Intralymphocytic sodium and free calcium concentration in relation to salt sensitivity in patients with essential hypertension

In order to clarify the relation between salt sensitivity and changes in intracellular sodium ([Na]i) and free calcium concentration ([Ca2+]i) after salt loading, [Na]i and [Ca2+]i were determined in lymphocytes of twenty patients with essential hypertension under a low salt diet (3 g/day) and a high salt diet (20 g/day) for seven days, respectively. They were classified as "salt-sensitive" (n = 10) or "nonsalt-sensitive" (n = 10) on the basis of the changes in blood pressure after salt loading. Both lymphocytic [Na]i and [Ca2+]i were significantly increased with salt loading in salt-sensitive patients (p less than 0.05 for both), while they were not affected by salt loading in nonsalt-sensitive patients. Lymphocytic [Ca2+]i showed a positive correlation with lymphocytic [Na]i under both low salt diet (r = 0.62, p less than 0.01) and high salt diet (r = 0.70, p less than 0.01) in all patients in both groups. In addition, a close and positive correlation was observed between the changes in lymphocytic [Na]i and those in lymphocytic [Ca2+]i after salt loading in all patients in both groups (r = 0.80, p less than 0.001). These results suggest that the increase in [Ca2+]i, possibly linked with the increase in [Na]i, may be involved in elevation of blood pressure in the salt-sensitive patients after salt loading.     

Serum ionized calcium, parathormone and plasma renin activity in essential arterial hypertension

Given the significance of the calcium ion in the pathogenesis of essential arterial hypertension, blood levels of total and ionised calcium, phosphorus, parathormone, blood renin activity as well as urinary calcium and phosphorus were assayed in a group of hypertensives and a comparable control group with normal blood pressure. The results showed reduced ionised calcium in the blood of the hypertensives together with hyperparathyroidism and increased calciuria. In addition, the link between parathormone and mean blood pressure levels suggests that parathormone itself play a primary role in the genesis of high blood pressure. Finally the connection between renin activity in the plasma and ionised calcium in the serum suggests that the two hormone systems are closely linked and may interact via the calcium ion.     

Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism

Circulating levels of the calcium-regulating hormones, calcitonin, calcitriol, and parathyroid hormone, were analyzed in relation to plasma renin activity in 10 persons with normal blood pressure and in 51 persons with essential hypertension. Calcitriol (p less than 0.008) and parathyroid hormone (p less than 0.01) levels were elevated in hypertensives with low renin activity, whereas calcitonin levels were higher in patients with high renin activity (p less than 0.008), compared with normotensive controls and other hypertensive patients. Continuous relationships were observed between calcitriol levels and plasma renin activity in all patients (r = -0.65, p less than 0.001) and between parathyroid hormone levels and urinary sodium excretion in hypertensive patients with low renin activity (r = -0.63, p less than 0.01). Together, these results support a linkage between calcium metabolism and renin-sodium factors in essential hypertension. Calcium-regulating hormones and the renin-aldosterone system may coordinately mediate the blood pressure effects of differing dietary calcium and sodium intakes at the cellular level by altering cellular handling of monovalent and divalent ions.     

Increased plasma vasopressin in low renin essential hypertension

Baseline plasma vasopressin concentrations were measured in 48 men (all 50 years old) with decreased plasma renin concentration and untreated, sustained essential hypertension and in 29 healthy normotensive men. Mean hypertensive plasma vasopressin concentration was more than twice as high as the corresponding normotensive level (15.7 +/- 2.2 [SE] vs 7.5 +/- 1.0 pg/ml; p less than 0.001). Plasma renin concentration in the hypertensive group was reduced compared with that in the normotensive group (0.28 +/- 0.04 vs 0.46 +/- 0.06 Goldblatt units X 10(-4)/ml). These differences appeared despite virtually identical serum osmolality, creatinine clearance, and urinary sodium excretion in the two groups. In the first 38 hypertensive subjects, arterial plasma epinephrine concentrations were significantly increased over those of the first 28 control subjects (99 +/- 12 vs 68 +/- 6 pg/ml; p less than 0.025). In contrast to those with low renin essential hypertension, 35 men with normal renin essential hypertension (all 40 years old) had normal plasma vasopressin levels that were not significantly different from those in a comparable normotensive control group (3.7 +/- 0.8 vs 3.5 +/- 0.4 pg/ml). Arterial epinephrine concentrations were not significantly different between normal renin subjects and the control group. After 6 weeks of treatment with the nonselective beta-adrenergic receptor blocker oxprenolol in 11 subjects with low renin hypertension, blood pressure was reduced and the plasma vasopressin concentration fell from 27.6 +/- 6.4 to 13.5 +/- 4.2 pg/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Furosemide and plasma renin activity in essential hypertension.

