Natriuretic hormones (NH) may be divided into two groups on the basis of whether their identity is known or unknown. Some prostaglandins, catecholamines, kinins, insulin, calcitonin, and vasopressin belong to the first group. However, it must be stressed that although the natriuretic action of the hormones listed has been repeatedly documented, the role of the hormones in the physiology or pathophysiology of renal sodium excretion has not been completely clarified.¹⁾ Since the initial observations of de Wardener and coworkers²⁾ (1961), many investigators have attempted to determine whether there is indeed a second group consisting of NH of unknown identity.

Biologic effects that have been claimed for the putative NH include (1) natriuresis, (2) inhibition of sodium transport (antinatriferic activity), (3) Na⁺-K⁺ ATPase inhibition, and (4) increased vascular reactivity.³⁾

NH has recently become known as the atrial natriuretic factor (ANF), which is considered to be released from atrial granules and ouabain-like factor (OLF) with no known releasing site. However, there are reports about the isolation of OLF from the hypothalamus^4,5) and the kidney in salt loaded rats.^6,7) Furthermore, it’s been already known that this OLF can be detected in patients with chronic uremia, those suffering from water immersion, idiopathic hyperaldosteronism, skull injury, high-salt diet and loading, idiopathic edema and during space travel under no gravitation.^1,5,7,8)

Ylitalo et al.⁹⁾ (1979) have reported that if salt is not restricted from the diets of animals which have undergone removal of 70–80% of the renal mass by surgical means, the blood pressure rises. A study carried out by Ylitalo and Gross¹⁰⁾ in 1979 indicates that increased blood flow and decreased plasma renin activity in renal mass surgically reduced rats can be observed. Schmidt et al.¹¹⁾ also found in renal mass reduced dogs that, unless salt is restricted in the diet, fractional excretion of Na in each nephron increases and that there might be a substance provoking natriuresis in plasma. On the other hand, in the same animals, with salt restriction none of increased fractional excretion of Na occurred and provoked natriuresis when plasma is injected.

The factors determining the level of the blood pressure are mainly the volume of the extracllular fluid and the changes in peripheral vascular resistance, and the contributing elements are the renal blood volume, the glomerular filtration rate, the ability of the kidneys to excrete Na, plasma renin activity, PG, kallikrein system, and cell membrane Na⁺ transport defect. Among these elements, the cell membrane Na⁺ transport defect, that has been studied most, was supposed by Bianchi and Barlassina in 1983 to be a result of inhibited Na⁺-K⁺ ATPase activity by OLF, but the correlation between OLF and cell membrane Na⁺-K⁺ ATPase activity has not been clarified.^12–15)

This study has been carried out for a further investigation of the relationship between the erythrocyte membrane Na⁺-K⁺ ATPase and OLF in reduced renal mass, hyporeninemic, hypertensive rats.

As the result of the work of Schwartz et al.,²⁰⁾ it has been known that Na⁺-K⁺ ATPase, a special enzyme located within the cell membranes of animals, has a sodium pump activity with features of receptor and Na⁺-K⁺ exchange. The functional unit for Na⁺-K⁺ ATPase has 2 subunits, α and β, which consist of polypeptide chains. Within the inner surface of the α -subunit; (1) receptors for various drugs and hormones, (2) ion-pump function, and (3) ATPase are considered to be present. In other words, β -subunits contain binding sites ; one for cardioactive steroid, one for ATP, three for Na⁺ ions, and two for K⁺ ions. Therefore, the action occurs in such a way that 3 moles of Na⁺ ions are transported out of the cell against its electrochemical and concentration gradients, and this transport is coupled with the active transport of 2 moles of K⁺ ions into the cell. During the whole process, through the hydrolysis of ATP to ADP providing the energy for transport, a remaining cation outside the cell creates a resting membrane potential.^19–22)

