Abnormal red cell sodium content and efflux in Japanese patients with essential hypertension

Net sodium (Na) efflux and potassium (K) influx were determined in Na-loaded/K-depleted erythrocytes derived from 37 patients with essential hypertension and 25 age-matched normotensive subjects with no family history of hypertension, together with the measurement of basal red cell sodium and potassium contents. Intraerythrocyte sodium content was significantly higher in the essential hypertensives than in the normotensives (10.9 +/- 1.4 vs 10.0 +/- 1.2 mmol/L X cells, mean +/- SD, p less than 0.02), but potassium content was nearly equal between the two groups. Net Na efflux in the hypertensives was significantly reduced compared with that in the normotensives (4.57 +/- 0.70 vs 5.18 +/- 1.02 mmol/L X cells X hr, p less than 0.01), but both net K influx and net Na/K flux ratio were not significantly different between the two groups. Net Na efflux and K influx showed a significant inverse correlation with red cell sodium content (r = -0.64 and r = -0.56, respectively, p less than 0.001). These results suggest that the reduced net Na efflux with the increase of red cell sodium content may be related to the pathogenesis of essential hypertension. However, it is impossible to determine the genetic marker of essential hypertension by using the net Na/K flux ratio of Japanese subjects, although Garay et al. have reported that this index was abnormally low in the case of Europeans.     

Assessment of red cell sodium transport in essential hypertension

Abnormal erythrocyte Na+ transport has been reported in patients with essential hypertension and some first-degree relatives. The two major techniques now employed for estimating Na+ transport--Na+/Li+ countertransport and Na+/K+ cotransport--are rather intricate and time consuming. Furthermore, the precise nature of the transport processes being measured is not clear. We have developed a simpler, more direct technique based on measurement of 22Na+ accumulation by erythrocytes. 22Na+ uptake by red cells from patients with essential hypertension averages twice normal. Indeed, of 21 patients with essential hypertension, only 2 patients had values within the upper end of the normal range. In 12 patients with secondary hypertension and no family history of essential hypertension, erythrocyte 22Na+ accumulation was within normal limits. Control experiments indicate that our technique for estimating red cell 22Na+ uptake is highly reproducible and shows little day-to-day variation. This procedure for the assessment of erythrocyte Na+ transport should be useful in differential diagnosis and the presymptomatic identification of individuals genetically prone to essential hypertension.     

Enhanced sodium retention after acute nitric oxide blockade in mildly sodium loaded patients with essential hypertension

In essential hypertension (ESS) whole body and vascular nitric oxide (NO) synthesis is generally thought to be reduced. We therefore investigated the systemic and renal responses to acute treatment with N(G)-monomethyl-l-arginine (L-NMMA), a competitive NOS-inhibitor, in 12 patients with ESS and 18 healthy controls (CON) in a randomized, placebo-controlled study. Main effect parameters were renal hemodynamics (glomerular filtration rate [GFR] and renal plasma flow [RPF]), systemic blood pressure (BP), and fractional excretions of sodium (FE(Na)) and lithium (FE(Li)). Experiments were performed on two occasions for each subject studying the effects of either L-NMMA (3 mg/kg intravenously) or placebo. The patients with ESS were studied after at least 14 days off antihypertensive medication. Renal hemodynamics were assessed by the clearances of (125)I-hippuran (RPF) and (51)Cr-EDTA (GFR). The L-NMMA induced a significant increase in systemic BP and significant reductions in RPF, FE(Na), and FE(Li) in both groups. The increase in diastolic BP was significantly attenuated in ESS (ESS: 8% +/- 2% v CON: 14% +/- 2%, P < .05). The GFR and RPF were equally reduced by L-NMMA in both groups (RPF(ESS): -19% +/- 4% v RPF(CON): -15% +/- 3%, P = not significant [NS]). However, the reduction in FE(Na) was enhanced in ESS (ESS: -42% +/- 7% v CON: -25% +/- 3%, P < .01). The FE(Li) decreased equally in both groups (ESS: -17% +/- 2% v CON: -17% +/- 6%, P = NS). It is concluded that acute NO blockade in ESS is accompanied by a reduced systemic pressor response, an unchanged renal hemodynamic response, and an enhanced reduction in FE(Na). The results suggest that patients with essential hypertension are highly dependent on NO to maintain sodium excretion.     