Changes in arterial blood pressure, renal electrolyte excretion, and plasma renin activity in response to repeated doses of furosemide were measured in 12 patients with essential hypertension admitted to the medical service for electrolyte balance studies. Eighty and 120 mg/day furosemide in divided doses for 5 to 10 days produced a prompt increase in renal sodium excretion. Urinary Na/K concentration ratios, which were elevated during peak natriuresis, returned to control levels following the initial diuretic response. In 2 patients with high initial levels of plasma renin activity, arterial blood pressure was not reduced by furosemide, and more potent antihypertensive agents were required to control the blood pressure. In the remaining patients, furosemide produced a significant decrease in systolic and diastolic blood pressure. There was a general upward shift of plasma renin levels in terms of 24-hour renal sodium excretion in those who demonstrated an antihypertensive response to the drug. However, the average increase in plasma renin activity after repeated doses of furosemide was not statistically significant and no correlation was demonstrated between the level of plasma renin activity after furosemide and the blood pressure lowering effect of the drug.     

The multiple factors affecting plasma renin activity in essential hypertension

Seventy-nine patients with essential hypertension were evaluated for peripheral renin activity in response to injection of 60 mg of furosemide and to upright posture. Age and supine diastolic blood pressure were found to be significant determinants of responsiveness, with contributions from sex and race. Patients with impaired responsiveness were predominantly older and female, while the group of hyperresponders was younger, male, and had significantly lower supine diastolic pressures. Aldosterone responses in relation to changes in peripheral renin activity were found to be nearly random with both furosemide and with posture. Thus, patients could be subdivided into renin subgroups, but not into parallel aldosterone subgroups. Data on four patients with primary hyperaldosteronism were discussed for comparison.     

Pathogenesis of essential hypertension with low renin: responses of plasma renin activity to various stimulation tests in essential hypertension.

Plasma renin activity (PRA) was measured in 14 control subjects and 27 patients with essential hypertension (EH) (low renin group: 9, normal renin group: 11, and high renin group: 7) before and after the following stimulation tests. Test procedures: 1) Circadian rhythm (0600, 1600 and 2400h). 2) Adrenal stimulation test (ACTH: 12.5 I.U.). 3) Adrenal suppression test (Dexamethasone: 1.0 mg). 4) Metopirone test (1.5 g). 5) Angiotensin II infusion test (8 ng/kg/min). 6) Saline infusion test (1000 ml/hr). Patients with low PRA showed significantly lower levels of PRA than those of other two groups in circadian rhythm, after 2 hours of ACTH infusion and after angiotensin II infusion. Furthermore, these patients showed significantly higher responses of PRA than other two groups after furosemide test under dexamethasone and after metopirone test. In case of saline infusion test, patients with low and normal PRA did not show significantly decreased levels of PRA after the infusion, though all patients with high PRA and all control subjects showed significantly decreased levels of PRA. From the present studies, it might be concluded that patients with low PRA has an unknown mineralocorticoid excess which is ACTH dependent and 11 hydroxylated and some of hypertensive patients have an abnormality in their renin-angiotensin-aldosterone volume feed back loop as a factor for hypertension.     

Increased platelet cytosolic free calcium concentration in essential hypertension

Cytosolic free calcium concentration [Ca2+] was studied in platelets of hypertensive patients with the use of the fluorescent indicator Quin 2/AM. Cytosolic free Ca2+ was significantly higher in platelets of hypertensive patients than in those of normotensive subjects (241 +/- 9 versus 192 +/- 7 nmol/l, n = 58 and 57, respectively P less than 0.001). When all 115 subjects were included, there was a significant correlation between cytosolic free Ca2+ and systolic or diastolic blood pressure (r = 0.262, P less than 0.0025 and r = 0.251, P less than 0.0025, respectively). Intracellular Quin 2 concentration was measured to evaluate the formaldehyde production (a product of Quin 2/AM hydrolysis which has been described as reducing the adenosine triphosphate (ATP) production). The Quin 2 concentrations in platelets of the two groups of subjects were observed to be similar (0.41 +/- 0.03 versus 0.38 +/- 0.03 mmol/l, n = 8 and 7 for hypertensives and normotensives, respectively). The effects of prostaglandin E1 (PGE1), an adenylate cyclase stimulator, on cytosolic free Ca2+ were studied. The presence of 10(-7) mol/l PGE1 lowered the Ca2+ in platelets of hypertensive patients only, suppressing the difference between the two groups.     

