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(Hypertension. 1997;30:94-98.)
© 1997 American Heart Association, Inc.

Articles

Elevation of Ouabainlike Compound Levels With Hypertonic Sodium Chloride Load in Rat Plasma and Tissues

Kaoru Yamada; Atsuo Goto; Hiroshi Nagoshi; Yoshitake Terano; ; Masao Omata

From the Department of Human Dry Dock, Sanraku Hospital, Toykyo (K.Y.); Second Department of Internal Medicine, University of Tokyo (A.G., H.N., M.O.); and Department of Physiology, Osaka City University (Y.T.) (Japan).

Correspondence to Kaoru Yamada, MD, Department of Human Dry Dock, Sanraku Hospital, 2-5 Kanda-surugadai, Chiyoda-ku, Tokyo 101, Japan.

	Abstract

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Abstract A major biologically active endogenous digitalis-like factor in the mammalian body may be an isomer of ouabain (ouabainlike compound, OLC). However, the exact role of OLC in sodium homeostasis is still unclear, and acute isotonic volume expansion does not enhance the secretion of OLC. We tested the hypothesis that OLC may be more important in the response to acute hypertonic NaCl load rather than isotonic volume expansion. We injected intraperitoneally 2 mL of 20% NaCl solution into male Wistar rats (n=34) and measured OLC levels in plasma, hypothalamus, pituitary, and adrenal at baseline (n=10) and 1, 2, and 4 hours (n=8 for each). In response to hypertonic NaCl loading, plasma Na-K ratio was elevated at 2 and 4 hours (P<.01). OLC levels in pituitary increased (P<.01) at 1 hour. Thereafter, plasma OLC levels increased at 2 and 4 hours (P<.05; basal, 75±11 pmol/L [±SEM]; 1 hour, 55±11; 2 hours, 130±24; 4 hours, 156±20). Concomitantly, OLC levels in adrenal increased at 2 and 4 hours (P<.01; basal, 1.7±0.2 pmol/g; 1 hour, 4.5±0.9; 2 hours, 5.0±0.7; 4 hours, 6.8±2.2). A significant correlation was observed between OLC levels in plasma and adrenal (P<.05). Plasma Na-K ratio positively correlated with OLC levels in plasma (r=.51, P<.01) and adrenal (r=.48, P<.01). Similar injection of physiological saline solution or hypertonic sucrose solution in physiological saline did not increase OLC levels in plasma and tissues. These findings indicate the elevation of OLC levels in plasma, pituitary, and adrenal in response to acute hypertonic NaCl load in rats and suggest that OLC may be involved in the response to the hypernatremic state.

Key Words: ouabain • homeostasis • hypernatremia • digitalis-like factor

	Introduction

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The significance of a conserved cardiac glycoside binding site on Na⁺,K⁺-ATPase through evolution has been unclear. Analogous to the identification of the opioid peptides as ligands of the opiate receptor, much evidence suggests the existence of endogenous digitalis-like factors (EDLFs) that bind to the cardiac glycoside binding site and inhibit Na⁺,K⁺-ATPase activity.^{1 2 3 4 5} After three decades of searching, two groups of investigators identified a ouabain isomer (ouabainlike compound, OLC) from human plasma or bovine hypothalamus as a plausible EDLF.^{6 7 8}

Elevated circulating levels of EDLF have been associated with excess body fluid volume and hypertension, suggesting important roles of EDLF in sodium homeostasis and the regulation of long-term blood pressure.^{1 2 3 4 5} Although recent studies point to a contribution of OLC to several hypertensive mechanisms, its exact role in sodium homeostasis is still unclear. It is generally thought that salt retention and plasma volume expansion somehow would trigger the secretion of OLC as a natriuretic factor. However, acute isotonic plasma volume expansion in conscious dogs does not enhance OLC secretion,^{9 10} and plasma OLC is not correlated with atrial pressure in patients with congestive heart failure.¹¹

Mechanistic differences have been documented between natriuresis in response to hypertonic NaCl load with or without volume expansion and that caused by isotonic volume expansion.^{12 13 14} The rise in plasma sodium and/or tonicity rather than increase in blood volume is important in natriuresis with a hypertonic sodium load.¹⁵ Immunohistochemical studies suggest the presence of OLC in the paraventricular and supraoptic nuclei of mammalian hypothalamus, areas closely involved in the control of plasma sodium and tonicity.¹⁶ Our previous finding indicated that brain OLC may be involved in natriuresis caused by central administration of a hypertonic NaCl solution.¹⁷ In the present study, we tested the hypothesis that OLC may be more important in the response to acute hypertonic NaCl load rather than isotonic volume expansion. For this, we injected intraperitoneally a high NaCl solution into rats and examined the changes of OLC levels in plasma and several potential sites of OLC production and/or secretion.

