State Of Sodium Balance Research Articles

The effect of active diuretic therapy on the sodium balance in patients with acute decompensation of chronic heart failure

Background. Active dehydration of patients with acute decompensation of chronic heart failure (АDCHF) was often accompanied by the development of hyponatremia. This increased the time of hospitalization and worsened the prognosis. The complication was associated with the side effects of furosemide.
 Aim. To compare the effect of dehydration and the state of sodium balance after using different methods of parenteral administration of furosemide at an early stage of treatment of АDCHF.
 Materials and methods. Patients with АDCHF (n=125) were divided into two groups. Group 1 received furosemide as bolus injections, group 2 as an extended intravenous infusion. The process of dehydration was controlled by the amount of urine and body weight loss per day. The effect was considered satisfactory if the body weight decreased by 1.02.0 kg per day. The plasma sodium level was studied on 1, 5, 10 days.
 Results. In group 2, the satisfactory effect of dehydration was observed 1.7 times more often than in group 1 (p0.05). In group 2 patients on the 5th day of therapy, the number of cases of hyponatremia was 2.3 times less (p0.05). Hyponatremia developed little in patients with a satisfactory effect of dehydration. On the 10th day, the number of cases of hyponatremia in the groups did not significantly differ.
 Conclusion. Prolonged intravenous infusion of furosemide allowed more control of the dehydration process and the plasma sodium level at an early stage of therapy in patients with АDCHF.

Gastrorenal communication: sniffing and tasting.

A video slideshow introduction to the Symposium by organiser Pedro A. Jose can be found here.

State-Dependent Expression of Pressure Diuresis in Conscious Rats

Abstract. In 1967, Guyton and Coleman modeled pressure diuresis as the underlying, essential, long-term mechanism that regulates arterial pressure when sodium intake changes. Other mechanisms that influence renal function interact with pressure diuresis to achieve sodium balance and determine the blood pressure. Increases in sodium intake suppress sodium conserving mechanisms and activate natriuretic mechanisms; decreases in sodium intake have the opposite effect. If the Guyton-Coleman model is correct, then pressure diuresis should be more readily detected in animals on a high-salt diet than in animals on a low-salt diet. We measured spontaneous changes in arterial pressure and urine flow in conscious rats fed low-salt (0.4% NaCl) and high-salt (8.0% NaCl) chow. For 10 rats fed a high-salt diet, arterial pressure and urine flow were positively correlated in 19 of 32 (59%) trials. In 10 rats fed a low-salt diet, a positive correlation was observed in 10 of 33 (30%) trials. Chi-square analysis revealed that differences in Na+ content of the diet were significantly associated with the probability of a positive relationship between blood pressure and urine flow. These results support the hypothesis that the expression of pressure diuresis across time is dependent on the state of sodium balance.

Angiotensin II as a cardiovascular risk factor.

A renin-angiotensin level that is inappropriately high for the systemic blood pressure and the state of sodium balance is now recognized to be one of the modifiable cardiovascular risk factors. Angiotensin acts both as a circulating hormone and as a locally acting paracrine/autocrine/intracrine factor. The adverse effects of angiotensin on the heart include the mechanical results of elevated resistance to the pumping function of the myocardium, as well as the effects of neurohumoral abnormalities on various cardiac structures. In addition, cardiac damage follows acute ischaemic injury or chronic energy starvation due to coronary artery disease, attributable to either mechanical obstruction (atherosclerotic and/or thrombotic) or functional stenosis (vasospasm). Activation of the renin-angiotensin system has several haemodynamic and humoral consequences, all of which may damage the myocardium. These include acute myocardial ischaemia, left-ventricular hypertrophy, arrhythmias, alterations in the coagulation-fibrinolysis equilibrium, increased oxidative stress, and pro-inflammatory activity. A brief review of some of the mechanisms by which activation of the renin-angiotensin system can inflict damage on the heart is presented.

State-dependent expression of pressure diuresis in conscious rats.

