Leucocyte cation transport in essential hypertension: its relation to the renin-angiotensin system.

Leucocyte cation transport measured when patients received a normal sodium intake and the response of the renin-angiotensin system to changes in sodium intake were studied in 22 patients with essential hypertension. The rate constant for total leucocyte sodium efflux measured during a normal diet was significantly correlated with the plasma renin activity measured during a low sodium diet. Impairment of leucocyte sodium transport was significantly greater in eight patients whose plasma renin activity failed to rise into the normal range during the low sodium diet as compared with the 14 other patients, whose renin system responded normally to sodium restriction. These results provide further suggestive evidence for the hypothesis that there is a circulating sodium transport inhibitor that may be important in the pathogenesis of essential hypertension.     

Calcium and abnormal reactivity of vascular smooth muscle in hypertension

It has been well documented that vascular smooth muscle (VSM) reactivity, as well as calcium sensitivity in response to neurotransmitters is increased in a number of blood vessels in established hypertension. Regulation of VSM reactivity involves the interaction of neurotransmitters and blood-borne hormones with specific receptors on target cell membranes. This results in phospholipase-C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and the generation of two second messengers: inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG) both of which act synergistically to produce muscle contraction. We will summarize recent findings in this review which suggest that in essentially hypertensive patients and spontaneously hypertensive rats (SHR), the activation of phospholipase C in response to hormones is increased. Further, we will discuss how increases in phospholipase C activation via GTP-binding proteins may explain the observed increases in Ca2+ influx through potential- and receptor-operated Ca2+ channels, increased activation of protein kinase-C and increased [Ca2+]i in hormone-stimulated blood platelets and VSM cells in the hypertensive state. In addition to these defects, a decrease in the plasma membrane Ca2+ pump and Ca2+-binding proteins has been demonstrated in hypertension. Thus, it appears that the defect in Ca2+ metabolism in the hypertensive vessels is multifocal. All these defects in Ca2+ metabolism together may lead to an increase in peripheral vascular resistance with a concomitant increase in blood pressure.     

Calcium antagonists in exercise-induced asthma.

Ten patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled verapamil (estimated dose 3 mg) and sodium cromoglycate (estimated dose 12 mg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after running on a treadmill for eight minutes. There was no significant change in baseline FEV1 values after each agent. In the exercise periods, however, FEV1 fell by 45.4% (SEM 4.0) after saline inhalation, 18.4% (5.1) after sodium cromoglycate, and 16.7% (4.3) after verapamil. The inhibitory effects of sodium cromoglycate and verapamil were comparable and significantly different from saline (p less than 0.02 and p less than 0.01 respectively). Nevertheless, considerable intrasubject variability was observed. The findings suggest that mediator release, which is calcium dependent, may play an important part in exercise-induced asthma, and calcium antagonists may inhibit post-exercise bronchoconstriction by their blocking effect on calcium channels.     

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.     

Calcium transport in isolated bone cells. II. Calcium transport studies

Calcium transport was studied in bone cells isolated from fetal rat calvaria. ⁴⁵Ca uptake experiments revealed an active component of calcium exchange. Calcium uptake was inhibited by iodoacetamide, DNP, CCCP and oligomycin and appeared to be dependent on medium phosphate concentration. Initial influx values exhibited saturation kinetics from 0.6 mM to 1.5 mM extracellular calcium. Efflux of ⁴⁵Ca from loaded cells increased in the presence of iodoacetamide, DNP and CCCP. Incubation of the cells af 4° C inhibited both influx and efflux of calcium. Parathyroid hormone had no consistent effect on calcium uptake although characteristic increases in cyclic AMP levels were seen with the hormone. Calcitonin appeared to cause a transient increase in calcium uptake.     

Calcium regulation in neurons: transport processes.

The ionic stoichiometry of the major Ca2+ transport mechanisms in neurons is still a matter for debate. The past year has seen some particularly interesting developments in this field, not least the finding that the neuronal Na(+)-Ca2+ exchange may be able to transport K+.     