Generally, the sensitivity of Na⁺-K⁺ ATPase to cardioactive steroid is markedly decreased in the lower animals, including rats, although it is not known this is due to a ouabain-resistance gene or to conversion into ouabain-insensitive Na⁺-K⁺ ATPase after the synthesis of the enzyme.²²⁾ There are known factors influencing the receptors directly or indirectly. The indirectly controlling factors are (1) ligands of ATP, ADP, Pi, Mg⁺⁺, and K⁺, (2) proteolytic enzyme, (3) intracellular enzymes, and (4) genetically produced ouabain controlling protein, and the directly controlling factors are (1) cardioactive steroids, (2) “endogenous factors,” and (3) thyroid hormone, aldosterone, glucocorticoid, catecholamine. Vasodilators, calcium channel blockers, PGE₂, vanadium, and dilantin, as exogenous factors, are also directly controlling factors.^20,22–24)

So far, the “endogenous factor” has been reported to be isolated from the plasma, urine, kidney, heart, brain, and skin.^3,25–27) According to several researchers, “endogenous factor” has been variably known as (1) “endogenous digitalis” (endigin, endoxin), or OLF, (2) natriuretic factors, and (3) “hypertensive factor” isolated from hypertensive patients, and it is not definitely clarified yet whether these are one substance or somewhat modified forms or substances released from different sites.²²⁾ Recently, NH has been considered to be divided largely into two groups. One is ANF (or auriculin, cardionatrin, atriopeptin), a peptide consisting of 21–33 amino acids with a molecular weight of 3,000–15,000 dalton, which is released from the atria, but not from the ventricles. Amino acid sequences are defined both in humans (28 a.a.) and rats (21–33 a.a.), but its action mechanism cannot be explained as yet. Even though ANF has a strong effect on both sodium excretion and diuresis and, by depressing vascular resistance, leads to vasodilation, there has been no connection between it and Na⁺-K⁺ ATPase activity. Now the interesting topics being focused on are the isolation of antibodies to ANF and the action mechanism.^28,29)

The other factor in NH is OLF (circulating sodium pump inhibitor) and this seems to be released from the hypothalamus or the kidney. There are reports of studies done on animals and humans in one of which OLF is described as having a low molecular weight of less than 500 daltons, and in another of which, as having a high molecular weight of 1,500–10,000 daltons.^3,30) OLF, which is readily soluble in an organic solvent, and heat-stable, is a peptide digested by prolidase, but not by trypsin and other enzymes. It’s release can be detected by the increase in amount of extracllular fluid such as that which occurs in chronic uremics.^31,32) This OLF acts on the renal collecting ducts and tubules and, by inhibiting Na reabsorbtion, its action cause a strongly enhanced Na excretion and diuresis. However, on the other hand, OLF inhibits the efflux of Na from the cell membrane by acting on the erythrocytes, leukocytes, platelets, nerve cells and smooth muscle cells of the vessel. In other words, OLF may partially inhibit the Na⁺–K⁺ pump in vascular smooth muscle, thereby causing an increase in norepinephrine secretion from nerve cells, and in intracellular Na⁺ ion concentration. Then, because the vascular smooth muscle cells contain a Na⁺ – Ca⁺⁺ exchange transport system in their plasma membrane, more free calcium ion than normal is delivered to these cells. This caused the in creased vascular tone and peripheral vasaular resistance that elevates the blood pressure.^{5,15,30,33–36)}

It has been known that the NH, play an important role in controlling glomerulotubular balance of Na along with the glomerular filtration rate and the aldosterone. OLF has been detected in chronic uremia, water immersion, primary hyperaldosteronism, head trauma, high salt diet or loading, and idiopathic edematous patients.^1,5,7,8) Louis and Favre⁷⁾ (1980) discovered the existence of OLF in the kidney of the rat that had been rapidly loaded with Ringer’s solution, and they were able to observe its action on the renal collecting duct. Kim et al.³⁷⁾ (1984) also observed the decrease in Na⁺-K⁺ ATPase activity of the renal cortex and the increase in the Na⁺ renal tubular reabsorption, by inhibiting renal tubular Na⁺-K⁺ ATPase with the release of OLF from the hypothalamus. This occurs when the circulating blood volume is increased by the rapid infusion of saline or Ringer’s solution.