Platelet cytosolic proton and free calcium concentrations in essential hypertension

Alterations in the metabolism of intracellular messengers, such as calcium and cyclic adenosine 5'-phosphate (cAMP), have been reported in essential hypertension. Since intracellular pH (pHi) participates in the control of fundamental cell functions, we looked for changes in platelet cytosolic H+ concentration [( H+]i) in hypertension and investigated whether or not its impaired metabolism is linked to the calcium handling abnormalities. The fluorescent pH indicator BCECF has been used to evaluate intracellular H+ concentration in platelets, unstimulated ex vivo, from normotensive (n = 20) and hypertensive patients (n = 20). Cytosolic [H+] was 20% lower in hypertensive than in normotensive subjects (49.5 +/- 3.4 and 61.8 +/- 2.2 nmol/l cells, respectively, P less than 0.005; mean pHi values were 7.21 and 7.33, respectively). Platelet cytosolic H+ and free Ca2+ concentrations ([Ca2+]i) were determined in parallel in 15 normotensive and 15 hypertensive patients. [Ca2+]i was found to be 19% higher (P less than 0.01), and [H+]i 22% lower (P less than 0.02), in the hypertensive patients compared with the normotensive subjects. Platelet pHi and [Ca2+]i were increased simultaneously in some hypertensive patients. These results are compatible with the hypothesis of an in vivo activation of platelets in hypertension. If a similar alkalinization exists in smooth muscle cells, it may participate in cell proliferation and in an enhanced sensitivity to agonists, two parameters thought to be involved in blood pressure elevation.     

Relationship between plasma renin profile and leptinaemia in patients with essential hypertension

Both leptin and the renin-angiotensin system (RAS) can influence the activity of the sympathetic nervous system, water and electrolyte metabolism as well as vascular remodelling, which are all involved in the regulation of arterial blood pressure. Thus leptin and the RAS may act together in the pathogenesis of essential hypertension. The present study aimed to answer the following question: does an interrelationship exist between leptinaemia and the plasma renin activity (PRA) profile in normotensive and hypertensive subjects? Forty-three patients with essential hypertension (EHP) (23 females, 20 males, mean age 39.0 +/- 1.8 years, mean body mass index (BMI) 26. 8 +/- 0.6 kg/m2, mean arterial pressure (MAP) 123 +/- 2 mm Hg) and 32 healthy subjects (NTS) (18 females, 14 males, mean age 38.6 +/- 2. 2 years, mean BMI 25.4 +/- 0.5 kg/m2, MAP 95 +/- 1 mm Hg) were examined. Plasma leptin levels were estimated once after the administration of a diet containing 100-120 mmol Na/day and after overnight 8-h recumbency. PRA was estimated twice: first after the administration of a diet containing 100-120 mmol Na day and overnight 8-h recumbency (PRA I), and a second time after 3 days of sodium restriction (20 mmol Na/day), and 3 h of upright position (PRA II). Antihypertensive drugs were withdrawn 7 days before the study. In EHP plasma leptin concentration was insignificantly higher than in NTS (14.0 +/- 2.0 vs10.8 +/- 1.5 ng/ml respectively). Only females with hypertension showed a significant positive correlation between plasma leptin concentrations (expressed as the logarithmic values) and PRA I. Using the multiple regression analysis, in all studied subjects (EHP and NTS together), logarithm (log) of plasma leptin concentrations was significantly related to gender, BMI and MAP. Multiple regression analysis performed separately for EHP or NTS revealed a significant relation of log plasma leptin concentrations with gender and BMI. A significant correlation was found between log leptinaemia values and BMI, mean and systolic blood pressure respectively if the whole group of subjects (EHP+NTS) or EHP and NTS separately were analysed. Especially in hypertensive women a highly significant correlation was found between log plasma leptin concentrations and MAP. We conclude that a significant relationship between leptinaemia and PRA does exist in females with EH and that participation of both PRA and leptin in the pathogenesis of EH in females seems to be likely.     

