Potassium softens vascular endothelium and increases nitric oxide release.

In the presence of aldosterone, plasma sodium in the high physiological range stiffens endothelial cells and reduces the release of nitric oxide. We now demonstrate effects of extracellular potassium on stiffness of individual cultured bovine aortic endothelial cells by using the tip of an atomic force microscope as a mechanical nanosensor. An acute increase of potassium in the physiological range swells and softens the endothelial cell and increases the release of nitric oxide. A high physiological sodium concentration, in the presence of aldosterone, prevents these changes. We propose that the potassium effects are caused by submembranous cortical fluidization because cortical actin depolymerization induced by cytochalasin D mimics the effect of high potassium. In contrast, a low dose of trypsin, known to activate sodium influx through epithelial sodium channels, stiffens the submembranous cell cortex. Obviously, the cortical actin cytoskeleton switches from gelation to solation depending on the ambient sodium and potassium concentrations, whereas the center of the cell is not involved. Such a mechanism would control endothelial deformability and nitric oxide release, and thus influence systemic blood pressure.

Dietary Sodium 'Controversy'-Issues and Potential Solutions.

PURPOSE OF REVIEW: High dietary sodium is estimated to be the leading dietary risk for death attributed to 1.8 million deaths in 2019. There are uniform recommendations to reduce sodium consumption based on evidence that increased dietary sodium is responsible for approximately a third of the prevalence of hypertension, and meta-analyses of randomized controlled trials show that sodium reduction lowers blood pressure, cardiovascular disease, and total mortality. Nevertheless, there is a perception that the beneficial effect of reducing dietary sodium is controversial. We provide experiential evidence relating to some sources of the controversy and propose potential solutions. RECENT FINDINGS: Inappropriate research methodology, lack of rigor in research, conflicts of interest and commercial bias, questions of professional conduct, and lack of policies to protect public interests are likely to contribute to the controversy about reducing dietary sodium. There is a failure to protect policies to reduce dietary sodium from nonscientific threats. Significant efforts need to be made to ensure the integrity of nutritional research and maintain public trust.

Cognitive impairment and white matter damage in hypertension: a pilot study.

OBJECTIVES: Hypertension has been associated with impaired cognition. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopy were applied to assess white matter abnormalities in treated vs untreated hypertension and if these correlated with neuropsychological performance. METHODS: Subjects were 40 patients with medically treated hypertension (mean age 69.3 years), 10 patients with untreated hypertension (mean age 57.6 years) and 30 normotensive controls (mean age 68.2 years). Hypertension was defined as a previous diagnosis and taking hypertensive medication, or a resting blood pressure of >140/90 mmHg on the day of assessment. RESULTS: Patients with treated hypertension performed worse on immediate (P = 0.037) as well as delayed memory tasks (P = 0.024) compared with normotensive controls. Cognitive performance was worse in untreated compared with treated hypertension on executive functions (P = 0.041) and psychomotor speed (P = 0.003). There was no significant correlation between cognition and any of the imaging parameters in treated hypertension. However, in untreated hypertension the results revealed a positive correlation between an executive functioning and attention composite score and DTI mean diffusivity values (P = 0.016) and between psychomotor speed and spectroscopy NAA/tCr levels (P = 0.015). CONCLUSIONS: These results suggest there is cognitive impairment in hypertension. Treated hypertension was associated with deficits in memory while untreated hypertension revealed a more 'subcortical' pattern of cognitive impairment.

Salt and blood pressure in children and adolescents.

To study the relationship between salt intake and blood pressure in children and adolescents, we analysed the data of a large cross-sectional study (the National Diet and Nutrition Survey for young people), which was carried out in Great Britain in 1997 in a nationally representative sample of children aged between 4 and 18 years. A total of 1658 participants had both salt intake and blood pressure recorded. Salt intake was assessed by a 7-day dietary record. The average salt intake, which did not include salt added in cooking or at the table, was 4.7+/-0.2 g/day at the age of 4 years. With increasing age, there was an increase in salt intake, and by the age of 18 years, salt intake was 6.8+/-0.2 g/day. There was a significant association of salt intake with systolic blood pressure as well as with pulse pressure after adjusting for age, sex, body mass index and dietary potassium intake. An increase of 1 g/day in salt intake was related to an increase of 0.4 mm Hg in systolic and 0.6 mm Hg in pulse pressure. The magnitude of the association with systolic blood pressure is very similar to that observed in a recent meta-analysis of controlled trials where salt intake was reduced. The consistent finding of our present analysis of a random sample of free-living individuals with that from controlled salt reduction trials provides further support for a reduction in salt intake in children and adolescents.

Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies.

Increased consumption of fruit and vegetables has been shown to be associated with a reduced risk of coronary heart disease (CHD) in many epidemiological studies, however, the extent of the association is uncertain. We quantitatively assessed the relation between fruit and vegetable intake and incidence of CHD by carrying out a meta-analysis of cohort studies. Studies were included if they reported relative risks (RRs) and corresponding 95% confidence interval (CI) of CHD with respect to frequency of fruit and vegetable intake. Twelve studies, consisting of 13 independent cohorts, met the inclusion criteria. There were 278,459 individuals (9143 CHD events) with a median follow-up of 11 years. Compared with individuals who had less than 3 servings/day of fruit and vegetables, the pooled RR of CHD was 0.93 (95% CI: 0.86-1.00, P=0.06) for those with 3-5 servings/day and 0.83 (0.77-0.89, P<0.0001) for those with more than 5 servings/day. Subgroup analyses showed that both fruits and vegetables had a significant protective effect on CHD. Our meta-analysis of prospective cohort studies demonstrates that increased consumption of fruit and vegetables from less than 3 to more than 5 servings/day is related to a 17% reduction in CHD risk, whereas increased intake to 3-5 servings/day is associated with a smaller and borderline significant reduction in CHD risk. These results provide strong support for the recommendations to consume more than 5 servings/day of fruit and vegetables.

Sodium and potassium intake and blood pressure.

There is increasing circumstantial evidence that the very high sodium diet combined with low potassium intake that most Western communities now eat may be, at least in part, responsible for the prevalence of high blood pressure. This circumstantial evidence combined with animal evidence has been considered sufficient in some countries to make a general recommendation to reduce sodium intake. If high sodium intake is an important cause of high blood pressure, it is not clear at the present time how it may do so. In this report, evidence is reviewed for one hypothesis suggesting an inherited defect in the kidney's ability to excrete sodium in patients who are going to develop essential hypertension, together with evidence for a raised concentration of an inhibitor of sodium transport. In patients with established hypertension, moderate restriction of sodium intake appears to lower blood pressure and moderate potassium supplementation to also lower blood pressure. While further evidence is required, particularly long-term studies, it would seem prudent to recommend to patients with essential hypertension or a strong family history of hypertension that they restrict dietary sodium intake moderately and increase dietary potassium intake by the consumption of more fruits and vegetables and, perhaps, the use of a potassium-based salt substitute. This regimen could obviate or reduce the need for drug treatment in some patients with mild to moderate hypertension.

Sodium is more important than calcium in essential hypertension.

There is much circumstantial and some direct evidence in humans to suggest that a high consumption of salt predisposes communities and individuals to the development of essential hypertension. Recent work has suggested possible mechanisms whereby a high salt intake could cause a rise in blood pressure in genetically susceptible persons. Restriction of salt intake in the diet lowers blood pressure in many subjects with high blood pressure and this fall in blood pressure is mediated in part by a diminished renin response to sodium restriction as hypertension develops. The effect of sodium restriction, like diuretics, is additive to most blood pressure lowering drugs, particularly those that inhibit the renin system such as beta-blockers and angiotensin converting enzyme inhibitors. Claims that a slight reduction in calcium intake may be important in the development of high blood pressure are disputed. Furthermore, no satisfactory hypothesis has been put forward to explain how a small reduction in dietary calcium intake could cause high blood pressure. Large increases in calcium intake have been reported to lower blood pressure in both normotensive and hypertensive humans. The three published studies, however, are not in agreement.

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)

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.

Ouabainlike Na+,K+-ATPase inhibitor in the plasma of normotensive and hypertensive humans and rats.

