Calcium antagonists in hypertension: relation to abnormal sodium transport.

Leucocyte sodium efflux rate constants and intracellular electrolyte contents were estimated in 13 patients with untreated essential hypertension. There was no correlation between intracellular sodium or potassium content or efflux rate constant and blood pressure. The patients were then treated with oral nifedipine and blood pressure controlled. Sodium efflux rate constants and electrolyte contents were estimated one and three months after the start of treatment. There was a significant fall in blood pressure, but mean sodium efflux rate constant and intracellular sodium content were unchanged. There was no correlation between the fall in blood pressure, initial sodium efflux, or intracellular sodium content. These data do not support the hypothesis that the sodium pump and intracellular sodium content have a direct role in generating raised blood pressure, or that treatment of hypertension with calcium antagonists corrects a fundamental alteration of calcium-sodium exchange across the cell membrane.     

Pregnancy induced hypertension: evidence for increased cell membrane permeability to sodium.

In a cross sectional study of 137 women of childbearing age (16-40) the effects of normal pregnancy, hypertensive pregnancy, and oral contraceptives on red cell electrolyte content and sodium efflux rates were examined and the results compared with values in a control group of normotensive, non-pregnant women. Efflux rate constants were significantly increased in normotensive pregnancy and in women taking oral contraceptives. This was associated with a significant increase in sodium permeability in the contraceptive group. A much larger increase in sodium permeability and efflux rate constant was seen in the hypertensive group. The results permit a hypothesis that the hormonal changes induced by pregnancy and oral contraceptives increase membrane permeability to sodium and stimulate sodium efflux. The rise in blood pressure associated with use of oral contraceptives may have a similar aetiology to that occurring in pregnancy induced hypertension.     

Acute effects of angiotensin-converting enzyme inhibitor on erythrocyte sodium ion transport in essential hypertension.

The acute effects of angiotensin-converting enzyme inhibitor, captopril, on sodium ion transport systems were investigated in essential hypertensive and normotensive subjects. The passive sodium efflux through the erythrocyte membrane was significantly higher and erythrocyte sodium-potassium cotransport was lower in patients with essential hypertension when compared with normal subjects. However, sodium-potassium pump activity and sodium-lithium countertransport did not differ significantly between the hypertensive patients and the normal subjects. Immediately after captopril administration, erythrocyte passive sodium efflux and sodium-potassium cotransport returned to normal levels in the hypertensive subjects. Although the plasma renin activity and plasma aldosterone concentration were altered by captopril, they did not correlate with changes in any sodium transport system. These results suggest that the changes in sodium transport systems which occur immediately after captopril administration may contribute, at least in part, to its antihypertensive action.     

Evidence for a circulating sodium transport inhibitor in essential hypertension.

The active sodium transport of white cells and red cells obtained from patients with essential hypertension was impaired. Incubating white cells from normotensive subjects in serum obtained from patients with essential hypertension caused an impairment in sodium transport in the white cells of normotensive subjects similar to that found in the white cells of hypertensive patients. The impairment in sodium transport was due to a fall in the ouabain-sensitive component of the total sodium efflux rate constant. These results show that the serum of patients with essential hypertension contains a substance which influences sodium transport and that it has ouabain-like activity. They also suggest that it is this substance which causes the impairment in sodium transport in the leucocytes of patients with essential hypertension. These findings support the hypothesis that the rise in blood pressure in patients with essential hypertension is due to an increased concentration of a circulating sodium transport inhibitor which is continuously correcting a tendency for sodium retention by the kidney.     

Sodium,potassium, and rate constants for sodium efflux in leucocytes from hypertensive Jamaicans.

Leucocyte sodium and potassium content and concentrations were measured along with ouabain-sensitive and ouabain-insensitive rate constants for sodium efflux in 14 controls and 20 black patients with essential hypertension. Leucocyte sodium content was significantly increased in the patients (mean 101.1 +/- 7.8 mmol/kg dry solids v 74.5 +/- 7.6 mmol/kg dry solids; p less than 0.05), whereas the rate constants for sodium efflux were not significantly reduced. There was no difference between the two groups in cell potassium values. The increase in leucocyte sodium content in the presence of normal rate constants for sodium efflux suggests an increase in membrane permeability to sodium, which might be important in the pathogenesis of essential hypertension.     

Erythrocytic cation transport receptor numbers and activity in pregnancies complicated by essential hypertension and pre-eclampsia.

Various functions of erythrocytic cation transport were studied in normotensive and hypertensive pregnancy (women with pre-eclampsia and essential hypertension). The results showed that in pregnancy there is an increase in the number of erythrocytic glycoside binding sites accompanied by a proportional increase in the active inward transport of rubidium (used as a substitute for potassium). There was no evidence of an effect of pregnancy on intraerythrocytic sodium concentrations. These changes were apparently entirely attributable to pregnancy and not affected by pre-eclampsia or essential hypertension. It is suggested that these alterations indicate an adaptive increase in sodium pump numbers and activity secondary to a tendency for the intraerythrocytic sodium concentration to rise during pregnancy and compensating for that tendency.     