	Methods

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Experimental Protocol
Male Wistar rats weighing 400 to 500 g were maintained on normal rat chow and tap water. The following procedures were in accordance with the guidelines of the Animal Experiment Committee of the University of Tokyo.

Experimental rats (n=24) received intraperitoneal injection of 2 mL of 20% NaCl solution (3.4 mol/L). We selected this NaCl concentration by taking into account the methods published in three previous reports.^{18 19 20} Since this solution contains sodium corresponding to 75% of total body sodium and is markedly hypertonic, the animals showed slight abdominal pain and distress during injection. However, after the injection, we did not observe convulsions or any apparent changes in the behavior of the rats. Rats had free access to drinking water after injection. Rats (n=8 for each time) were killed by decapitation 1, 2, and 4 hours after the injection. To obtain baseline values, control rats (n=10) without injection were similarly killed by decapitation. Another six rats were injected with 2 mL of 0.9% NaCl solution and were killed 2 hours after the injection.

In another experiment, we used a hypertonic sucrose solution to examine the effects of hyperosmolality independent of concurrent increases in plasma sodium concentration. Twenty-four rats were given intraperitoneal injections of approximately equimolar amounts of hypertonic sucrose (4 mL of 3.4 mol/L) in 0.9% NaCl solution instead of hypertonic NaCl solution (2 mL of 3.4 mol/L), and the animals (n=8 for each time) were killed by decapitation 1, 2, and 4 hours after the injection. Another 11 rats without injection served as controls.

Measurements of OLC and Electrolytes
Trunk blood was collected into a tube containing heparin (Ca²⁺ salt). The brain, pituitary, and right adrenal were removed, and the hypothalamus was dissected out according to the method described by Glowinski and Iversen.²¹

OLC levels in plasma, hypothalamus, pituitary, and adrenal were measured by radioimmunoassay for ouabain. Tissue samples were homogenized with 5 vol distilled water, and the homogenates were centrifuged at 15 000 rpm for 60 minutes. The supernatant and plasma sample (1.0 mL) mixed with an equal volume of 0.1% trifluoroacetic acid solution were applied to a Sep-Pak C18 cartridge that had been activated with methanol and equilibrated with distilled water. After complete washing with 30 mL distilled water, OLC was eluted with 3 mL of 25% acetonitrile in water. The eluate was evaporated and assayed for OLC as described previously.²²

Because we eluted the OLC-containing fraction with 25% acetonitrile in water from a Sep-Pak C18 cartridge, it is unlikely that our OLC levels included common adrenocortical steroids such as corticosterone, cortisol, and aldosterone. These steroids are too hydrophobic to be eluted at this acetonitrile concentration. The antiserum showed minimum cross-reactivity with common steroids such as cortisol, cortisone, progesterone, pregnenolone, deoxycorticosterone, dehydroepiandro-sterone sulfate, ß-estradiol, and testosterone as described previously.²² Polar metabolites of corticosterone and cortisol such as 6ß-OH-corticosterone and 6ß-OH-cortisol have a similar polarity to that of ouabain, and our sample might have contained these metabolites.²³ However, our antibody did not cross-react with 6ß-OH-corticosterone and 6ß-OH-cortisol at concentrations of 10^-4 to 10^-10 mol/L (unpublished data, 1995).

Plasma sodium and potassium concentrations were determined by flame photometry. Hematocrit values were also measured.

Statistical Analysis
Statistical evaluations were made by one-way ANOVA followed by Fisher's protected least significant difference using the StatView II software package (Abacus Concepts). Values are presented as mean±SEM; a value of P<.05 was taken as significant.

	Results

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Table 1 summarizes the changes in electrolyte concentrations and OLC levels in plasma and tissues after intraperitoneal injection of 20% NaCl solution. As expected, in response to sodium loading, plasma sodium concentrations increased 20% at 1 hour and 15% at 2 hours (both P<.01) and returned to control values at 4 hours. Plasma potassium concentrations increased 17% at 1 hour (P<.01) but decreased thereafter; the decrease was significant at 4 hours (P<.01). Plasma Na-K ratio was elevated at 2 and 4 hours (both P<.01).

View this table: [in this window] [in a new window]   Table 1. Effects of Intraperitoneal Injection of Isotonic or Hypertonic NaCl Solution on Measured Parameters

Hematocrit levels were increased at 4 hours after injection of the hypertonic NaCl solution compared with baseline values, suggesting probable intravascular volume depletion.

In response to sodium loading, plasma OLC levels increased 75% and 100% at 2 and 4 hours (both P<.05), respectively. The OLC levels in pituitary doubled 1 hour after sodium loading (P<.01). The OLC levels in adrenal progressively increased, tripling at 2 hours (P<.05) and quadrupling at 4 hours (P<.01). On the other hand, a trend for decreased OLC levels in hypothalamus was found at 2 hours. The tissue OLC level was greater than the plasma concentration under all conditions. For example, the adrenal-to-plasma ratio was greater than unity and was around 43 at 4 hours.