Association between plasma renin activity and metabolic cardiovascular risk factors in essential hypertension

Objectives. To study the relationships between plasma renin activity and metabolic cardiovascular risk factors in patients with essential hypertension.
Subjects and design. Patients with uncomplicated essential hypertension ( n =36) with a diastolic blood pressure of 95–115 mmHg were studied. Assessment of plasma renin activity (PRA) related to urinary sodium excretion was used to define subgroups with high ( n =12), medium ( n =16) and low renin profiles ( n =8).
Main outcome measures. Fasting plasma lipid levels were determined. Glucose, insulin and C-peptide responses to standard oral glucose tolerance test (OGTT) were measured.
Results. Patients with high PRA had higher levels of plasma cholesterol (6.13±0.81 versus 4.67±0.7 mmol L^-1, P <0.05) and triglycerides (2.14±0.18 versus 0.98±0.13 mmol L^-1, P <0.05), than the low PRA group. HDL-cholesterol levels were lower in the high renin group than in the low renin group (1.05±0.04 versus 1.26±0.09 mmol L^-1, P <0.05). Insulin and C-peptide sums were higher in high PRA group (33.8±1.2 versus 25.1±0.9 and 2.6±0.3 versus 1.9±0.4 ng L^-1, P <0.05), than in the low PRA group.
Conclusions. Essential hypertensive patients with a high renin profile display more pronounced dyslipidaemia and higher levels of plasma insulin than patients with a low renin profile. This may be one explanation for higher incidence of cardiovascular disease previously reported in high PRA group.     

Mineralocorticoid secretion in essential hypertension with normal and low plasma renin activity.

In 19 control subjects, 33 patients with essential hypertension and normal plasma renin activity (PRA) and 11 patients with low PRA, secretory rates of 18-hydroxy-11-deoxy-corticosterone (18-OH DOC), 11-deoxycorticosterone (DOC) and corticosterone were measured. Patients with low PRA were significantly older and had higher arterial pressure and slightly lower plasma potassium levels than patients with normal PRA. Mean 18-OH DOC secretion rate was higher in patients with normal PRA (603 +/- 112 SEM mug/24 hr) than in control subjects (219 +/- 19) and considerably higher (P less than 0.001) in patients with low PRA (1800 +/- 472). DOC and corticosterone secretion rates were within normal limits in most hypertensive patients. Plasma aldosterone was significantly higher in the hypertensive population than in control subjects whereas no significant difference was observed between the low- and normal-renin groups. A significant (P less than 0.01) mutual positive correlation was found between the secretion rates of 18-OH DOC, DOC and corticosterone in patients with low plasma renin activity. In contrast, there was no correlation between the secretion rates of the three mineralocorticoids in control subjects and patients with normal plasma renin activity. These data suggest a biosynthetic variation of the mineralocorticoid pathways in essential hypertension.     

Relationships between plasma catecholamines, renin, age and blood pressure in essential hypertension

The aim of this study was to examine the interrelationships between age, plasma catecholamines, plasma renin activity (PRA) and blood pressure in essential hypertensive (EH) patients. PRA, plasma noradrenaline (NA) and adrenaline (A) were measured in 76 consecutive EH patients (WHO stages 1-2, aged 24-66 years) and in 28 normotensive subjects (aged 25-64 years) studied at rest in supine position after 5 days of normal fixed sodium and potassium intake. Both plasma NA and A were slightly but significantly higher in EH patients (p less than 0.05). While no relationship was found between the various parameters in normotensive subjects, in EH patients, particularly those at WHO stage 2, plasma NA was directly related to mean blood pressure (MBP) (p less than 0.001) and PRA (p less than 0.01). Plasma A was weakly related to MBP (p less than 0.05); PRA was inversely related to age (p less than 0.01) but no relationship was found between NA or A and age. Partial correlation analysis confirmed all these relationships. In fact, NA was related to MBP also considering constant PRA (p less than 0.001) or age (p less than 0.001), and NA was related to PRA also considering constant MBP (p less than 0.01) or age (p less than 0.001). Acute pharmacological alpha- and beta-blockade, with labetalol 100 mg i.v., induced a reduction of MBP which was directly related to basal plasma NA (p less than 0.001). These results support the view that in EH the sympathetic nervous system might be in part responsible for PRA levels and for the severity of hypertension.