The hemodynamics in young patients with borderline hypertension

Hemodynamics in supine position were studied echocardiographically in 56 young patients with borderline hypertension and 56 age-matched normotensive subjects. In hypertensive patients, the cardiac index (CI) did not increase, but the total peripheral resistance (TPR) increased significantly (p less than 0.005). The hypertensive patients were classified into 2 groups, according to the level of the CI. In patients in group A ("normal" CI), the CI, heart rate and the mean circumferential fiber shortening velocity (mVCF) were normal, but the TPR was increased significantly. In patients in group B ("high" CI), the CI, heart rate and the mVCF increased significantly (hyperkinetic state), but the TPR was normal. Plasma renin activity (PRA) was significantly higher in patients in group B than the normal subjects, but the level of PRA in patients in group A was normal. These findings support the hypothesis that sympathetic nervous activity increases in patients in group B, but not in those in group A. Therefore, this study provides evidence that the TPR is abnormal in patients with borderline hypertension, and an impaired neurogenic activity seems to be important in the early stage of hypertension, as in borderline hypertension associated with a hyperkinetic circulatory state (group B).     

Elevated blood viscosity in patients with borderline essential hypertension

In patients with borderline hypertension, total peripheral resistance (TPR) is either elevated or abnormally related to cardiac output. Since blood viscosity is one determinant of TPR, we compared various components of blood viscosity in 25 patients with borderline hypertension and 25 normal subjects. Under all experimental blood flow conditions examined, blood viscosity directly correlated with systolic and diastolic blood pressure (p less than 0.05 or better) and was greater in the hypertensive than in normal subjects. Venous hematocrit and plasma viscosity were higher in the hypertensive patients. These latter rheologic abnormalities accounted for the increased blood viscosity at higher shear rates. At lower shear rates, increased red cell aggregation, primarily mediated by elevated fibrinogen concentration, accounted for the higher blood viscosity in the hypertensive subjects. We conclude that even relatively small elevations in arterial pressure are associated with increased viscous resistance of blood to flow, and that the increased blood viscosity is a consequence of increased hematocrit, plasma viscosity, and red cell aggregation.     

Hemodynamic study of 85 patients with borderline hypertension

Hemodynamic changes in supine and upright position (50 ° head-up tilt) and during exercise were studied in 40 normal subjects and 85 patients with borderline hypertension. The latter were classified in 2 groups, according to the level of cardiac index. In group I, with patients in the supine position, cardiac index, stroke index, heart rate and plasma volume were normal, but total peripheral resistance was increased (P < 0.01). During upright tilt, orthostatic decrease of mean arterial pressure (P < 0.05) was observed, and the increase in total peripheral resistance was not greater than in normal subjects. The hemodynamic response to exercise was similar to that of normal subjects. In patients in group II, cardiac index, stroke index and heart rate were increased (P < 0.001), but plasma volume was decreased (P < 0.01) and total peripheral resistance was below normal (P < 0.001). With patients in the upright position, diastolic orthostatic hypertension was observed (P < 0.001) and total peripheral resistance was greater than normal (P < 0.01) despite an abnormal fall of cardiac index (P < 0.05). The hemodynamic response to exercise indicated that total peripheral resistance did not decrease as in normal subjects and in patients of group I (P < 0.001). This study provides evidence that (1) total peripheral resistance is abnormal in patients with borderline hypertension, but only during upright tilt and exercise in patients with high cardiac index, and (2) 2 main disorders seem to be important in the early stage of hypertension: abnormality of blood volume (or blood volume distribution, or both) and impaired neurogenic activity.     