In contrast, as shown in Table 1, no significant changes in any parameters were observed 2 hours after physiological saline injection compared with baseline values.

As shown in Fig 1, OLC levels in adrenal correlated significantly with OLC levels in plasma (r=.40, P<.05) and pituitary (r=.39, P<.05). Correlation analysis between OLC levels and plasma electrolytes revealed a significant negative correlation between plasma OLC levels and potassium concentrations (r=-.56, P<.01). A positive correlation was found between plasma OLC levels and Na-K ratio (r=.51, P<.01, Fig 2A). A significant correlation was also observed between OLC levels in adrenal and plasma Na-K ratio (r=.48, P<.01, Fig 2B).

View larger version (15K): [in this window] [in a new window]   Figure 1. Relations between ouabainlike compound (OLC) levels in adrenal and in plasma (A) or pituitary (B). OLC levels in adrenal correlated significantly with those in both plasma (r=.40, P<.05) and pituitary (r=.39, P<.05).

View larger version (15K): [in this window] [in a new window]   Figure 2. Relations between plasma Na-K ratio and ouabainlike compound (OLC) levels in plasma (A) or adrenal (B). Plasma Na-K ratio correlated significantly with OLC levels in both plasma (r=.51, P<.01) and adrenal (r=.48, P<.01).

Table 2 summarizes the changes in electrolyte concentrations and OLC levels in plasma and tissues after intraperitoneal injection of hypertonic sucrose in isotonic saline solution. In response to sucrose administration, plasma sodium concentrations decreased and plasma potassium concentrations increased significantly at 1, 2, and 4 hours. Plasma Na-K ratio decreased significantly. Hematocrit levels were markedly increased at all time points, suggesting intravascular volume depletion. In contrast to the results obtained from hypertonic NaCl loading, plasma OLC levels did not increase after the injection of the hypertonic sucrose solution. The OLC levels in hypothalamus also remained unaltered. On the other hand, OLC levels in pituitary and adrenal were significantly decreased at 1, 2, and 4 hours.

View this table: [in this window] [in a new window]   Table 2. Effects of Intraperitoneal Injection of Hypertonic Sucrose in Isotonic NaCl Solution on Measured Parameters

	Discussion

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OLC binds to cardiac glycoside receptors and reduces the activity of the Na⁺,K⁺-ATPase. Such a change within the kidney could, at least theoretically, produce a natriuresis by impairing active sodium transport out of the tubular epithelial cells. Therefore, it is generally thought that salt retention and plasma volume expansion somehow trigger OLC secretion.^{1 2 3 4 5} However, the role of OLC as a natriuretic factor has been controversial. Our hypothesis was that OLC may be more important in the response to acute hypertonic NaCl load rather than isotonic volume expansion.

For this, we injected intraperitoneally a 20% NaCl solution containing sodium corresponding to 75% of total body sodium in the rat. We admit that administration of such a huge amount of sodium may not be a physiological condition, but our goal was to find out clear effects, if any, of hypertonic sodium loading on OLC levels. In contrast to 20% NaCl solution, 0.9% saline solution did not affect OLC and electrolyte levels at 2 hours after injection. This finding strongly suggests that the changes in OLC and electrolyte levels with a hypertonic sodium load were not attributable to a natural time course but were caused by a specific effect of hypertonic NaCl loading.

In the present study, plasma OLC levels increased 75% and 100% at 2 and 4 hours after hypertonic NaCl loading, respectively. OLC levels in adrenal and pituitary at least transiently increased after hypertonic NaCl loading. By contrast, plasma OLC levels did not increase after hypertonic sucrose loading despite addition of similar amounts of osmoles. Furthermore, OLC levels in pituitary and adrenal decreased after hypertonic sucrose loading. What could be the mechanism or mechanisms that led to the different behavior of OLC between two types of hypertonic loading?