Ion transport in erythrocytes of Prague hypertensive rat

The Prague hypertensive rat is a unique strain exhibiting genetic hypertension in which a hypertensive line (PHR) was bred in parallel with a normotensive one (Prague normotensive rat--PNR) from the same parental pair. Sodium efflux from Na(+)-loaded erythrocytes into Mg2(+)-sucrose medium was measured in these two strains as well as in spontaneously hypertensive rats (Okamoto-Aoki, SHR) and in normotensive outbred Wistar rats. Kinetic parameters--maximal velocity and apparent dissociation constant (reflecting the affinity for internal sodium)--were calculated. It was found that PHR as well as SHR had a higher Na+ leak and a decreased activity of the ouabain-sensitive Na+ transport as compared to Wistar rats. Furosemide-sensitive Na+ transport was substantially lower in erythrocytes of both hypertensive strains (PHR and SHR) than in the respective normotensive strains (PNR and Wistar).     

Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible mediation of Na/H exchanger isoform-1

Garlic causes reduction in blood pressure (BP), however the role of Na/H exchanger (NHE) which mediates hypertension and related tissue-damage is poorly understood. In this study the effect of an established dose of raw garlic extract was investigated on the expression of NHE-1 and -3 and sodium pump activity in a 2K-1C model of hypertension in rats. 2K-1C animals showed high BP, increased serum concentration of PGE2 and TxB2, hypertrophy of the unclipped kidneys, but not in the clipped kidneys In addition, NHE-1 and NHE-3 isoforms were increased in both the 2K-1C kidneys, whereas alpha-actin was increased in the clipped but not in unclipped kidneys. Sodium pump activity was decreased in the clipped kidneys, but remained unchanged in the unclipped kidneys. Garlic treatment reduced the induction of NHE-1 only in the unclipped 2K-1C kidneys, whereas garlic treatment increased the sodium pump activity in both the 2K-1C kidneys. These findings demonstrate that the antihypertensive action of garlic is associated with a reversal of NHE-1 induction in the unclipped kidneys. Induction of NHE isoforms together with a reduced sodium pump activity might cause necrosis in the 2K-1C clipped kidneys due to cellular retention of Na+. On the other hand, activation of sodium pump by garlic extract in the kidneys should reduce intracellular Na+ concentration and normalize BP. These findings signify the use of garlic in the treatment of hypertension.     

23Na NMR evaluation of human erythrocytes Na+/K+/CL-cotransport. A study in elderly hypertensives.

The behaviour of sodium transport systems across the cell membrane has been poorly investigated in elderly hypertension. Sodium efflux driven by Na+/K+/Cl-cotransport activity was therefore investigated (using a novel NMR-spectroscopy method) in 5 elderly hypertensive males (mean age 78 +/- 5 years) and 5 normotensive controls (mean age 79 +/- 3 years). In order to exclude any change in cotransport activity secondary to metabolic abnormalities, both patients and controls were non-obese and had normal glucose and lipid metabolisms. The Na+/K+/Cl-cotransport evaluation was performed after three months of pharmacological wash-out, under a diet containing 120 mEq of Na+/day. The resulting data showed that Na+ efflux due to outward Na+/K+/Cl-cotransport was higher in hypertensive group than in the normotensive one (0.50 +/- 0.10 mmol Na+/l cells/hr. vs 0.33 +/- 0.03 mmol Na+/l cells/hr., respectively, p < 0.05). Intracellular Na+ content was similar in both groups. At variance with previous data from the literature, our findings indicate that the Na+/K+/Cl-cotransport activity is elevated in elderly hypertensives.     

Active efflux of lithium from erythrocytes of manic-depressive subjects

Lithium transport kinetics, studied under physiological conditions in erythrocytes obtained from manic-depressive patients, are characterized by asymmetric rate constants of efflux and influx. The efflux constants, which are more than twice as large as the influx constants, correlate well with the $\text{in vivo}$ distribution of lithium between erythrocytes and plasma. The efflux process, which is not inhibited by ouabain and is therefore distinct from the sodium-potassium pump, is characterized by Michaelis - Menten kinetics and a large energy of activation. There appears to be a normal endogenous inhibitor which regulates the activity of the postulated lithium pump.     

Blood pressure control during weight reduction in obese hypertensive men: separate effects of sodium and energy restriction.