Acute volume expansion, increased sodium intake, and restraint on sodium excretion endow the plasma with an increased capacity to inhibit sodium transport. Cytochemical techniques can detect the presence of Na+K+-adenosine triphosphatase (ATPase) inhibitor in the plasma of normal humans and rats, the concentration of which is controlled by salt intake. The substance responsible appears to originate in the hypothalamus, where the concentration is also controlled by salt intake. The plasma concentration of the cytochemically detectable Na+,K+-ATPase inhibitor is substantially raised in the plasma of patients with essential hypertension, spontaneously hypertensive rats (SHR) and of Milan hypertensive rats. The concentration of activity in the hypothalamus of SHR is also considerably raised. These findings demonstrate that these forms of hypertension are associated with a rise in the concentration of a cytochemically detectable circulating Na+,K+-ATPase inhibitor that under normal circumstances is controlled by salt intake.

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.

Captopril and nifedipine in combination for moderate to severe essential hypertension.

The effects of the addition of a calcium entry antagonist, nifedipine (20-mg tablet twice a day), to an angiotensin converting enzyme inhibitor, captopril (25 mg three times a day), and the addition of captopril to nifedipine were observed in two separate studies in patients with essential hypertension. After 4 weeks of captopril therapy alone, mean arterial pressure fell by 12 mm Hg, and with the addition of nifedipine to captopril for a further month, blood pressure fell by an additional 10 mm Hg. In a separate group of patients treated with the same doses, mean arterial pressure fell by 17 mm Hg with nifedipine treatment alone; when captopril was added to the nifedipine therapy for an additional month, mean arterial pressure fell by a further 11 mm Hg. These blood pressures were measured 2 hours after the last dose; however, there was less of a fall in blood pressure when it was measured 12 hours after the last dose. This study confirms that captopril and nifedipine have a marked additive effect on blood pressure in whichever order they are given, but it shows that the combination is relatively short-acting.

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.

Structural skin capillary rarefaction in essential hypertension.

A reduction in the density of capillaries (rarefaction) is known to occur in many tissues in patients with essential hypertension. This rarefaction may play a role in increasing peripheral resistance. However, the mechanism underlying this capillary rarefaction is not understood. The aim of this study was to assess the extent of structural versus functional capillary rarefaction in the skin of dorsum of fingers in essential hypertension. The capillary microcirculation was examined with video microscopy before and after maximizing the number of perfused capillaries by venous congestion. The study group comprised 17 patients with essential hypertension (mean supine blood pressure, 155/96 mm Hg) and 17 closely matched normotensive controls (mean blood pressure, 127/77 mm Hg). We used intravital video microscopy with an epi-illuminated microscope to examine the skin of the dorsum of left middle phalanx before and after venous congestion at 60 mm Hg for 2 minutes. A significantly lower mean capillary density occurred at baseline in hypertensive subjects versus normotensive subjects. With venous occlusion, capillary density increased significantly in both groups; however, maximal capillary density remained significantly lower in the hypertensive subjects than in the normotensive subjects. The study strongly suggests that much of the reduction in capillary density in the hypertensive subjects is caused by structural (anatomic) absence of capillaries rather than functional nonperfusion.

Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality.

We recently showed that rarefaction of skin capillaries in the dorsum of the fingers of patients with essential hypertension is due to the structural (anatomic) absence of capillaries rather than functional nonperfusion. It is not known whether this rarefaction is primary (ie, antedates the onset of hypertension) or secondary (ie, as a consequence of sustained and prolonged elevation of blood pressure [BP]). The aim of the present investigation was to study skin capillary density in a group of patients with mild borderline hypertension to assess whether rarefaction antedates the onset of sustained elevation of BP. The study group included 18 patients with mild borderline hypertension (mean supine BP, 136/83 mm Hg), 32 normotensive controls (mean BP, 126/77 mm Hg), and 45 patients with established essential hypertension (mean BP, 156/98 mm Hg). The skin of the dorsum of the fingers was examined by intravital capillary videomicroscopy before and after venous congestion at 60 mm Hg for 2 minutes. Patients with borderline essential hypertension had the lowest resting capillary density when compared with normotensive controls and patients with established hypertension. Maximal capillary density with venous congestion in the borderline group remained the lowest. The study confirmed that patients with borderline essential hypertension have skin capillary densities that are equally low as or even lower than patients with established hypertension. Both groups had significantly lower capillary densities than normal controls. One explanation for the results is that capillary rarefaction may be due to an early structural abnormality in essential hypertension.

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.

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.

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)