The effect of sodium and potassium loading on urinary kallikrein-like activity in young patients with borderline hypertension

We studied the effects of a potassium supplement on urinary kallikrein excretion in a setting of high sodium intake after sodium deprivation with diuretics in young patients with borderline hypertension. Eleven patients, who took the potassium supplementation during the high sodium diet period, showed lower increments in mean blood pressure with salt loading than 12 patients without the potassium supplementation. In the non-potassium-supplemented patients, urinary kallikrein was increased significantly when plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary aldosterone were increased during the diuretic treatment. It was decreased significantly when the other hormones were decreased during the sodium load. During the high sodium diet period, PRA, PAC and urinary aldosterone were greater in the potassium-supplemented patients than in the non-potassium-supplemented ones, but urinary kallikrein excretion was not higher when potassium was supplemented. Thus, the present results did not support the theory that the kallikrein-kinin system may be involved in the natriuretic and antihypertensive effects of potassium. In addition, these finding suggest that some kallikrein-modulating factor(s) may counteract the increased urinary kallikrein excretion with the augmented renin-angiotensin-aldosterone system during salt loading with potassium supplementation.     

Personality traits of persons with borderline arterial hypertension and patients with essential hypertension

A study of 402 individuals with marginal arterial hypertension (MAH) and patients with essential hypertension (EH), stages 1, 2 and 3, demonstrated a variety of psychopathologic syndromes (hypochondria, anxiety, hysteria, depression, cardiophobia) in 52.8, 77.3, 82.5 and 80%, respectively. Specific personality features have been identified as pertaining to MAH (hyperthymism, sthenism, demonstrativeness, psychasthenia) and EH (psychasthenia, intraversion, cycloidy).     

Attenuation of the microcirculation in young patients with high-output borderline hypertension

Previous studies have shown abnormalities of the microvasculature in the spontaneously hypertensive rat and human subjects with established hypertension. We have studied the conjunctival microvasculature in relation to systemic and forearm hemodynamics in 24 normal subjects (NL) and 10 subjects with intermittent elevation of blood pressure (BHT). Macrophotographs of the conjunctival circulation were measured for arteriolar diameter and density of arterioles, capillaries, and venules. Blood pressure was measured by Arteriosonde, cardiac index by echocardiography, and forearm hemodynamics by mercury-filled strain-gauge venous occlusion plethysmography. Average diastolic blood pressure in the NL group was 74 +/- 1.7 mm Hg, while that of the BHT subjects was 89 +/- 3.1 mm Hg (p less than 0.005). Capillary density, venous density, and total vascular density were significantly lower in the BHT than NL group, while arteriolar density did not differ significantly. Cardiac index was significantly higher, and peripheral vascular resistance significantly lower, in the BHT as compared to the NL subjects. Forearm blood flow was higher in the NL subjects. The diameter of the preterminal arterioles of the BHT subjects was 27% greater than NL (p less than 0.02). The capillary density was inversely related to the cardiac index (r = -0.482, p less than 0.01), but was not related to blood pressure (r = -0.207). We conclude that the high cardiac output phase of early essential hypertension in humans is accompanied by a reduction in the number of filtering capillaries, and that the rarefaction of capillaries is more closely related to the elevation of cardiac output than to raised blood pressure.     

Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension

A cellular calcium-magnesium antagonism seems to be involved in the pathogenesis of primary hypertension. Total plasma, intracellular, and membranous calcium (Ca) and magnesium (Mg) contents were determined in 39 untreated patients with essential hypertension (EH) and 40 normotensive healthy subjects (NT). Membranous and intracellular measurements were performed in erythrocytes. Ca and Mg contents were measured by atomic absorption spectroscopy and membrane protein was determined according to Bradford's method as a membranous reference. There was no significant difference in plasma Ca (NT: 2.60 +/- 0.15 v EH: 2.64 +/- 0.17 mmol/L) and Mg concentrations (NT: 0.83 +/- 0.12 v EH: 0.87 +/- 0.14 mmol/L) in the studied groups. Intracellular Mg (NT: 1.72 +/- 0.15 mmol/L v EH: 1.64 +/- 0.19 mmol/L) and Ca (NT: 2.06 +/- 0.20 mmol/L v EH: 2.10 +/- 0.24 mmol/L) contents were also not significantly different between groups. Membrane Ca content was significantly increased in the EH group (2.23 +/- 0.32 micromol/g membranous protein) compared to controls (1.05 +/- 0.30 micromol/g membranous protein, P < .01). On the contrary, membranous Mg content was significantly decreased compared to controls (0.31 +/- 0.09 v 0.50 +/- 0.10 mmol/g membranous protein content, P < .01). The Ca/Mg ratio in membranes was significantly increased in EH as compared to healthy subjects (P < .01) and correlated to mean arterial blood pressure values (r = 0.47, P < .01). We conclude that the membranous alterations of Ca and Mg metabolism, shown by increased Ca/Mg ratio in red cell membranes of hypertensive subjects, may play a role in the pathogenesis of primary hypertension.     