In 1967, Guyton and Coleman modeled pressure diuresis as the underlying, essential, long-term mechanism that regulates arterial pressure when sodium intake changes. Other mechanisms that influence renal function interact with pressure diuresis to achieve sodium balance and determine the blood pressure. Increases in sodium intake suppress sodium conserving mechanisms and activate natriuretic mechanisms; decreases in sodium intake have the opposite effect. If the Guyton-Coleman model is correct, then pressure diuresis should be more readily detected in animals on a high-salt diet than in animals on a low-salt diet. We measured spontaneous changes in arterial pressure and urine flow in conscious rats fed low-salt (0. 4% NaCl) and high-salt (8.0% NaCl) chow. For 10 rats fed a high-salt diet, arterial pressure and urine flow were positively correlated in 19 of 32 (59%) trials. In 10 rats fed a low-salt diet, a positive correlation was observed in 10 of 33 (30%) trials. Chi-square analysis revealed that differences in Na+ content of the diet were significantly associated with the probability of a positive relationship between blood pressure and urine flow. These results support the hypothesis that the expression of pressure diuresis across time is dependent on the state of sodium balance.

Urinary dopamine excretion in conscious rats: effect of carbidopa in different states of sodium balance.

Urinary dopamine excretion was studied in seven different groups of rats (n = 6-12) with the following treatment regimens: normal chow and tap water (controls, CON), single administration of furosemide 20 mg/kg i.p. on day 1 and subsequent feeding of low sodium chow (low salt, LS), normal chow and 1% NaCl as drinking water (high salt, HS), normal chow and 1% NaCl plus deoxycorticosterone acetate 1 mg/kg/day i.p. (high salt plus DOCA, HS+DOCA); carbidopa 20 mg/kg/day p.o. (CDP) was administered in animals on normal chow (CON+CDP), in high salt rats (HS+CDP), and in rats on high salt plus DOCA (HS+DOCA+CDP). On day 5, rats were placed in metabolic cages with free access to their respective drinking solution; chow was withheld. Urine was collected for 24 h and analyzed for sodium, creatinine, and dopamine. Urinary dopamine excretion rates did not change in proportion to large differences in sodium excretion in LS, HS, and HS+DOCA animals compared to CON. Only when urinary dopamine excretion of HS rats was compared to the LS group there was a moderate, but significant increase of 27%. In the groups treated with CDP renal dopamine excretion was decreased by approximately 60% in comparison to the groups with the respective treatment condition but without CDP. Urinary sodium output was unchanged by CDP in CON+CDP animals compared to CON. In HS+CDP and HS+DOCA+CDP groups renal sodium excretion was reduced by half compared to the HS and HS+DOCA groups, respectively. However, this effect was accompanied by a similar, approximately 55% reduction of oral volume and sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of endogenous endothelin on renal functions in rats

This study was conducted to determine the involvement of endogenous endothelin (ET), a novel potent vasoconstricting peptide, in systemic and renal hemodynamics and in the renin-angiotensin system by inhibiting ET action via infusion of a specific ET antiserum at a time of altered sodium balance. Infusion of 1:50 diluted ET antiserum, which completely inhibited renal vasoconstriction by the exogenously administered ET (0.25 to 1.0 nmol/kg), caused an increase in urinary sodium excretion and fractional excretion of sodium and a decrease in plasma renin concentration without significant changes in blood pressure, heart rate, glomerular filtration rate, renal plasma flow, and urine volume compared with the values with nonimmune serum in conscious rats fed a low-salt diet. A time control study showed no significant changes in all parameters. These results suggest that the state of low- compared to high-salt intake causes a relatively stronger activity of endogenous ET, and that the endogenous ET contributes to the adaptative modulations of sodium excretion via renal tubular action and renin release in association with the changed state of sodium balance.

Two forms of vasoconstriction in systemic hypertension

Clinical, pharmacologic and biochemical evidence characterizes essential hypertension as a heterogeneous spectrum of pathophysiologic substances rather than the single entity it has long been presumed to be. Although the causes of essential hypertension remain obscure, 2 different mechanisms for long-term vasoconstriction that sustain diastolic hypertension in the experimental and clinical forms of primary aldosteronism and renovascular hypertension can also be identified and quantified among patients with essential hypertension. The first mechanism is renin independent, requires antecedent sodium retention and appears related to abnormal membrane transport of calcium. This vasoconstriction is identified by low plasma renin and ionized calcium and is correctable by sodium depletion or calcium channel or α blockade. The second vasoconstrictor mechanism is renin mediated and involves an increase in cytosolic calcium. This mechanism is quantifiable by the plasma renin level or the hypotensive response to an antirenin-system drug (converting enzyme inhibitor, β blocker or saralasin). Depending on the state of sodium balance, these 2 mechanisms contribute reciprocally to maintenance of arteriolar tone in experimental models, in both normal and hypertensive people, and in patients with congestive heart failure. In these situations, at the extremes of the range of plasma renin values, one or the other mechanism predominates, whereas in the medium range of renin values both mechanisms can be operative. These interrelations provide a basis for applying more precisely tailored therapy and for stratifying patients pathophysiologically for further study.

