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 +/- 11 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 less than 0.05; 24-hour urinary sodium 195 +/- 14 mmol).(ABSTRACT TRUNCATED AT 250 WORDS)

How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man?

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.

Lack of effect of dietary potassium on renal lithium clearance in man.

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.

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

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. 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptides and tubular sodium handling during normal daily life in men.

The relationship between segmental renal tubular sodium handling (using the renal clearance of ingested lithium as a marker of proximal tubular sodium handling) and circulating plasma levels of atrial natriuretic factor (ANF) was studied in a sample of 295 untreated men drawn from a male population at work under their usual living conditions. Plasma ANF was positively and significantly related to sodium excretion at the distal nephron, indicating that this hormone interacts with a distal renal tubular site to influence the control of sodium excretion in man.

Potassium channel stimulation in normal subjects and in patients with essential hypertension: an acute study with cromakalim (BRL 34915).

We studied the acute effects of the potassium channel opener cromakalim on blood pressure, the renin-angiotensin-aldosterone system and renal function in eight patients with essential hypertension and five normal subjects. In the hypertensive patients, blood pressure decreased significantly from 2 to 6 h after treatment with cromakalim 1.5 mg compared with placebo, but was unchanged in the normotensives. In both groups, the heart rate and plasma renin activity increased after the administration of cromakalim compared with placebo; however, plasma aldosterone was unchanged. There was no significant change in urinary electrolyte excretion in either group; urine flow decreased after the administration of cromakalim compared with placebo in normal subjects, but not in patients with essential hypertension. Cromakalim lowers blood pressure acutely in patients with essential hypertension but not in normotensive subjects. This may be due to a greater reflex response in the normal subjects or to specific effects of cromakalim on mechanisms causing the high blood pressure.

Prolonged decrease in blood pressure after atrial natriuretic peptide infusion in essential hypertension: a new anti-pressor mechanism?

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 alpha-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.(ABSTRACT TRUNCATED AT 250 WORDS)

Raised plasma levels of atrial natriuretic peptides in Addison's disease.

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 levels 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.

Negative feedback mechanisms: evidence that desensitization of pineal alpha 1-adrenergic responses involves protein kinase-C.

alpha 1-Adrenergic stimulation of the pinealocyte translocates protein kinase-C, which, in turn, has an important positive effect on pineal cell function; translocation amplifies beta-adrenergic stimulation of both cAMP and cGMP. In the present report negative feedback effects of protein kinase-C are described, including inhibition of alpha 1-adrenergically induced increases in cytosolic Ca2+ ([Ca2+]i), phosphatidylinositol hydrolysis, and cGMP in beta-adrenergically stimulated cells. Time-course studies of cGMP and [Ca2+]i responses indicated that the onset of inhibition by the protein kinase-C activator 4 beta-phorbol 12-myristate 13-acetate (PMA) is rapid (less than 5 min). In contrast, PMA has no inhibitory effect on norepinephrine stimulation of cAMP accumulation or the induction of arylalkylamine N-acetyltransferase activity, a cAMP-dependent enzyme. This is consistent with the finding that PMA substitutes for the positive effect of alpha 1-activation and directly potentiates beta-adrenergic stimulation of cAMP production. Although PMA does inhibit alpha 1-adrenergic potentiation of cGMP in beta-adrenergically treated cells, it does not inhibit the potentiation of the cGMP response in beta-adrenergically stimulated cells produced by high K+, A23187, and ouabain, agents that translocate protein kinase-C secondary to elevation of [Ca2+]i. This suggests that translocation of protein kinase-C does not block an effect of Ca2+, but probably blocks an earlier step in adrenergic activation, presumably the alpha 1-adrenergic stimulation of [Ca2+]i. Finally, pretreatment of cells with an alpha 1-agonist markedly reduced cAMP and cGMP responses to subsequent beta-adrenergic stimulation. The data indicate that the following negative feedback mechanism is present in the pinealocyte: alpha 1-adrenoceptor-dependent elevation of [Ca2+]i----protein kinase-C translocation----inhibition of alpha 1-adrenergic dependent elevation of [Ca2+]i. This mechanism appears to function physiologically to provide a negative feedback signal which limits adrenergic responses that are dependent on an increase in [Ca2+]i, including the cAMP and cGMP increases.