Calcium role in base-line and ADH-stimulated sodium transport in frog skin

Treatment of ventral frog skin with serosal A23187 calcium ionophore caused an initially transient increase in transepithelial sodium transport. After 60 min of treatment with A23187, a steady-state transport value was reached which was significantly lower than the initial one. Furthermore, it was found that ionophore treatment greatly inhibited the natriferic response to ADH and to 8br-cAMP. A further analysis on the possible ionophore action mechanism was carried out through pretreatment of the skin with indomethacin, very powerful prostaglandin synthesis inhibitor. In the experimental conditions reported, A23187 seems no longer capable of inducing a transient increase in sodium transport, although it does inhibit the natriferic response to ADH.     

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.     

Calcium bioavailability and its relation to osteoporosis.

The balance of data suggests that calcium intake has a positive influence on bone mass in premenopausal women and has a preventive effect on the rate of bone loss in postmenopausal women. Even small advantages in bone mass provide great reductions in fracture rates. However, the majority of studies have tested the relationship of calcium intake and bone mass using calcium supplements. Few intervention studies have manipulated calcium intake through foods. Calcium is only useful to the skeleton once it is absorbed. Therefore, the bioavailability of dietary calcium becomes important in the prevention and treatment of osteoporosis. Isotopic tracer techniques have only recently been employed in the labeling of foods with calcium isotopes for evaluation of calcium absorption. Milk calcium is usually the referent food which is typically absorbed at 20-40% depending on the calcium status of the subject. The absorptive efficiency of most vegetable sources is as good or better than for dairy foods, unless they have high concentrations of oxalic acid (spinach, for example) or phytic acid (wheat bran cereal, for example). Few vegetable sources are concentrated sources of calcium. Therefore, it would be difficult to obtain adequate intakes of calcium to protect against osteoporosis without liberal use of dairy products in the diet. Alternately, calcium supplements provide concentrated amounts of absorbable calcium, but they do not provide other nutrients necessary for skeletal growth and maintenance.     

Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension

Data obtainedduring the last two decades show that spontaneously hypertensive rats,an acceptable experimental model of primary human hypertension, possessincreased activity of both ubiquitous and renal cell-specific isoformsof theNa⁺/H⁺exchanger (NHE) andNa⁺-K⁺-2Clcotransporter. Abnormalities of these ion transporters have been foundin patients suffering from essential hypertension. Recent geneticstudies demonstrate that genes encoding the - and -subunits ofENaC, a renal cell-specific isoform of theNa⁺-K⁺-2Clcotransporter, and 3-, 1-, and 2-subunits of theNa⁺-K⁺pump are localized within quantitative trait loci (QTL) for elevated blood pressure as well as for enhanced heart-to-body weight ratio, proteinuria, phosphate excretion, and stroke latency. On the basis ofthe homology of genome maps, several other genes encoding these transporters, as well as theNa⁺/H⁺exchanger andNa⁺-K⁺-2Clcotransporter, can be predicted in QTL related to the pathogenesis ofhypertension. However, despite their location within QTL, analysis ofcDNA structure did not reveal any mutation in the coding region of theabove-listed transporters in primary hypertension, with the exceptionof G276L substitution in the1-Na⁺-K⁺pump from Dahl salt-sensitive rats and a higher occurrence of T594Mmutation of -ENaC in the black population with essential hypertension. These results suggest that, in contrast to Mendelian forms of hypertension, the altered activity of monovalent ion transporters in primary hypertension is caused by abnormalities ofsystems involved in the regulation of their expression and/or function.Further analysis of QTL in F₂hybrids of normotensive and hypertensive rats and in affected siblingpairs will allow mapping of genes causing abnormalities ofthese regulatory pathways.     

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 raised concentration of a circulating sodium transport inhibitor in essential hypertension.

A cytochemical technique that measures the ability of plasma to stimulate guinea-pig renal glucose-6-phosphate dehydrogenase (G6PD) activity in vitro, which is a marker of its ability to inhibit Na+-K+-adenosine-triphosphatase (Na+-K+-ATPase), was used in 19 patients with essential hypertension and 23 normotensive, healthy subjects. The ability of plasma to stimulate G6PD was significantly greater in the hypertensive patients when they were taking their normal sodium diet than in the normotensive subjects, and was significantly correlated with blood pressure. The ability of plasma to stimulate G6PD was inversely correlated with plasma renin activity in the hypertensive patients and increased with age and sodium intake in the normotensive subjects. These results support the hypothesis that essential hypertension, and also perhaps the increase in blood pressure with age in communities that consume large quantities of salt, is in part due to an increase in a circulating concentration of an inhibitor of Na+-N+-ATPase.