Calcium Antagonists and Sodium Balance

The acute blood pressure lowering effect of nifedipine as a capsule was enhanced by a high-sodium intake in both normotensive and hypertensive subjects. In a double-blind, randomised, placebo-controlled study, the longer-term effect of nifedipine as a tablet in hypertensives was also greater on a high sodium intake than on a normal or low sodium diet. In hypertensive patients who were already on regular treatment with nifedipine, the addition of a thiazide diuretic for 1 month did not cause any significant additional fall in blood pressure despite untoward metabolic side effects. These findings, therefore, strengthen the view that there is a link between the blood pressure lowering activity of calcium entry antagonists and the state of sodium balance.

Changes in adrenal responsiveness and potassium balance with shifts in sodium intake.

Dietary sodium modulates the aldosterone response to angiotensin, but available evidence does not indicate whether there is a gradual change in adrenal responsiveness with intermediate sodium intakes or a sharp shift from a low to a high responsive level at some threshold sodium intake. Nine normal subjects received angiotensin II infusions while in balance on five levels of sodium intake over two orders of magnitude, 3 to 300 mEq sodium per day. Basal plasma renin activity, plasma aldosterone and plasma angiotensin II concentrations gradually fell as dietary sodium intake increased. The adrenal was quite sensitive to the state of sodium balance since a shift in sodium intake of as little as 20 mEq (e.g. 10 to 30 mEq/day) induced a significant change in basal plasma aldosterone. Adrenal responsiveness to infused angiotensin varied inversely with the log of urinary sodium excretion over the entire range of sodium intake, indicating that there is a gradual modulation of adrenal responsiveness with changes in dietary sodium. In addition, despite a constant dietary potassium intake, serum potassium gradually fell from 4.55 +/- .06 to 3.98 +/- .07 mEq/l, (P less than 0.02), as sodium intake increased, partly due to increased urinary potassium excretion (mean cumulative potassium loss of 129 mEq). Thus, changes in potassium balance may be important in modulating the sodium-associated variation in aldosterone secretion.

The contribution of PGI2 to the effects of captopril in conscious dogs in differing states of sodium balance

There is some evidence that increased prostaglandin synthesis may mediate some of the effects of the angiotensin converting enzyme inhibitor captopril. The potential role of prostaglandin (PG)I2 in this process was assessed by measurement of changes in urinary 6-keto-PGF1 alpha excretion after captopril in eight sodium replete and depleted conscious dogs. In sodium replete animals captopril induced a small decrease in blood pressure, transient increases in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, and progressive increases in plasma renin activity (PRA) and urinary sodium excretion. By contrast, during sodium depletion captopril induced a large decrease in blood pressure, a transient increase in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, an early large but transient increase in PRA and small progressive increase in sodium excretion. The time course of changes after captopril suggested that increased PGI2 synthesis may contribute to the transient decrease in renal vascular resistance. The increase in PRA during sodium depletion was not associated with any change in urinary 6-keto-PGF1 alpha excretion.

Does renin determine the blood pressure response to calcium entry blockers?

Male Wistar rats with one-kidney, one clip renal hypertension were maintained on either a regular or a low salt diet for 3 weeks after clipping. At that time mean blood pressure in the unanesthetized rats was equally elevated in sodium-depleted (n = 17) and in sodium-replete rats (n = 19), but plasma renin activity was significantly higher in the former (p less than 0.05). Infusion of the calcium entry blocker verapamil at a rate of 0.05 mg/kg/minute decreased blood pressure within 60 minutes to a similar extent in rats kept on a salt-deficient diet and in rats fed a regular salt diet. In all rats taken as a group, there was a close, direct correlation (r = 0.87, p less than 0.001) between the magnitude of the blood pressure response to verapamil and the pretreatment blood pressure levels. Verapamil markedly accelerated heart rate and stimulated renin release in all rats. In additional groups of sodium-depleted (n = 8) and sodium-replete renal hypertensive rats (n = 7), nifedipine administration (4 micrograms/kg/min i.v.) within a 45-minute observation period caused a blood pressure fall (p less than 0.001) and heart rate acceleration (p less than 0.001) that were comparable in both groups. These findings suggest that in the rat with renal hypertension the short-term blood pressure response to the calcium antagonists verapamil and nifedipine is not influenced by the state of sodium balance and plasma renin activity. In this experimental model of hypertension, the magnitude of the blood pressure lowering effect of calcium entry blockers appears to be proportional to pretreatment blood pressure levels.

