Abnormal Relationship between Dietary Sodium Intake and Red Cell Sodium Transport in Salt-Sensitive Patients with Essential Hypertension

The effects of high sodium intake on erythrocyte ²²Na efflux rate constants were studied in 25 patients with essential hypertension and 9 normal subjects. With changes in sodium intake from 100 mEq to 300 mEq/day, both total and ouabain sensitive ²²Na efflux rate constants decreased significantly (p < 0.001) in “salt-sensitive” patients (-0.031 ± 0.005 and -0.035 ± 0.006 /hr, respectively), but these responses were variable in “nonsalt-sensitive” patients and in normal subjects. The “salt-sensitive” patients showed a significant increase in their body weight, while intraerythrocyte sodium contents remained unchanged in the both groups. These results suggest that the abnormal change in membrane Na-K-ATPase activity may, at least in part, be involved in the mechanism of sodium susceptibility in patients with essential hypertension.     

Defective Renal Dopamine D1 Receptor Function Contributes to Hyperinsulinemia-Mediated Hypertension

Hyperinsulinemia is reported to play a role in hypertension, as abnormalities in blood pressure regulation and sodium handling exist in diabetes mellitus. Kidney dopamine promotes sodium excretion via the activation of renal D1 receptors. Because there is a close relationship between renal D1 receptor function and sodium excretion, it is hypothesized that a defect in this mechanism may contribute to decreased sodium excretion and hypertension during hyperinsulinemia. Renal D1 receptor function was studied in insulin-induced hypertension in male Sprague Dawley rats. Insulin pellets were implanted subcutaneously for controlled insulin release for three weeks; sham rats served as a control. Compared to control rats, insulin pellets increased plasma insulin levels by eight fold and decreased blood glucose by 40%. Insulin also caused a 22 mmHg increase in mean arterial blood pressure compared to control animals. The intravenous infusion of SKF-38393, a D1 receptor agonist, increased sodium excretion in control rats, but SKF-38393 failed to produce natriuresis in hyperinsulinemic animals. Renal proximal tubules from hyperinsulinemic rats had a reduced D1 receptor number, defective receptor-G protein coupling, and blunted SKF-38393 induced Na, K-ATPase inhibition. Insulin seems to reduce D1 receptor expression and coupling to the G-protein, leading to a reduced D1 receptor-mediated Na, K-ATPase inhibition, and a diminished natriuretic response to SKF-38393. These phenomena could account for sodium retention and hypertension associated with hyperinsulinemia.     

Endogenous Inhibition of Red Blood Cell Na,K-ATPase in Essential and Pregnancy-Induced Hypertension

Digoxin-like inhibitors of Na, K-ATPase have been implicated in the pathophysiology of essential(EH) and pregnancy-induced hypertension(PIH). A technique that enhances dissociation of digoxin from red blood cells(RBC) was used to displace endogenous digoxin-like substances from RBCs. RBC membranes were preincubated in Na and ATP(Release) or Na, K, Mg and ATP (Retention) prior to measuring ATPase activity. Groups studied were: 39 men with EH and 34 controls plus 10 women with PIH and 17 normotensive controls. All displayed similar increases in Na, K-ATPase activity (24.0±7.9%) following Release. Plasma digoxin immunoreactivity(DI) was measured in pregnant women, m= 0.25±0.07 ng/ml. No DI was detected in nonpregnant women, but RBCs from these women demonstrated the same increase in Na, K-ATPase activity after Release. The 24% increase in activity achieved by Na and ATP preincubation can be reversed by adding K and Mg to the Release suspension. However, after RBC-bound digoxin is displaced by Release preincubation, addition of K and Mg cannot promote renewed binding and pump inhibition. Thus, the observed endogenous inhibition is not due to displacement of a digoxin-like substance but probably is related to alteration of the enzyme-membrane interaction. Furthermore, even though pregnant women demonstrate DI, an inhibitory susbstance with digoxin-like binding could not be recognized using theis technique.     