"Inner picture of the disease" in persons with borderline arterial hypertension and in patients with hypertension

Individual attitude to disease was evaluated in 249 individuals with marginal arterial hypertension and patients with essential hypertension (EH). Anxiety, hypochondriac and neurasthenic types of response to raised arterial blood pressure were predominant. Hypertensive patients, prone to crises, mostly showed anxiety and neurasthenic response to arterial hypertension, while anosognosic response was less common, as compared to people with occasional hypertensive crises. In hypertensive males, as opposed to females, anosognosic perception of the disease prevailed, while the cardiophobic variant was less common.     

Enhanced red cell sodium-hydrogen exchange in microvascular angina

OBJECTIVES: Enhanced calcium content in arterial smooth muscle cells andaltered reactivity of coronary vessels to alkalinization havebeen reported in angina pectoris due to impaired motility ofcoronary arteries. An altered function of sodium-hydrogen exchange,a ubiquitous membrane transport system that links proton effluxto calcium drifts, may mediate these phenomena. DESIGN AND SUBJECTS: Twenty patients with microvascular angina (stable effort angina,reversible perfusion defects during effort thallium 201 heartscintigraphy, and angio-graphically normal coronary arteries)were compared to 20 patients with stable effort angina due tocoronary atherosclerosis and 20 healthy subjects. The sodium-hydrogenexchange was defined as the initial fraction of the amiloride-sensitiveproton efflux from red cells with inhibited anion exchanger(pHi 6·00–6·05) into an Na⁺-containing medium(pHo 8·00–8·05). 12-0-tetradecanoylphorbol-13-acetate(TPA, 600 nmol. 1^–1) and staurosporine (100 nmol. 1^–1)were used as phosphorylation modulators in vitro. RESULTS: The mean red blood cell Na⁺/H⁺ exchange was increased in patientswith microvascular angina (451±37 vs 142±17 and124±21 µmol H⁺. 1 cells^–1. min^–1, P<0·01).TPA and staurosporine abolished differences between the groups. CONCLUSION: Microvascular angina is associated with enhanced Na⁺/H⁺ exchangein erythrocytes, probably due to more extensive phosphorylationof the membrane antiporter sites.     

Free serotonin level in the blood of patients with borderline and essential hypertension

Serotonin appears to play an important part in the pathogenesis of essential hypertension. Various studies have shown, that the metabolism of serotonin may be disturbed in some pathological conditions for example in hypertension. It concerns also the changed mechanisms of uptake and release of serotonin. The certain blood vessels may become more hypersensitive to the vasoconstrictor effects of serotonin in patients with hypertension than in normal subjects. During chronic treatment with ketanserin, S2-serotonergic antagonist, blood pressure is reduced in spontaneously hypertensive rats and in humans. This fact can also indicate indirectly, that that serotonin plays a part in the pathogenesis of essential hypertension. The aim of the study was to determine the concentration of free serotonin (S) in the blood of 15 patients with sustained essential hypertension in the mean age 32.8 +/- 1.8, of 23 patients with borderline essential hypertension in the mean age 29.0 +/- 3.0 and of 10 normal subjects in the mean age 31.1 +/- 1.7 years. Plasma free serotonin was determined by fluorometric method. All patients and controls were investigated at the hospital. They were on normosodium diet, without drugs for last two weeks. The fasting blood samples were collected in the supine position. Free serotonin blood concentration was significantly higher in hypertensive group than in normal subjects. The important difference of serotonin blood concentration between two groups of hypertensive patients was noticed. It was significantly higher in group of patients with sustained hypertension, than in group with borderline hypertension (p less than 0.05). Our results are similar to the observations of other authors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of amyl nitrite on left ventricular relaxation in patients with borderline hypertension