Blood pressure effects of renin inhibition by human renin antiserum in normotensive marmosets.

The effects on blood pressure of an antiserum against pure human kidney renin were studied in conscious and anesthetized (pentobarbital, 24 mg X kg-1 i.p.) small new world monkeys (common marmosets). The antiserum inhibited the enzymatic activity of renin by 50% in a dilution of 1:45,000 in marmoset and 1:50,000 in human plasma. The antiserum (0.2 ml i.v.) decreased blood pressure in conscious marmosets on normal sodium intake by 15 +/- 5 (SD) mmHg and after salt depletion by 31 +/- 13 mmHg. A converting enzyme inhibitor (teprotide, 2 mg X kg-1 i.v.) induced a comparable fall in blood pressure: -16 +/- 10 and -30 +/- 10 mmHg, respectively. Similar effects were observed on blood pressure of anesthetized marmosets. The correlation between pretreatment plasma renin concentration and the maximum fall in blood pressure was significant and identical for the experiments with antiserum and teprotide. These results demonstrate that antisera against human renin can be used for the specific blockade of the renin-angiotensin system in primates. In normotensive marmosets the renin-angiotensin system participates in the maintenance of blood pressure, to a degree depending on the state of sodium balance.

The Relationships between sodium intake and “The state of sodium balance”

The Relationships between sodium intake and “The state of sodium balance”

Regulation of aldosterone secretion during altered sodium intake

The interactions of the renin-angiotensin system with other factors in the regulation of aldosterone secretion were analyzed during altered sodium in the rat. During sodium restriction, the rise in aldosterone secretion was accompanied by trophic changes in the adrenal glomerulosa zone including increased angiotensin II receptors and enzymes of early and late steps in the aldosterone biosynthetic pathway. All these effects of sodium restriction were reproduced by infusion of angiotensin II, and could be prevented by administration of the converting enzyme inhibitor, SQ 14,225. These findings indicate that the adrenal secretory and trophic responses to sodium restriction are mediated by angiotensin II. In hypophysectomized rats, the basal activities of the enzymes of the early aldosterone biosynthetic pathway were reduced, contributing to the blunted aldosterone responsiveness to sodium deficiency. However, sodium restriction for 6 days significantly increased adrenal glomerulosa angiotensin II receptors and enzymes of the early and late aldosterone biosynthetic pathway, indicating that the pituitary gland is not necessary for the adrenal effects of angiotensin II. In contrast to the prominent glomerulotropic actions of angiotensin II in rats on normal or low sodium intake, infusion of angiotensin II during high sodium intake did not increase blood aldosterone, angiotensin II receptors, or 18-hydroxylase activity, indicating that the trophic actions of the octapeptide are determined by the state of sodium balance. In recent studies, other factors including potassium, dopamine and somatostatin have been shown to potentiate or inhibit the actions of angiotensin II on the adrenal gland. The ability of such factors to influence the effects of angiotensin II could serve as a protective mechanism to modulate aldosterone responses to angiotensin II when elevations in the circulating level of the peptide occur in the absence of sodium deficiency.

The role of the sympathetic nervous system in the modulation of sodium excretion.

To investigate the existence of opposing renal noradrenergic and dopaminergic modulation of renal sodium excretion, urinary excretion rates of NE, DA and DOPAC were measured in different states of sodium balance. A natriuretic index, DOPAC/NE, was found to correlate closely with the state of sodium balance in normal men subjected to very low (10 mEq/d) or very high (800 mEq/d) sodium intake. Additional studies utilizing rapid sodium and volume expansion and contraction confirmed the utility of this natriuretic index. Hypertensive men demonstrated significantly lower values for this index than did normotensive subjects under similar study conditions. These studies provide new evidence of abnormalities in the adrenergic-dopaminergic system in human hypertension and support a link between these systems and renal sodium handling.

The renin system for understanding human hypertension: evidence for blood pressure control by a bipolar vasoconstriction-volume mechanism. Prorenin as a determinant of renin secretion.

