-ATPase activity and membrane fluidity in patients with essential hypertension and in normotensive controls.

OBJECTIVES: To measure calcium,magnesium-ATPase (Ca-ATPase) activity and membrane fluidity in patients with essential hypertension compared with normotensive subjects; to investigate the interrelationship between membrane fluidity and the activity of the Ca-ATPase; and to assess the importance of circulating lipids on the Ca-ATPase and membrane fluidity. METHODS: Ca-ATPase and membrane fluidity were measured in erythrocyte membranes. Kinetic parameters [maximal activity (Vmax), apparent dissociation constant and allosteric number] of the Ca-ATPase activity were measured, in the presence of saturating calmodulin, in 38 normotensives and 57 essential hypertensives. Fluorescent polarization anisotropy, as an index of membrane fluidity, was measured, using the fluorescent probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and trimethylammonium DPH (TMA-DPH) in 37 normotensives and 44 hypertensives. Of these 22 were paired for age, sex and race. RESULTS: There was no significant difference in the Vmax and allosteric number of the Ca-ATPase between the normotensives and hypertensives, but there was a trend for the hypertensives to have a reduced calcium affinity. In contrast, hypertensive subjects had significantly lower membrane fluidity. Sex and serum triglycerides level were important determinants of membrane fluidity in both groups. Comparisons between normotensives and hypertensives demonstrated decreased fluidity in the hypertensives independent of sex and serum triglycerides level, although the differences, especially with TMA-DPH, were more pronounced in the females. In both groups there were negative correlations between Vmax and both DPH and TMA-DPH anisotropy. CONCLUSION: The present study demonstrates that essential hypertension is associated with a generalized alteration in the erythrocyte membrane physical and chemical properties. However, despite the positive correlation between Vmax and membrane fluidity, the present study also demonstrates that essential hypertension is not associated with a major abnormality in the activity of the erythrocyte Ca-ATPase in isolated membranes.

Is atrial natriuretic peptide-guanosine 3',5' cyclic monophosphate coupling a determinant of urinary sodium excretion in essential hypertension?

OBJECTIVES: (1) To compare urinary guanosine 3',5' cyclic monophosphate (cyclic GMP) excretion between normotensive subjects and essential hypertensive patients; (2) to determine the influence of changes in sodium intake on urinary cyclic GMP excretion in response to the neutral endopeptidase inhibitor candoxatril in essential hypertensives. DESIGN: (1) Twenty-five normotensive subjects and 25 patients with established essential hypertension not on treatment; (2) Single oral dose of candoxatril in eight patients with essential hypertension after equilibration on a low- or high-sodium diet in a placebo-controlled, double-blind, randomized, crossover study. METHODS: Blood pressure was measured by ultrasound sphygmomanometry. Atrial natriuretic peptide (ANP) and urinary cyclic GMP were measured by radioimmunoassay. Group comparisons were made using unpaired t-tests and two-way analysis of variance. RESULTS: Plasma ANP was significantly raised in patients with essential hypertension compared with the normotensive group, but there was no difference in urinary cyclic GMP excretion. Plasma ANP increased significantly on the high- compared with low-sodium diet. After candoxatril, there were significant diet-related increases in plasma ANP and urinary sodium excretion up to 6 h after drug administration. There were similar increases in urinary cyclic GMP excretion on both diets, but there were no consistent differences in this excretion between the low- and high-sodium diets. CONCLUSIONS: These observations not only point to the importance of ANP-cyclic GMP coupling as a determinant of the natriuretic response to endopeptidase inhibition, but also suggest that the excretion of urinary cyclic GMP can be influenced by other factors in addition to circulating ANP.

A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism.

BACKGROUND: The presence of the deletion allele of the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with an excess risk of vascular disease and diabetic nephropathy. OBJECTIVE: To examine the importance of this polymorphism as a determinant of hypertension and impaired glucose metabolism in a population-based study of three ethnic groups and assess the potential modifying effect of gender. DESIGN: Population-based cross-sectional study in South London. The population-based sample of 1577 men and women, age 40-59 years, was obtained from stratified random sampling of general practice lists where 25% of the residents were born outside the UK. The ACE I/D polymorphism was determined for 1366 individuals (86.6%): 462 whites, 462 of African descent and 442 of South Asian origin. RESULTS: The genotype frequency within each ethnic group was in Hardy-Weinberg equilibrium. The frequencies were similar in whites and those of African descent (II, ID, DD: 18.4%, 49.6%, 32.0% for whites and 18.4%, 50.5%, 30.9% for those of African descent), but there was a much higher frequency of the II genotype in those of South Asian origin (39.8%, 41.8%, 18.3%; chi2 = 77.6; P < 0.0001). There was no association between the I/D polymorphism and impaired glucose metabolism in any ethnic group. There were also no significant associations between the I/D polymorphism and hypertension in whites and in those of South Asian origin. This contrasts with a highly significant association between the D allele and hypertension in women of African descent (OR = 2.54; 95% CI 1.38-4.65; P = 0.003) but not in men of African descent (0.79; 0.36-1.72) (test for differences between sexes P = 0.023). CONCLUSIONS: These observations provide estimates of the frequency distribution of the ACE I/D polymorphism in whites, in people of African descent and in people of South Asian origin. Moreover, these results highlight the potential importance of gender-dependent interactions between genetic background and expression of hypertensive phenotype.

Mononuclear leucocyte intracellular free calcium--does it correlate with blood pressure?

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 10(-4) M ouabain reduced 86 rubidium (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.

Angiotensin converting enzyme insertion/deletion polymorphism: association with ethnic origin.

OBJECTIVE: To determine the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in several ethnic groups: Caucasian Europeans, Black Nigerians, Samoan Polynesians and Yanomami Indians. RESULTS: The ratio of the frequencies of the II, ID and DD genotypes were 1:2:1 in the Europeans, but there was a tendency towards a higher frequency of the D allele in the Nigerians. In contrast, the Samoans and the Yanomami Indians displayed a much higher frequency of the I allele than of the D allele. CONCLUSION: The relationship between ACE genotype and disease in these latter groups is still not known, but the present results clearly suggest that ethnic origin should be carefully considered in the increasing number of studies on the association between I/D ACE genotype and disease aetiology.

In-vivo intracellular pH at rest and during exercise in patients with essential hypertension.

BACKGROUND: Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium-hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. OBJECTIVES: To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. METHODS: Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. RESULTS: Mean resting pHi in the hypertensive (7.05 +/- 0.04) and normotensive groups (7.06 +/- 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 +/- 0.03 in males and 7.02 +/- 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 +/- 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 +/- 0.19; P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 +/- 0.03 pH units/min and not significantly different in normotensives (0.08 +/- 0.02; P = 0.4). CONCLUSIONS: These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.

N-terminal pro atrial natriuretic peptide in human plasma.

N-Terminal pro ANP (atrial natriuretic peptide) in human plasma has been measured by radioimmunoassay after extraction on Sep-Pak cartridges. Immunoreactive N-terminal pro ANP circulates in human plasma at higher levels than alpha-hANP (approximately 20-fold higher in normal subjects) and was elevated in patients with essential hypertension, cardiac transplantation and patients with chronic renal failure. In chronic renal failure patients undergoing hemodialysis, C-terminal ANP (ANP 99-126), but not N-terminal ANP, declined significantly after dialysis. Gel filtration experiments demonstrated a single peak of N-terminal ANP immunoreactivity, eluting in parallel with synthetic human pro ANP 1-67, indicating a similar molecular size and the absence of low molecular weight N-terminal fragments.