Low TRH-TSH Responses in Human Essential Hypertension

Thirty female and male essential hypertensive patients and eigtheen normotensive controls were submitted to the TRH-TSH conventional test (200 ug intravenously, bolus injection of TRH). Supramaximal doses of 400 and 600 ug were repeated with a week interval to each subject. Hypertensives showed a significant lower response to both conventional and supramaximal TRH doses. Hypothalamic-pituitary-thyroid axis abnormalities, secondary to TRH-receptor alterations could account for this result.     

Is Red Cell Sodium Transport a Function of Pressure?

Sodium ef flux from normal red cells was measured as a function of pressure to test whether abnormal sodium transport in hypertension is a direct consequence of the increased arterial pressure. Red cells were loaded with ²²Na and sodium efflux was measured at 37°C while the samples were in a bomb at constant pressures of 200 mmHg or 517 mmHg. Control samples were incubated concurrently at atmospheric pressure and the same temperature. The effect of preincubation of blood at 200 mmHg for 3.5 h on sodium efflux was also measured.

²²Na efflux and first order efflux rate constants were similar in high and normal pressure samples in each case. These findings suggest that acute changes in pressure have no effect on erythrocyte sodium efflux, which in turn implies that abnormal membrane transport in hypertension is not a consequence of the raised arterial pressure.     

Sodium transport inhibitors in pregnancy-induced hypertension

In blacks and whites of similar socioeconomic background, the incidence of pregnancy-induced hypertension (PIH) is probably the same. In underdeveloped coutries, however, PIH is often a life-threatening complication of pregnancy. Recent theories as to the etiology of PIH include the suggestion that vascular tone may be increased as a result of inhibition of active sodium transport in vascular smooth muscle. This may be the result of an inhibitor of sodium transport present in the serum. The literature concerning the demonstration of endogenous sodium transport inhibitors and endogenous digoxinlike immunoreactivity (EDLI) in PIH is reviewed and discussed.     

Leucocyte Alkaline Phosphatase Elevation in Human Acute Leukaemia Derived Cell Lines Cultured in Diffusion Chambers

Leucocyte alkaline phosphatase (LAP) was histochemically detected in 7 to 18 % of cells in tissue culture lines derived from the peripheral blood or bone marrow of each of 5 patients with untreated acute myelogenous or monomyelogenous leukaemia and in 30 % of cells in a clonal line of a rat promyelocytic leukaemia. Following transfer to diffusion chambers intraperitoneally implanted into total body irradiated rats, LAP levels were detected in up to 92 % of human and 80 % of rat leucocytes. There was no associated morphologic differentiation. In rat leukaemia cells peroxidase and myeloid specific esterase also increased from tissue culture levels. Return of cells to tissue culture decreased enzymes to pre-implant levels. Addition of plasma or peritoneal fluid from irradiated rats to cells in tissue culture again induced LAP. In contrast, LAP was not increased under these conditions with cell lines derived from patients with acute lymphatic leukaemia, or Sezary cell leukaemia. These studies indicate that a humoral factor in peritoneal fluid and plasma of irradiated rats increases LAP in human as well as rat leucocytes.     

T细胞免疫与高血压的研究进展

原发性高血压是多基因遗传和多种环境因素共同作用下的复杂疾病,免疫机制在高血压的发生、发展和治疗中占据重要的作用。T淋巴细胞作为最重要的免疫细胞,参与了其病理生理及炎症过程。近年来,调节性T细胞与高血压的关系尤其受到关注,并取得了一定的研究成果,开辟了高血压的免疫治疗这个全新的领域。现对近年来T细胞免疫与高血压的研究进展做简要综述。     

Abnormalities of Vascular Wall Sodium Content in Dogs with Benign and Malignant Renal Hypertension

