Effects of aspirin on renal sodium excretion, blood pressure, and plasma and extracellular fluid volume in salt-loaded rats

The effect of aspirin administration and presumed blockade of prostaglandin synthesis on renal sodium excretion, plasma and extracellular fluid volumes, and blood pressure were examined in rats on a high sodium intake. After acute salt loading aspirin treated rats showed an impaired sodium excretion, while no changes in glomerular filtration rate were observed. In chronically loaded rats (7 weeks) administration of aspirin induced significant increases in both plasma and extracellular fluid volume, but no significant changes in blood pressure were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.     

Effects of aspirin on renal sodium excretion,blood pressure,and plasma and extracellular fluid volume in salt-loaded rats

The effect of aspirin administration and presumed blockade of prostaglandin synthesis on renal sodium excretion, plasma and extracellular fluid volumes, and blood pressure were examined in rats on a high sodium intake. After acute salt loading aspirin treated rats showed an impaired sodium excretion, while no changes in glomerular filtration rate were observed. In chronically loaded rats (7 weeks) administration of aspirin induced significant increases in both plasma and extracellular fluid volume, but no significant changes in blood pressure were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.     

Reduced natriuresis after oral sodium load in cholestatic rats: role of compartment volumes and ANP

The purpose of this study was to assess the participation of the atrial natriuretic peptide (ANP)-cGMP system in electrolyte and volume handling of cholestatic rats submitted to an acute oral sodium load. Cholestasis was induced by ligation and section of the common bile duct (n = 51). Control rats were sham operated (n = 56). Three weeks after surgery, 24-hr urinary volume, sodium, potassium, cGMP and creatinine excretion were measured. Three days later, animals received 10 mmol/kg NaCl (1 M) by gavage, and urinary excretion was measured for 6 hr. In parallel groups of rats, plasma volume, electrolytes and ANP concentration, extracellular fluid volume (ECFV), and renal medullary ANP-induced cGMP production were determined in basal conditions or 1 hr after oral sodium overload. As compared with controls, cholestatic rats had a larger ECFV and higher plasma ANP (67.2 +/- 5.2 vs 39.7 +/- 3.5 pg/ml), but lower hematocrit and blood volume, and were hyponatremic. Cholestatic rats showed higher basal excretion of sodium, potassium, and volume than controls, but equal urinary cGMP. After the NaCl overload, cholestatic rats showed a reduced sodium excretion but equal urinary cGMP. One hr after sodium overload, both groups showed hypernatremia, but whereas in control rats ECFV and ANP increased (50.7 +/- 4.1 pg/ml), in cholestatic rats ECFV was unchanged, and plasma volume and ANP were reduced (37.5 +/- 5.8 pg/ml). ANP-induced cGMP production in renal medulla was similar in cholestatic and control nonloaded rats (14.2 +/- 5.2 vs 13.4 +/- 2.6 fmol/min/mg). One hr after the load, medullary cGMP production rose significantly in both groups, without difference between them (20.6 +/- 3.1 vs 22.7 +/- 1. 7 fmol/min/mg). We conclude that the blunted excretion of an acute oral sodium load in cholestatic rats is associated with lower plasma ANP due to differences in body fluid distribution and cannot be explained by renal refractoriness to ANP.     

Neural mechanisms in body fluid homeostasis

Under steady-state conditions, urinary sodium excretion matches dietary sodium intake. Because extracellular fluid osmolality is tightly regulated, the quantity of sodium in the extracellular fluid determines the volume of this compartment. The left atrial volume receptor mechanism is an example of a neural mechanism of volume regulation. The left atrial mechanoreceptor, which functions as a sensor in the low-pressure vascular system, is located in the left atrial wall, which has a well-defined compliance relating intravascular volume to filling pressure. The left atrial mechanoreceptor responds to changes in wall left atrial tension by discharging into afferent vagal fibers. These fibers have suitable central nervous system representation whose related efferent neurohumoral mechanisms regulate thirst, renal excretion of water and sodium, and redistribution of the extracellular fluid volume. Efferent renal sympathetic nerve activity undergoes appropriate changes to facilitate renal sodium excretion during sodium surfeit and to facilitate renal sodium conservation during sodium deficit. By interacting with other important determinants of renal sodium excretion (e.g., renal arterial pressure), changes in efferent renal sympathetic nerve activity can significantly modulate the final renal sodium excretion response with important consequences in pathophysiological states (e.g., hypertension, edema-forming states).     