Endocrine and renal response to water loading and water restriction in normal man.

1. Nine normal subjects (eight male, one female) on a fixed daily intake of 150 mmol of sodium and 80 mmol of potassium, were randomized to receive either 3 days of 1.0 litre total water intake/24 h (food + fluid) or 4 days of 6.8 litres total water intake/24 h, and were then crossed over after a 3 day control period (2.7 litres water/24 h). 2. During water restriction, urine volume fell from 1.94 litres/24 h to less than 1 litre/24 h by the first day and was 0.77 litre/24 h on the final day. Plasma atrial natriuretic peptide levels were unchanged from baseline despite a large increase in plasma vasopressin and plasma and urine osmolality. Urinary sodium was unaltered throughout, while urinary potassium was increased on the final 2 days of water restriction. 3. During water loading, urine volume increased from 1.85 litres/24 h to 5.44 litres/24 h on the first day and remained at approximately 6 litres/24 h for the final 3 days. Plasma atrial natriuretic peptide showed no change. Plasma vasopressin and plasma and urine osmolality were reduced. Urinary sodium and potassium output were unchanged from baseline. 4. These results suggest that changes in plasma atrial natriuretic peptide are unlikely to be involved in the normal homoeostatic response to changes in water balance in man.

Plasma atrial natriuretic peptide in essential hypertension. Comparison with normotensive subjects and effects of changes in dietary sodium intake.

Plasma levels of atrial natriuretic peptide (ANP) in 106 patients with essential hypertension with a supine mean blood pressure (mean +/- SEM) of 128.9 +/- 1.6 mmHg and not on treatment were significantly higher than those in 47 normotensive subjects (supine mean blood pressure 93.9 +/- 1.2 mmHg) with mean values of 17.2 +/- 1.1 and 8.6 +/- 0.6 pg/ml, respectively (P less than 0.001). Similar results were found in a subgroup of 35 hypertensive patients identically matched in terms of age, sex, and race with 35 normotensive subjects. Plasma levels of ANP were correlated significantly with age in normotensive subjects and with age and blood pressure in the hypertensive patients. In 12 hypertensive patients studied on a low (10 mmol sodium/day), on their usual sodium intake (around 120 mmol sodium/24 hr) and on a high (350 mmol sodium/day) intake, plasma ANP increased approximately twofold by the fifth day of the high sodium intake, but there was no significant difference between the plasma levels on their usual sodium intake and those on the fifth day of the low sodium intake. Supine mean blood pressure on the patients' usual sodium intake was 119.3 +/- 2.7 mmHg and was reduced to 110.0 +/- 3 mmHg by the fifth day of the low sodium intake (P less than 0.005). However, there was no significant difference between the blood pressure levels on their usual and high sodium intake (118.3 +/- 3.0 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of high potassium or low sodium diet on vascular Na+,K+-ATPase activity and blood pressure in young spontaneously hypertensive rats.

These studies were designed to investigate whether the antihypertensive effects of high potassium or low sodium diets are related to changes in vascular Na+,K+-adenosine triphosphatase (ATPase) activity. Vascular Na+,K+-ATPase was measured as ouabain-sensitive rubidium uptake in aorta incubated in buffer or plasma from spontaneously hypertensive rats (SHR) fed either a high potassium, a low sodium, or a normal diet for 2 weeks. The high potassium diet significantly increased Na+,K+-ATPase activity, whereas the low sodium diet significantly decreased activity. There was no evidence of a ouabainlike factor in plasma. The increased pump activity on the high potassium diet appeared to be due to an increase in maximum activity (Vmax) of the enzyme, rather than to an increased affinity for potassium. Potentially, an increase in Na+,K+-ATPase activity could contribute to the antihypertensive effect of potassium by hyperpolarizing the cell membrane. The decrease in vascular Na+,K+-ATPase activity on a low sodium diet probably is unrelated to its depressor effect, but it may be a homeostatic mechanism for maintaining sodium balance in the animal.