The water and sodium content of the saphenous vein was measured in 26 dogs with one-kidney, one wrapped hypertension. For comparison, the same measurements were performed on the contralateral saphenous vein which was removed prior to the induction of hypertension. Malignant hypertension characterized by blindness and a rise in plasma renin activity, developed in 10 dogs. The course of hypertension in the remaining 16 dogs was benign. In benign hypertension, the water and sodium content of the saphenous vein was increased. In contrast, the water content of the saphenous vein was unchanged and its sodium content fell in dogs with malignant hypertension. The dogs with malignant hypertension had a greater sodium content of the saphenous vein prior to the induction of hypertension than the dogs with benign hypertension. The findings indicate that the loss of body water and sodium that has been described in malignant hypertension also affects the composition of blood vessels. The sodium content of blood vessels may be a predictor of the dog's response to a hypertension-producing stimulus.     

Effect Of Changes in Sodium Intake on Cell Transport Parameters

Changing sodium intake from 70–200 mmol/day elevates blood pressure in normotensive volunteers by 6/4 mmHg. Older people, people with reduced renal function on a low sodium diet and people with a family history of hypertension are more likely to show this effect. The rise in blood pressure was associated with a fall in plasma volume suggesting that plasma volume changes do not initiate hypertension.

In normotensive individuals the most common abnormality in membrane sodium transport induced by an extra sodium load was an increased permeability of the red cell to sodium. Some normotensive individuals also had an increase in the level of a plasma inhibitor that inhibited Na-K ATPase. These individuals also appeared to have a rise in blood pressure.

Sodium intake and blood pressure are related. The relationship differs in different people and is probably controlled by the genetically inherited capacity of systems involved in membrane sodium transport.     

Effect of Shiga Toxin 2 on Water and Ion Transport in Human Colon In Vitro

Shiga toxin-producing Escherichia coli (STEC) colonize the lower segments of the human gastrointestinal tract, causing gastrointestinal and systemic diseases. In this study, the effects of Shiga toxin 2 (Stx2) on fluid absorption and ion transport in the human colon were examined. Net water movement (Jw) and short-circuit current (Isc) were simultaneously measured across the colonic mucosa incubated with crude or purified Stx2. Stx2 significantly inhibited the absorptive J_w with no effect on the basal I_sc after 60 min of exposure. These effects may be due to the inhibition of a nonelectrogenic transport system present in the surface colonic villus cells. Morphological studies of the colonic mucosa treated with crude or purified Stx2 demonstrated a selective damage in the absorptive villus epithelial cells. These findings suggest that Stx2 inhibits water absorption across the human colon by acting on a specific cell population: the mature, differentiated absorptive villus epithelium.     

Human Tissue Kallikrein Attenuates Hypertension and Secretes into Circulation and Urine After Intramuscular Gene Delivery in Hypertensive Rats

Systemic delivery of the human tissue kallikrein transgene has been shown to markedly delay the increase of blood pressure in hypertensive rat models. To demonstrate potential hypotensive effects of kallikrein via local delivery, adenovirus carrying the human tissue kallikrein gene was inoculated into quadriceps of spontaneously hypertensive rats (SHR). A single intramuscular injection of the kallikrein gene caused a significant delay of blood pressure increase for 5 weeks. The expression of human tissue kallikrein and its mRNA was identified solely in injected muscle. Immunoreactive human tissue kallikrein was detected in the muscle as well as in the circulation and urine of adult and newborn rats. Urinary kinin and cGMP levels increased significantly in rats receiving kallikrein gene delivery as compared with rats receiving control virus containing the LacZ gene. The detection of human tissue kallikrein in rat urine after local gene delivery into the muscle provides direct evidence that circulatory kallikrein can be secreted into the urine.     

Low Dose of ACE-Inhibitor Enhances Sodium Excretion in Volume Expanded Patients with Borderline Hypertension

Borghi C, Boschi S, Costa FV, Bacchelli S, Degli Esposti D, Immordino V, Piccoli M, Ambrosioni E.: Low dose of ACE-inhibitor enhances sodium excretion in volume expanded patients with borderline hypertension.