A body of evidence indicates that all hypertensive phenomena ranging from mild disorders to fulminant malignant hypertension can be profitably analyzed by assessing the relative contribution of two final determinants of the arterial blood pressure--the degree of arteriolar vasoconstriction and size of the volume filling the arterial tree. The latter function is largely determined by the state of sodium balance. Renin-sodium profiling and separate testing with specific pharmacologic probes are the basic tools for quantifying these factors in individual patients. This bidimensional analysis of blood pressure phenomena has considerable practical value for identifying and treating curable renovascular and adrenocortical forms. Beyond this, the analysis provides pathophysiologic information of practical value for characterizing and treating individual patients in the whole spectrum of human hypertensive diseases including essential hypertension. This new analytical scaffold also identifies key physiologic questions for future research. About 90 percent of the circulating renin occurs in an inactive form as a possible prorenin, which could be an important regulatory point for renin release. In response to stimuli prorenin rises and falls with active renin. Beta blockade may lower active renin by blocking the conversion process. At the physiological level the activation and/or release of renin appears to be primarily determined by sodium-volume changes perceived by a distal tubular mechanism.

Differential renal effects of cyclooxygenase inhibition in sodium-replete and sodium-deprived dog.

We studied the renal effects of the cyclooxygenase inhibitor sodium meclofenamate (M) (5 mg/kg, iv) in the pentobarbital-anesthetized dog that had been maintained on an elevated (100 meq/day) or on a reduced (< meq/day) sodium intake, and during the administration of antiotensin II in the sodium-replete dog, or the angiotensin receptor blocker [Sar1-Ala8]angiotensin II in the sodium-deprived dog. In the sodium-replete dog, M did not affect mean arterial blood pressure (MABP), renal blood flow (RBF), glomerular filtration rate, (GFR), or urine volume (V), but reduced the urinary excretion of sodium (UNaV) by 47%, and of immunoreactive PGE2 (iPGE2) by 90%. However, in the sodium-replete dog during angiotensin II infusion (3 ng . kg-1 . min-1, iv), M reduced RBF by 35%, GFR by 24%, V by 72%, and iPGE2 by 94%. Similarly, in the sodium-deprived dog M reduced RBF by 34%, GFR by 28%, and iPGE2 excretion by 89%. However, M did not affect RBF or GFR in the sodium-deprived dog during infusion of [Sar1-Ala8]angiotensin II (6 microgram . kg-1 . min-1, iv), although iPGE2 excretion was reduced by 84%. This study demonstrates that the effects of M on renal hemodynamics in the dog vary with the state of sodium balance and suggests that a prostaglandin(s) contributes to maintenance of renal blood flow during activation of the renin-angiotensin system.

Is the Renin-Sodium Profile Helpful in Evaluating Hypertension?

LARAGH and colleagues 1 have long advocated measurement of plasma renin activity (PRA) routinely in the evaluation of hypertensive patients. They have presented an elaborate and somewhat complicated schema for using the PRA as an aid in diagnostic evaluation and in selecting drugs. Reliable measurements of PRA are not readily available to many physicians, and when they are, care must be taken to control, so far as is possible, those variables that influence PRA, such as physical activity, normal diurnal variations, drugs (eg, estrogens, diuretics, and antihypertensive agents), and sodium intake. Laragh et al recommend that blood be drawn at the same time of day (noon), after the patient has been ambulatory for several hours, and that the urinary sodium excretion for the previous 24 hours be measured to estimate the state of sodium balance. Does the information provided by a renin-sodium profile justify this meticulous attention to detail and the

Influence of sodium balance on ACTH/adrenal corticosteroid dose-response curves in the dog.

In order to define short-term ACTH/corticosteroid dose-respone characteristics, we infused ACTH for 1 h at each of five incremental rates into pedigreed male beagle dogs in four different states of sodium balance. Progressive sodium depletion was associated with progressive increased in basal (pre-ACTH) plasma levels of renin, angiotensin II, aldosterone, 18-hydroxycorticosterone (18-OH-B), and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC). Administration of dexamethasone significantly reduced the preinfusion levels of cortisol, aldosterone, 18-OH-B, and 18-OH-DOC. The threshold dose of ACTH required to elicit an aldosterone response during low-sodium intake was similar to that for cortisol, but was higher during normal or high-sodium intake. Steepest portions of the dose-response curves were at lower rates of ACTH infusion for cortisol than for aldosterone, and maximum increment was much greater for cortisol (60-fold) than for aldosterone (12-fold). Whereas the slopes of ACTH/aldosterone and ACTH/18-OH-B dose-response curves were steepened by lower sodium diets, the ACTH/cortisol response was significantly flattened by severe sodium depletion. We conclude that ACTH is a potent and direct-acting short-term regulator of aldosterone secretion, subject to modification by altered sodium balance.