The effects of systemic hypertension on left ventricular relaxation properties remain largely undefined. To assess such effects 22 normal volunteers and 15 patients with borderline hypertension were examined. The tangent to the echocardiographic left ventricular posterior wall endocardium was measured in diastole and was normalized for end-diastolic dimension to yield normalized velocity of relaxation. This velocity of relaxation was measured at rest and throughout inhalation of amyl nitrite. Mean value +/- standard deviation (SD) from rest to peak amyl nitrite effect for the normal group and for the patients with borderline hypertension was 3.3 +/- 0.6 leads to 7.2 +/- 1.1 and 3.0 +/- 0.8 leads to 4.4 +/- 1.1 s-1, respectively. All 22 persons in the normal group and 2 of the 15 patients with borderline hypertension attained normalized velocity of relaxation greater than 5.5 s-1 with administration of amyl nitrite. Multivariate analysis in the normal group identified heart rate, mean arterial pressure, and fractional shortening as the best predictors of normalized left ventricular relaxation velocity (r = 0.85; p less than 0.001). The increase in the normalized velocity of relaxation induced by amyl nitrite is blunted in patients with borderline hypertension. These changes in left ventricular relaxation identify early cardiac involvement and may prove clinically useful in hypertensive patients.     

Attenuated vasodilator responses to Mg2+ in young patients with borderline hypertension

Limb vascular responses to magnesium (Mg2+) and potassium (K+) ions were studied in 19 young patients with borderline hypertension (BHT) and compared with those of 22 age-matched normotensive subjects (NT) by measuring the forearm blood flow response to intra-arterial infusion of magnesium sulfate and potassium chloride using venous occlusion plethysmography. Percent decrements of forearm vascular resistance with Mg2+ infusions were significantly less in BHT subjects than in NT (-37.2 +/- 4.2% versus -53.0 +/- 2.0%, p less than 0.05, during the infusion of 0.1 meq Mg2+/min, and -52.2 +/- 4.3% versus -65.6 +/- 1.5%, p less than 0.05, during the infusion of 0.2 meq Mg2+/min). Moreover, the relation of the magnitude of Mg2+ response to initial vascular resistance in six of 10 BHT subjects lies above the 95% confidence interval for predicted values calculated for response points in 11 NT subjects, suggesting attenuated vasodilator responses of Mg2+ in a significant proportion of BHT subjects. In contrast, the response points to K+ in eight of nine BHT subjects fall within the 95% confidence interval, suggesting normal vasodilator responses to K+ in the majority of BHT subjects. Furthermore, the effect of small increments in local serum calcium concentrations on Mg2(+)- and K(+)-induced vasodilation was studied in normal volunteers. Isosmolar CaCl2 solution infused into the same brachial artery at a rate of 0.09 meq/min severely blunted the vasodilating actions of Mg2+ (-30.1 +/- 6.5% versus -65.8 +/- 3.2%, p less than 0.01, during the infusion of 0.2 meq Mg2+/min) but did not affect those of K+ (-63.1 +/- 3.1% versus -55.9 +/- 3.8%, NS, during the infusion of 0.154 meq K+/min). It appears that Mg2(+)-induced vasodilation should be due to the antagonistic action of Mg2+ to calcium, but K(+)-induced vasodilation might not be directly related to calcium movement. Thus, these attenuated responses to Mg2+ but normal responses to K+ in BHT subjects may indicate an underlying defect in vascular Mg2+ metabolism, which ultimately may be related to the alterations in calcium handling by plasma membranes rather than to the abnormalities of membrane Na(+)-K+ pump activity.