D. R. J. Singer

Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension

Background: Rarefaction of skin capillaries in people with intermittent borderline essential hypertension suggests a primary or an early abnormality that may antedate the onset of sustained hypertension. Objective: To compare skin capillary density in subjects with and without a family history of essential hypertension. Subjects: 21 normotensive individuals, one or both of whose parents had essential hypertension (mean age 39.3 years; blood pressure 124/79 mm Hg); 21 normotensive controls with no family history of hypertension (age 46.3 years; blood pressure 124/78 mm Hg). Methods: The skin of the dorsum of the fingers was examined by intravital capillary microscopy before and after venous congestion at 60 mm Hg for two minutes. Results: By analysis of variance, both baseline and maximum skin capillary density were lower in subjects with a family history of essential hypertension than in those with no family history (baseline: 67 v 79 capillaries per field, p = 0.008; maximum: 74 v 93 capillaries per field, p < 0.0005). Conclusions: Capillary rarefaction in essential hypertension may occur before the increase in blood pressure and could, at least in part, reflect a primary rather than a secondary abnormality.

Concentrations of N-terminal ProANP in human plasma: evidence for ProANP (1-98) as the circulating form.

Plasma levels of immunoreactive N-terminal ProANP have been measured in plasma from 19 healthy individuals, 15 patients with essential hypertension, 8 cardiac transplant recipients and 8 patients with chronic renal failure using two separate radioimmunoassays (RIAs), one directed against ProANP (1-30) and the other against ProANP (79-98). The mean concentrations of ProANP (1-30) and ProANP (79-98) were elevated in these groups of patients. There were positive correlations between levels of ProANP (1-30) and ProANP (79-98), with a correlation coefficient of 0.97 (P less than 0.001, n = 50). In healthy individuals a 2-1 (isotonic) saline infusion significantly increased both ANP (99-126) (P less than 0.05, n = 8) and N-terminal ProANP (P less than 0.005, n = 8) within 15 min of the end of the infusion. Plasma N-terminal ProANP levels were still significantly elevated after 75 min (P less than 0.05, n = 8) and 225 min (P less than 0.05, n = 8), by contrast ANP (99-126) had returned to basal values. Gel filtration of plasma extracted on Sep-Pak C-18 from normal individuals and patients gave a single immunoreactive peak for N-terminal ProANP as measured by both N-terminal ProANP assays, indicating an absence of small N-terminal fragments and the presence of a single high molecular weight form. These studies demonstrate that the major circulating N-terminal ANP in man is probably ProANP (1-98) and that it is cosecreted with ANP (99-126).

Sodium restriction in hypertensive patients treated with a converting enzyme inhibitor and a thiazide.

When the function of the renin system is inhibited, blood pressure becomes more dependent on changes in sodium and water balance. Diuretics alone and sodium restriction alone are additive to converting enzyme inhibitor therapy. However, it is not known if these two ways of reducing sodium balance are additive in the presence of established converting enzyme inhibition. We therefore performed a double-blind crossover study of the effects of moderate sodium restriction in 21 patients with essential hypertension who were already being treated with the combination of a converting enzyme inhibitor and a diuretic. After 1 month of captopril (50 mg twice daily) and hydrochlorothiazide (25 mg once daily) therapy, with their usual sodium intake, average supine blood pressure was 147/96 ± 5/3 (SEM) mm Hg 2 hours after treatment Patients then reduced their sodium intake to around 80-100 mmol/day for the remainder of the study. After 2 weeks of sodium restriction, they entered a double-blind, randomized, crossover study of Slow Sodium (100 mmol sodium/day) compared with Slow Sodium placebo, while continuing sodium restriction and the above treatment. During the double-blind study, after 1 month of treatment with captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium placebo, supine blood pressure 2 hours after treatment was 138/88 ±4/2 mm Hg (24-hour urinary sodium 104±ll mmol). After 1 month of captopril (50 mg twice daily), hydrochlorothiazide (25 mg once daily), and Slow Sodium tablets, supine blood pressure 2 hours after treatment was 147/91 ±5/2 mm Hg (p<0.05; 24-hour urinary sodium 195 ±14 mmol). Mean supine blood pressure fell with moderate sodium restriction by 5±2% at 2 hours and 7 ±2% at 12 hours after treatment with captopril and hydrochlorothiazide. The decrease in blood pressure was significantly correlated with the reduction in sodium intake. These results clearly demonstrate that a moderate reduction in salt intake does have a further blood pressure-lowering effect in patients already treated with the combination of captopril and a diuretic. This moderate change in diet provides an effective and well-tolerated way to improve blood pressure control in patients treated with the combination of an angiotensin converting enzyme inhibitor and a diuretic

Investigation of the plasma concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients.

Investigation of the plasma concentrations and circulating forms of BNP and ANP in orthotopic cardiac transplant recipients

Secretion of atrial natriuretic peptide from the heart in man.