The separate and combined effects of dietary energy and sodium restriction on regulation of blood pressure were investigated in 30 middle aged obese men with essential hypertension attending the outpatient department. In group 1 (n = 15) a basal period with no dietary restriction was followed by a period taking an energy reduced diet (5.1 MJ; 1230 kcal), the sodium intake being supplemented and hence unchanged (1:ErSn). In group 2 (n = 15) the basal period preceded a control period with no intervention, which was followed by taking a diet restricted in energy (5.1 MJ; 1220 kcal) and sodium (2:ErSr). During period 1:ErSn there were reductions in heart rate and urinary noradrenaline output but not in systolic or diastolic blood pressure. Body weight decreased by 4.9-11.7 kg and urinary sodium excretion did not change. In period 2:ErSr urinary sodium output was reduced by 81.4 (SEM 17.8) mmol(mEq)/24 h and there was a weight loss of 8.2 (SEM 0.7) kg. Systolic and diastolic blood pressures fell significantly, as did the heart rate and urinary noradrenaline excretion. These results show that in hypertensive obese men a moderate weight reducing diet decreases indices of sympathetic nervous system activity. Reduction of blood pressure to the normotensive range was observed only when there was a concomitant restriction of sodium intake.     

Characteristics of sodium transport in pig (Sus scrofa) erythrocytes

Sodium content, sodium transport (ouabain-sensitive efflux rate of sodium, oMosNa; and ouabain-sensitive efflux rate constant of sodium, oKosNa), [3H]ouabain binding capacity, and Na+, K+-ATPase activity were measured in erythrocytes from young pigs (Sus scrofa). The sodium content, sodium transport, and the number of sodium pumps (assessed by ouabain binding capacity) were lower in the pig compared to the human erythrocytes. The efflux rate constant of sodium, oKosNa was 36% and the ouabain binding capacity was 60% of those in human, suggesting the degree of activation of sodium pump units is much lower.     

Potassium transport in the rabbit renal proximal tubule: Effects of barium,ouabain, valinomycin,and other ionophores

Summary Potassium fluxes in a suspension of rabbit proximal tubules were monitored using a potassium-sensitive extracellular electrode. Ouabain (10^–4 m) and barium (5mm) were used to selectively quantitate the potassium efflux pathway (105±5 nmol K⁺·mg protein^–1·min^–1) and the sodium pump-related potassium influx (108±7), respectively. These equal and opposite fluxes suggest that potassium accumulation in the cell occurs mainly through the sodium pump and that potassium efflux occurs mainly through barium-sensitive potassium channels. Thus the activity of the sodium pump (Na, K-ATPase) in the basolateral membrane of the proximal tubule is balanced by the efflux of potassium, presumably across the basolateral membrane, which has a high potassium permeability. In addition, the effect of valinomycin and other ionophores was examined on potassium fluxes and several metabolic parameters [oxygen consumption (QO₂), ATP content]. The addition of valinomycin to the tubules produced a net efflux of potassium which was quantitatively equivalent to the efflux produced by the addition of ouabain. The valinomycin-induced efflux was mainly due to the activity of valinomycin as a mitochondrial uncoupler, which indirectly inhibited the sodium pump by allowing a rapid reduction of the intracellular ATP. Amphotericin, nystatin, and monensin all produced large net releases of intracellular potassium. The action of the ionophores could be localized to the plasma or mitochondrial membrane and classified into three groups, as follows: (a) those which demonstrated full mitochondrial uncoupler activity (FCCP, valinomycin), (b) those which had no uncoupler activity (amphotericin B, nystatin); and (c) those which displayed partial uncoupler activity (monensin, nigericin).     

Effect of triamterene on leucocyte sodium and potassium levels in heart disease.

Sodium and potassium levels in plasma and leucocytes and the sodium efflux rate constants of leucocytes were measured in patients with congenital heart disease not on treatment, patients with valvular heart disease being treated with digoxin and conventional diuretics, and patients with valvular heart disease receiving digoxin and either conventional diuretics or triamterene or both. The group being treated with digoxin and conventional diuretics showed low cellular potassium levels, low sodium efflux rate constants, and a rise in cellular sodium levels. Patients given triamterene showed a rise in potassium levels in plasma and cells and in the sodium efflux rate constant.     

The Kinetics of Sodium Transport in the Toad Bladder : II. Dual effects of vasopressin

In the accompanying paper, a compartmental model for the toad bladder sodium transport system was developed. In the present paper, the model is tested by determining the effects of antidiuretic hormone on the pools and fluxes. It is shown that this hormone affects only that sodium pool previously designated as the transport pool, and that the effects are on two separate sites. In the first place, the hormone stimulates entry at the mucosal side of the transport compartment, and by this means brings about an increase in the amount of sodium contained in the compartment. Second, the hormone has a distinct stimulatory effect on the rate coefficient for efflux across the serosal boundary, the pump rate coefficient. Evidence is presented that under control conditions, the pump rate coefficient is a decreasing function of the pool size, a characteristic feature of a saturating system. Therefore, the effect of vasopressin in increasing both the pool size and the pump rate coefficient must be construed as a direct effect on the pump, and not one which is secondary to the increase in the pool size. Furthermore, it is shown that the effect of the hormone on the sodium pump is not dependent on the presence of sodium in the serosal medium.     