The purpose of the present study was to separately investigate the effects of two different dosages of captopril on pressor, vascular and humoral response to acute extracellular volume expansion in patients with borderline hypertension (BHT). Thirty-five patients were randomly allocated in two groups undergoing acute saline infusion (0.40 ml/min/kg for 45min and 0.15 ml/min/kg for 75 min) before and after a 7-day period of treatment with either placebo or captopril at the dose of 12.5 (LD-CAP) or 50 mg (HD-CAP) twice a day. At baseline the effects of LD-CAP were limited to an increase in PRA and to a decrease in plasma aldosterone whereas HD-CAP decreased systolic and diastolic blood pressure (SBP, DBP), forearm vascular resistance (FVR) and increased venous distensibility (VV₃₀) as well. After saline loading patients treated with HD-CAP showed an increase in SBP, DBP not observed in patients allocated to LD-CAP. Urinary sodium excretion in response to NaCl loading was selectively enhanced by LD-CAP (+25%) whereas HD-CAP did not (+6.3%). The present data suggest that low-doses of ACE-inhibitors acting through a selective blockade of RAA not associated with hemodynamic changes can enhance the natriuretic response to acute volume expansion in borderline hypertensives.     

脂质体介导人NIS基因转染肺癌A549细胞及其蛋白表达

目的 研究人钠/碘同向转运体(NIS)基因转染肺癌细胞及其蛋白表达.方法 鉴定质粒pcDAN3-hNIS中的插入基因NIS基因.培养的肺癌A549分为两组:实验组(转染pcDAN3-hNIS),对照组(转染pcDAN3).脂质体介导NIS基因转染肺癌细胞,采用Western Blot免疫印迹法和免疫组化法检测肺癌细胞中NIS蛋白的表达.结果 验组的肺癌细胞有NIS蛋白的表达,而对照组无表达,两组比较差异有显著性(P=0.000).结论 转染人NIS基因的肺癌细胞可表达NIS蛋白,为探索放射性碘治疗肺癌的研究提供理论依据.     

The Role of Endogenous Inhibition of Na-K-ATPase in Human Hypertension - Sodium Pump Activity as A Determinant of Peripheral Vascular Resistance

High sodium intake in the presence of an intrinsic or acquired defect in renal sodium excretion will result in extracellular fluid volume (ECFV) expansion which is accompanied by decreased baroreceptor reflex sensitivity. We have shown that ECFV-expansion also stimulates the secretion of an endogenous inhibitor of the Na-K-ATPase enzyme and high activity of this sodium transport inhibitor was detected in plasma of patients with primary aldosteronism, the most classical type of volume-dependent hypertension. Thus, vasoconstriction due to inhibition of sodium pump activity of the vascular smooth muscle cell may contribute to the pathogenesis of human arterial hypertension. In analogy, ouabain (8.5 μg/kg) when administered i.v. to healthy volunteers inhibited RBC - Na-K-ATPase by 49% and significantly increased peripheral vascular resistance by 24 - 36%. The calcium entry blocker nifedipine (10 mg orally) completely prevented ouabain-induced vasoconstriction suggesting that the action of ouabain was mediated by a rise in intracellular calcium. High potassium intake partially abolished the vasoconstrictor effect of ouabain and also significantly increased baroreceptor reflex sensitivity. The results of these studies support the concept that inhibition of the sodium and potassium pump of vascular smooth muscle cells by a yet putative endogenous inhibitor of Na-K-ATPase (natriuretic hormone) may represent a crucial mechanism in the pathogenesis of at least certain forms of essential and secondary hypertension in man.     