First, it is possible that the changes in plasma volume differed between the hypertonic NaCl and sucrose loading. Previous experiments demonstrated that when a solution was placed in the peritoneal cavity, it tended to assume the composition of a fluid in ionic and osmotic equilibrium with blood plasma.^{24 25} However, it is unlikely that blood electrolytes diffused into the peritoneal cavity because hypertonic sucrose solution was dissolved in a physiological saline solution in our study. Although sucrose diffuses into blood, this process is slow and would cause a shift of water from the vascular space into the markedly hypertonic peritoneal cavity. The resulting decrease in plasma volume is manifested in an elevated hematocrit, as shown in this study. Therefore, intravascular dehydration is more likely to occur under hypertonic sucrose loading. In the case of hypertonic NaCl loading, the situation appears to be more complex. There are two possibilities with respect to plasma volume—one in which water moves into the pool, and the other in which sodium moves out of the pool. The former would raise hematocrit and decrease plasma volume, and the latter would lower hematocrit and increase plasma volume. Initially, the rate of diffusion of sodium from the peritoneal fluid may be so rapid that this electrolyte excess causes a shift of water from the relatively hypotonic cellular compartment into the relatively hypertonic extracellular compartment. Although raised hematocrit values suggest decreased plasma volume at 4 hours, it is possible that plasma volume did increase early after NaCl injection. Thus, the transiently increased intravascular volume might have induced the rise in plasma OLC levels only after hypertonic NaCl loading.

Second, sodium- and/or potassium-sensing mechanisms may participate in the regulation of OLC levels in the rat body. In agreement with a previous report,¹⁸ plasma sodium rose markedly after NaCl administration. Plasma sodium concentrations, which increased at 1 and 2 hours, returned to control values at 4 hours. Plasma potassium concentrations increased at 1 hour but decreased at 4 hours. The elevation of plasma Na-K ratio paralleled the rise in plasma OLC at 2 and 4 hours. Plasma Na-K ratio positively correlated with OLC levels in both plasma and adrenal. A negative correlation was observed between plasma OLC levels and potassium concentration. A fundamental role of the Na⁺-K⁺ pump is to maintain the normal distribution of sodium and potassium to the different fluid compartments. Cardiac glycosides inhibit the Na⁺-K⁺ pump and increase serum potassium concentrations because of the release of potassium from the cells. Digoxin-specific Fab antibody fragments decrease serum potassium concentration by blocking the action of cardiac glycosides.²⁶ Endogenous OLC likely increases serum potassium concentration in a manner similar to that of exogenous cardiac glycosides. Several studies point to a close connection between OLC or Na⁺,K⁺-ATPase inhibitors and serum potassium concentration.^{27 28} Furthermore, we found a consistent fall in serum potassium concentration in the absence of OLC action in animals immunized against ouabain (unpublished observations, 1994). These findings indicate an important role of OLC in potassium homeostasis through the regulation of Na⁺-K⁺ pump activity. Since OLC inhibits the Na⁺-K⁺ pump and increases plasma potassium, it is more likely that the decrease in plasma potassium may precede and trigger the elevation of OLC levels. However, because there is no evidence for this in the present study or elsewhere, further evaluation is clearly necessary in future studies.

Several studies suggest that the central nervous system could be a potential source of OLC.⁷ It has been reported that brain OLC in situ may play an important role in the central regulation of cardiovascular function.²⁹ Our previous finding pointed to the important contribution of brain OLC to the natriuresis caused by central administration of a hypertonic NaCl solution.¹⁷ In the present study, we found a significant rise in pituitary OLC levels with hypertonic NaCl load, suggesting that OLC in pituitary may participate in peripheral hypertonic NaCl load. Our observations indicate that the destruction of central catecholaminergic neurons with 6-hydroxydopamine markedly reduces plasma OLC levels.³⁰ Therefore, it is possible that OLC spilled from the central nervous system (pituitary) may partly account for the elevation of OLC in the circulation in the present study.

Adrenal glands may also be a potential source of OLC.^{6 31} A recent report indicated that corticotropin stimulates OLC secretion from adrenal glands.³² Recently, we found that OLC levels in plasma and adrenal rise in response to swim stress in parallel to the expected elevation of corticosterone.³³ In the present study, OLC levels in adrenal progressively increased and tripled or quadrupled at 2 or 4 hours, respectively, concomitant with the rise in plasma OLC levels. A significant correlation was found between OLC levels in plasma and those in adrenal. The adrenal-to-plasma ratio of OLC was consistently greater than unity. A previous study indicated that the elevation of plasma ouabain over a severalfold range by prolonged infusion of ouabain did not to affect the adrenal level.³⁴ These findings suggest that the rise in adrenal OLC in our study is not a sequestration of plasma OLC but may be a primary event. Taken together, our data point to the adrenal as a more likely source of plasma OLC.

A major limitation of our study is that plasma sodium concentration increased well above the physiological range by hypertonic NaCl load. It remains to be determined whether increases in plasma sodium concentration within the physiological range could affect OLC levels in plasma and tissues.

In conclusion, our findings indicate the elevation of OLC levels in plasma, pituitary, and adrenal in response to hypertonic NaCl load in rats and suggest that OLC may be partly involved in the response to the hypernatremic state.

Received February 14, 1996; first decision April 23, 1996; accepted December 5, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamada, K. Articles by Omata, M. Search for Related Content PubMed PubMed Citation Articles by Yamada, K. Articles by Omata, M.