Reversal by verapamil of defect in sodium transport in leucocytes in essential hypertension.

The effect of treatment with verapamil on cell sodium transport was studied in the leucocytes of patients with essential hypertension. Previously described abnormalities of sodium efflux rate constant and intracellular sodium content were confirmed, the component of the sodium efflux rate constant sensitive to ouabain being lower and the intracellular sodium content higher in the patients compared with controls. Verapamil reversed these abnormalities and reduced blood pressure.     

Effect of gramicidin A and thallium ions on cation effluxes in frog sartorius muscle

The effluxes of potassium, rubidium, sodium and lithium from the sartorius muscle of Rana temporaria in magnesium-Ringer solution free of sodium and potassium have been studied with the flame-emission technique. The channel-forming antibiotic gramicidin A (2.5 X X10(-7)-1 X 10(-6) mol/l) enhanced the efflux of potassium and rubidium and increased the rate constants of these effluxes. Gramicidin had small if any effect on sodium and lithium effluxes and rate constants. After 60-100 min in a gramicidin-containing medium, the potassium efflux and the corresponding rate constant reached a steady-state level. This steady-state value depended on gramicidin concentration. Effect of gramicidin on both the potassium efflux and the rate constant was partially reversible. Thallium ions (2.5 X 10(-3) and 5 X 10(-3) mol/l) in sodium- and potassium- free magnesium Ringer solution caused a large increase in effluxes of all the cations examined (K+, Rb+ and Na+) both in presence and absence of gramicidin. Possible mechanisms of gramicidin and thallium effects are discussed.     

Stoichiometry of sodium-calcium exchange in cardiac sarcolemmal vesicles. Coupling to the sodium pump.

Vesicles isolated from cardiac muscle exhibited Na,Ca exchange activity which can be measured by 45Ca influx or efflux of by 22Na efflux. The stoichiometry of Na,Ca exchange was 3 Na:1 Ca. These vesicles also exhibited ATP-dependent 22Na transport which was inhibited by ouabain indicating that this activity is due to the sodium pump, an activity which is thought to reside only in the sarcolemma. The addition of calcium caused rapid efflux of 22Na from vesicles loaded by ATP-dependent 22Na uptake indicating that the Na,Ca exchange is located in the same vesicles as the sodium pump and is thus also a sarcolemmal activity.     

Pharmacological studies of smooth muscle from Dahl salt-sensitive and salt-resistant rats

The pharmacological properties of various isolated smooth muscle preparations from the Dahl strain of hypertensive rats were studied. The Dahl salt-sensitive (DS) rat was allowed to develop hypertension by increasing the dietary sodium from 0.4 to 4.0 or 8.0%. The Dahl salt-resistant (DR) rat remained normotensive on the same diet. The preparations studied were the thoracic aorta, tail artery, portal vein, anococcygeus, and the perfused mesenteric bed. The noradrenaline mean effective doses (ED50) either in the absence or presence of cocaine, were similar for tissues obtained from hypertensive DS or normotensive DR. The reactivities of the isolated perfused mesenteric preparation to noradrenaline, serotonin, and phenylephrine were similar in DS and DR. The ED50 for the relaxing effects of papaverine in noradrenaline-precontracted aorta was similar for tissues from DS and DR and the profile for the washout of noradrenaline-precontracted aorta with Krebs (with or without papaverine) was also similar in DS and DR. The results of this study were compared with similar studies performed using other models of hypertension. It is concluded that vascular changes are unlikely to play a major role in the etiology of hypertension in the Dahl rat model of essential hypertension.     

Failure of renal denervation to attenuate hypertension in Dahl NaCl-sensitive rats

In previous experiments we have demonstrated that the renal nerves play a significant role in all genetic and (or) induced models of hypertension that we have studied. The current experiments extended this research by investigating the contribution of the renal nerves to hypertension in the Dahl NaCl-sensitive rat. This was investigated by assessing the effect of bilateral phenol renal denervation carried out prior to initiation of a high NaCl (8% NaCl) diet. In two separate studies, renal denervation did not affect systolic blood pressure in either Dahl NaCl-sensitive rats or their normotensive counterparts, Dahl NaCl-resistant rats. Further, denervation did not increase absolute urinary sodium excretion, percent urinary sodium excretion, urinary volume output, or food or water intake; nor did it differentially alter creatinine clearance or body weight. Denervation was verified at the termination of each study by a greater than 80% depletion of renal noradrenaline stores. These results indicate that the renal nerves do not provide a major contribution to hypertension in the Dahl NaCl-sensitive rat.