Increased Serum Glycosidase Activity in Human Hypertension

Compared to values obtained in healthy normotensive control subjects, the serum activity of the lysosomal enzymes N-acetyl-β-D-glucosaminidase (NAG) and β-glucuronidase, was found to be elevated in patients with mild or borderline hypertension. The serum activity of the cytosolic enzyme lactate dehydrogenase was the same in the two groups. Serum NAG activity in hypertension was inversely correlated with glomerular filtration rate and renal plasma flow. Because of the greater variability of β-glucuronidase activity, there were no such correlations between the serum levels of this enzyme and the measurements of renal function.     

Typology of Na+ transport abnormalities in erythrocytes from essential hypertensive patients. A first step towards the diagnosis and specific treatment of different forms of primary hypertension

Over the last 5 years, several authors have measured apparent affinities and maximal translocation rates of the different erythrocyte Na⁺ transport systems in essential hypertensive patients. These kinetic studies have clearly shown that no unique red cell Na⁺ transport defect characterizes the whole population of essential hypertensive patients. Conversely,several complex patterns of erythrocyte Na⁺ transport abnormalities may be present in different subsets of essential hypertensive patients. These kinetic studies are now providing a more profound biochemical insight into the molecular heterogeneity of primary hypertension. In particular, they may permit the diagnosis and specific treatment of different forms of primary hypertension in the next decade.     

Elevated Levels of Circulating Cell Adhesion Molecules in Uncomplicated Essential Hypertension

Elevated levels of circulating soluble cell adhesion molecules are associated with the development of cardiovascular disease. We tested the hypothesis that circulating levels of soluble cell adhesion molecules are elevated in older men with uncomplicated essential hypertension, which may contribute to the increased risk of atherosclerosis in this population. Circulating levels of soluble intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin were measured in 11 hypertensive (69 ± 1 years) and ten normotensive (65 ± 1 years) older men who were free of overt atherosclerotic disease, diabetes, and dyslipidemia. The hypertensive subjects had higher (P < .05) circulating levels of soluble intercellular adhesion molecule-1 (232.4 ± 16.5 v 189.8 ± 11.1 ng/mL) and vascular adhesion molecule-1 (737.3 ± 65.6 v 565.7 ± 46.8 ng/mL) compared with their normotensive peers. However, there was no difference in the levels of soluble E-selectin between the hypertensive (51.1 ± 3.9 ng/mL) and normotensive (48.8 ± 6.6 ng/mL) subjects. Univariate analysis revealed a positive correlation between soluble intercellular adhesion molecule-1 and both systolic (r = 0.50, P = .02) and diastolic (r = 0.49, P = .03) blood pressure. In addition, soluble vascular adhesion molecule-1 was positively correlated with age (r = 0.60, P = .004) and systolic blood pressure (r = 0.43, P = .05). The results of this study support the hypothesis that circulating levels of soluble cell adhesion molecules are elevated in older men with uncomplicated essential hypertension.     

Sodium Elimination Rate and Blood Pressure during Normal and High Salt Intake in Subjects with and without Familial Predisposition to Hypertension

Abstract We have assessed the elimination rate of ²²Na (ER-²²Na), total exchangeable sodium (Na^E), blood pressure, plasma volume (PV), haematocrit, urinary noradrenaline (U-NA) and urinary 3-methoxy-4-hydroxymandelic acid (U-VMA) in normotensive men with (n=17) and without (n=15) familial predisposition to hypertension. All measurements were done during habitual salt intake and after four weeks of increased salt intake (ordinary intake + 12 g NaC1/daily). On ordinary salt intake, ER-²²Na, Na^E, blood pressure, PV, haematocrit, U-NA and U-VMA did not differ between the groups thus indicating a normal sodium turnover in both groups and a comparable activity of the sympathetic nervous system. After 10 days of high salt intake those without familial predisposition showed signs of volume expansion and decreased sympathetic activity and those with such predisposition showed insignificant changes in the same direction. After four weeks of increased salt intake, ER-²²Na had increased significantly and equally in both groups, while blood pressure and Na^E remained unchanged. This indicates that the predisposed individuals had a normal ability to cope with a prolonged increase in salt intake.