Effects of a high K+/low Na+ diet on blood pressure in young spontaneously hypertensive rats.

Blood pressure was measured after treatment with a high K+, a low Na+ and a combined high K+/low Na+ diet in young spontaneously hypertensive rats (SHR). A high K+ diet reduced blood pressure by approximately 10 mmHg during the development of hypertension. This decrease was accompanied by a significant increase in water intake and urine volume and a significant decrease in plasma renin activity (PRA). A low Na+ diet also decreased blood pressure significantly, but, in contrast to the high K+ diet, water intake and urine volume significantly decreased and PRA increased. When both diets were given together, the antihypertensive effects of both were eliminated. Thus while an increase in dietary K+ and a decrease in dietary Na+ are both effective antihypertensive regimens in SHR, the mechanism of action of each appears to be different and may be antagonistic in these animals.

Na+, K+ and water balance in young spontaneously hypertensive rats: relationship to blood pressure after high K+ treatment.

These studies were designed to investigate the effects of high dietary K+ on electrolyte and water balance in young spontaneously hypertensive rats (SHR) and to relate these effects to changes in blood pressure. The high K+ diet reduced blood pressure by approximately 10 mmHg during the development of hypertension. Blood pressure, however, plateaued at the same maximum level as control by age 13 weeks. Rats fed the high K+ diet showed a significant increase in water intake and urine volume throughout the treatment period but no change in plasma volume or extracellular fluid volume occurred. A slight natriuresis was also observed in rats on the high K+ diet, but this was not of sufficient magnitude to decrease total body Na+. These results confirm previous findings that K+ causes a diuresis and a natriuresis, but demonstrate that the diuretic action of K+ cannot explain its antihypertensive properties in young SHR.

Essential role of calcium influx in the adrenergic regulation of cAMP and cGMP in rat pinealocytes.

The role of Ca2+ in the adrenergic stimulation of pinealocyte cAMP and cGMP was investigated. In this tissue alpha 1-adrenoceptor activation, which by itself is without effect, potentiates beta 1-adrenergic stimulation of cAMP and cGMP 30- to 100-fold. The present results indicate that chelation of extracellular Ca2+ with EGTA or inhibition of Ca2+ influx with inorganic Ca2+ channel blockers (La3+, Co2+, Mn2+) markedly reduces the cyclic nucleotide response to norepinephrine, a mixed alpha 1- and beta-adrenergic agonist, but not to isoproterenol, a beta-adrenergic agonist. In addition, the potentiating effects of alpha 1-adrenergic agonists were mimicked by agents which elevate cytosolic Ca2+, including K+ (EC50 = 2 X 10(-2) M), ouabain (EC50 = 2 X 10(-6) M), ionomycin (EC50 = 3 X 10(-6) M), and A23187 (EC50 = 2 X 10(-6) M); each potentiated the effects of beta-adrenergic stimulation but had no effect alone. Together these results indicate that an alpha 1-adrenoceptor-stimulated Ca2+ influx is essential for norepinephrine to increase pinealocyte cAMP and cGMP.

Relation of plasma renin activity to the antihypertensive effect of MK 421 in the rat.

1 The effect of the angiotensin converting enzyme inhibitor, MK 421 (N-((S)-1-(ethoxycarbonyl)-3-phenylpropyl)L-Ala-L-Pro), on the blood pressure of two-kidney Goldblatt hypertensive rats has been investigated in relation to he initial plasma renin activity (PRA) and the initial blood pressure of the individual animals. 2 Blood pressure was monitored by an indirect tail-cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals. 3 The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension. 4 MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P less than 0.001) at all times tested. 5 It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin-angiotensin system which, in this model at least, is reflected by the PRA.