Welt³⁸⁾ (1969) was able to observe in chronic uremia that the erythrocyte Na⁺-K⁺ ATPase activity was markedly decreased. They were also able to observe, when uremic plasma was incubated with erythrocyte membranes prepared from normal subjects, erythrocyte Na⁺-K⁺ ATPase activity was markedly decreased. Yoon et al³²⁾ (1986) also had observed the markedly decveased erythrocyte Na⁺-K⁺ ATPase activity, in chronic dialytic uremic patients. Furthermore, markedly decreased erythrocyte Na⁺-K⁺ ATPase activity was observed when the supernates of the heated plasma prepared from chronic uremic patients was incubated with erythrocyte membranes from normal subjects. Although the inhibition of the cell membrane Na⁺-K⁺ ATPase in chronic uremia can be considered to be influenced by uremic toxins, such as phenolic acid and methylguanidine, metabolic acidosis, or vanadate within the body, the main point goes to the release of OLF by the accumulation of Na and water in the body.^39,41)

However, the inhibition of the erythrocyte Na⁺-K⁺ ATPase activity in chronic uremia can recover after renal transplantation. This may be explained by the fact that the activity, inhibited by OLF and other entities is overcompensated following renal transplantation.^42,44)

The pathogenesis of essential hypertension has been explained as being a result of interaction among the following factors : (1) genetic or acquired defect of Na excretion ability in the kidney, (2) environmental factors related to age and salt intake, (3) the factor inhibiting Na⁺-K⁺ ATPase activity during Na transport across the cell membrane, so called OLF, (4) and others, such as the renin-angiotensin system, catecholamine, the renal nerve, renal PG, and vasopressin. The elevated vascular resistance is due to increased intracellular Ca⁺⁺ ion concentration, which occurs as a consequence of increased intracellular Na⁺ and an increased norepinephrine release from the nerve cells by OLF which bring about such an interrelationship as OLF/inhibited Na⁺ Ca⁺⁺ exchange/hypertension.^13,15,33,45)

In this hyporeninemic, hypertensive group, the increased fractional excretion of urinary Na was 13 times higher than in the normotensive group, the erythrocyte Na⁺-K⁺ ATPase activity was decreased, and when heat-treated supernates of the plasma are incubated with the erythrocyte membranes from normal rats, the erythrocyte Na⁺-K⁺ ATPase activity is markedly decreased in comparison to that in the normotensive group. It is obvious that a mild uremic state was present in both groups and the possibility that inhibition of the erythrocyte Na⁺-K⁺ ATPase activity was due to uremia per se can also be considered. But, as in the hypertensive group, the pathogenesis of hyporeninemic hypertension can be based on the OLF secretion by the mechanism for controlling the Na accumulation following the administration of salt. Then, OLF, by accelerating the excretion of urinary Na and, on the other hand, inhibiting Na⁺-Ca⁺ exchange across the cell membranes of the vessel and enhancing norepinephrine secretion from the nerve cells, has explanations from both sides for the elevating of the blood pressure. This can be understood in a way, in that in chronic uremia, as renal function decreases, retention of P causes Ca to be at a low level which, therefore, increases plasma PTH, leading to high urinary excretion of P, this decreasing the plasma P level. But, on the other hand, this is thought to be a result of “trade-off,” a hypothesis explaining the various toxic reactions developed by PTH. In the coming years, the biological and chemical characteristics and secreting sites of OLF should be more throughly investigated and, in order to understand the pathophysiology of hypertension in various diseases, the chemical picture of Na⁺-Ca⁺⁺ exchange at the cellular level must be clarified.