Plasma concentrations of atrial natriuretic peptide were measured in eight patients undergoing elective cardiac catheterisation and angiography. All patients had normal resting pressures in the cardiac chambers and no clinical evidence of heart failure. Plasma atrial natriuretic peptide rose significantly from the superior vena cava into the right atrium and right ventricle. The increase into the right atrium was variable, with no increase in three subjects, but there was a consistent increase in all subjects from the superior vena cava to to the right ventricle. These findings in the right atrium are probably caused by inadequate mixing and streaming of blood from the coronary sinus containing high concentrations of atrial natriuretic peptide. There was no increase in the concentration of natriuretic peptide from the pulmonary artery to the left ventricle, but the concentrations in the left ventricle were significantly higher than in the superior vena cava. These findings demonstrate that the heart secretes atrial natriuretic peptides in the absence of cardiac failure. Studies based on sampling of the right atrium will not accurately measure cardiac secretion of atrial natriuretic peptide and will therefore be likely to obscure the mechanisms responsible for regulating its secretion. The right ventricle and pulmonary artery are the best sampling sites to measure atrial natriuretic peptide release from the right atrium.

Hormonal and renal responses to neutral endopeptidase inhibition in normal humans on a low and on a high sodium intake.

Abstract. Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2–4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4± 5.5 mmol on the low sodium diet and 73.1± 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.

A comparison of the acute effects of cicletanine and bendrofluazide on urinary electrolytes and plasma potassium in essential hypertension.

SummaryThe 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.Cicletanine 50 mg or 100 mg and bendrofluazide 5 mg caused no acute decrease in blood pressure compared to placebo for 24 h after treatment. In the 24 h after a single dose of cicletanine 50 mg there was no increase in urinary sodium, potassium or volume compared to placebo.After a single dose of cicletanine 100 mg there was a significant increase in 2 h urinary sodium excretion compared to cicletanine 50 mg and in the first 6 h a significant increase in urinary potassium compared to placebo. Urine volume did not change significantly.After bendrofluazide 5 mg urinary sodium excretion increased significantly in the first 6 h as well as in the subsequent 18 h compared to placebo and both cicletanine 50 mg and 100 mg. Urinary potassium excretion was also significantly increased in the first 6 h after bendrofluazide compared to placebo, and urine volume significantly increased from 6 to 24 h after bendrofluazide 5 mg compared to placebo and cicletanine 100 mg. Plasma potassium was significantly reduced and plasma renin activity significantly increased 24 h after bendrofluazide 5 mg but these measurements were not significantly different from placebo after cicletanine 50 or 100 mg.These results suggest that cicletanine 100 mg has milder acute natriuretic effects than the thiazide bendrofluazide 5 mg. In contrast cicletanine 50 mg is associated with no major acute renal effects. In view of evidence that with long-term treatment both cicletanine 50 and 100 mg have anti-hypertensive effects, these findings suggest that cicletanine may act by a different mechanism in lowering blood pressure at low and high dose.

Studies of Captopril Alone and in Combination with the Benzothiazepine Diltiazem or the Dihydropyridine Nifedipine in Treating Essential Hypertension

Calcium antagonists and converting enzyme inhibitors are now widely used as first line therapy for high blood pressure. This gradual move from the diuretics and β-blockers is, in part, due to fewer or different side effects and the perceived lack of deleterious metabolic effects. Calcium antagonists may be more effective in elderly and low-renin patients. However, this is likely to be due in part to the finding that calcium antagonists arc-more effective with a higher initial pressure. The efficacy of converting enzyme inhibitors is related to the initial level of plasma angiotensin II (Ang II) or plasma renin activity. However, patients with low plasma renin activity also have a fall in blood pressure with converting enzyme inhibitors, illustrating the importance of differences in Ang II receptor sensitivity to the prevailing level of Ang II. Many patients require the combination of more than one drug to control their blood pressure. Combining a converting enzyme inhibitor with either a dihydropyridine or a benzothiazepine calcium antagonist is a particularly effective approach to the treatment of patients with more severe essential hypertension.

Plasma and urinary nitrate in essential hypertension

1225). Supine BP was taken as the mean value of Introduction five readings obtained at 1–2 min intervals. There is considerable evidence to suggest that nitric oxide (NO) could be an important factor in the control of blood pressure (BP). However, there is Statistics controversy over the role of NO as a determinant of Group values are given as means ± s.d. Associations hypertension. were tested using Pearson correlation coefficients The objective of this study was to examine the and group comparisons using unpaired t-tests. A P association between NO activity and essential value of ,0.05 was taken as significant. hypertension. Plasma and urinary nitrate have been used as an index of endogenous NO as nitrate is one end-product of NO oxidation. Results

Moderate sodium restriction, angiotensin converting enzyme inhibition, and thiazide diuretic in the management of essential hypertension.

Dietary sodium restriction alone is effective in lowering blood pressure in some, but not all, patients with essential hypertension. Homeostatic mechanisms, including activation of the renin-aldosterone system, may counteract the effects of sodium restriction. Angiotensin converting enzyme (ACE) inhibitors are also effective as sole therapy in many patients with essential hypertension, but may be less effective in those with low-renin hypertension. The combination of dietary sodium restriction with blockade of the renin system by an ACE inhibitor is a particularly effective way to improve blood pressure control. Addition of a thiazide diuretic will reduce pressure further.