Fluid and sodium loss in whole-body-irradiated rats

Whole-body and organ fluid compartment sizes and plasma sodium concentrations were measured in conventional, GI decontaminated, bile duct ligated, and choledochostomized rats at different times after various doses of gamma radiation. In addition, sodium excretion was measured in rats receiving lethal intestinal radiation injury. After doses which were sublethal for 3-5 day intestinal death, transient decreases occurred in all the fluid compartments measured (i.e., total body water, extracellular fluid space, plasma volume). No recovery of these fluid compartments was observed in rats destined to die from intestinal radiation injury. The magnitude of the decreases in fluid compartment sizes was dose dependent and correlated temporally with the breakdown and recovery of the intestinal mucosa but was independent of the presence or absence of enteric bacteria or bile acids. Associated with the loss of fluid was an excess excretion of 0.83 meq of sodium between 48 and 84 h postirradiation. This represents approximately 60% of the sodium lost from the extracellular fluid space in these animals during this time. The remaining extracellular sodium loss was due to redistribution of sodium to other spaces. It is concluded that radiation-induced breakdown of the intestinal mucosa results in lethal losses of fluid and sodium as evidenced by significant decreases in total body water, extracellular fluid space, plasma volume, and plasma sodium concentration, with hemoconcentration. These changes are sufficient to reduce tissue perfusion leading to irreversible hypovolemic shock and death.     

Circulation, kidney function, and volume-regulating hormones during prolonged water immersion in humans.

To investigate whether prolonged water immersion (WI) results in reduction of central blood volume and attenuation of renal fluid and electrolyte excretion, these variables were measured in connection with 12 h of immersion. On separate days, nine healthy males were investigated before, during, and after 12 h of WI to the neck or during appropriate control conditions. Central venous pressure, stroke volume, renal sodium (UNaV) and fluid excretion increased on initiation of WI and thereafter gradually declined but were still elevated compared with control values at the 12th h of WI. Atrial natriuretic peptide (ANP) concentration in plasma initially increased threefold during WI and thereafter declined to preimmersion levels, whereas plasma renin activity, plasma aldosterone, and norepinephrine remained constantly suppressed. It is concluded that, compared with the initial increases, central blood volume (central venous pressure and stroke volume) is reduced during prolonged WI and renal fluid and electrolyte excretion is attenuated. UNaV is still increased at the 12th h of WI, whereas renal water excretion returns to control values within 7 h. The WI-induced changes in ANP, plasma renin activity, plasma aldosterone, and norepinephrine may all contribute to the initial increase in UNaV. The results suggest, however, that the attenuation of UNaV during the later stages of WI is due to the decrease in ANP release.     

Systemic vasodilatation and renal sodium excretion: Effects of hydralazine and diazoxide

The effects on renal sodium excretion of two systemic vasodilators, hydralazine and diazoxide, were investigated in volume expanded, anesthetized rats with unilaterally denervated kidneys. Urinary sodium excretion and fractional excretion of filtered sodium increased following hydralazine but decreased following diazoxide. Changes in renal hemodynamics were dissimilar as well: renal plasma flow was increased following hydralazine, but unchanged with diazoxide. All changes in renal sodium excretion and renal hemodynamics following hydralazine were prevented by pretreatment with indomethacin. Renal denervation accentuated the increases in fractional sodium excretion and renal blood flow that occured following hydralazine.Hydralazine and diazoxide differ substantially in their effects on renal sodium excretion, apparently due to the stimulation of renal prostaglandins by the former agent. Although renal innervation attenuates the natriuretic effect of hydralazine, stimulation of the sympathetic nervous system does not account for differences in the renal effects of these two drugs.     

Role of the renin-angiotensin system in the adaptation to high salt intake in immature rats

The response of the renin-angiotensin system, extracellular fluid volume, plasma volume, plasma sodium and mean arterial blood pressure to an increase in salt intake (8% NaCl in the diet for 10 days) was compared in immature (20 days) and adult (80 days) rats which were either sham-operated or uninephrectomised. Salt feeding induced a significant increase in plasma sodium in immature animals, and a greater suppression of the renin-angiotensin system in immature than in adult rats, although extracellular fluid volume, plasma volume and blood pressure remained unchanged. Following uninephrectomy, however, the renin-angiotensin system was maximally suppressed in both age groups and in younger animals extracellular fluid volume, plasma volume and blood pressure were significantly increased. It is concluded that (i) the renin-angiotensin system in immature rats is more responsive to a chronically increased salt intake, (ii) this greater responsiveness partly compensates for the lower natriuretic efficiency of the kidneys of immature rats, which becomes evident after reduction of renal mass, and (iii) these events bear a relation to the higher susceptibility of prepubertal rats to the hypertensive effect of a chronically increased salt intake.     

Influence of insulin on plasma concentration and renal excretion of sodium and potassium in normal, electrolytes depleted and aldosterone treated dogs

Effects of insulin on plasma concentration and renal excretion of sodium and potassium were compared in conscious dogs 1) maintained in water and electrolytes balance (Series 1, 10 dogs), 2) depleted of electrolytes by repeated i.v. loading with 20% mannitol (Series 2, 10 dogs), and 3) aldosterone treated (0.8 micrograms.kg-1.h-1 i.v., Series 3, 10 dogs). In each Series intravenous infusion of insulin at a rate of 0.05 U.kg-1.h-1 elicited transient increase in plasma sodium concentration and prolonged hypokalemia. Repeated loading with mannitol in Series 2 elicited significant elevation of plasma sodium, ADH and aldosterone concentrations, as well as decrease in extracellular fluid volume. Infusion of insulin in this Series elicited smaller decrease in plasma potassium concentration and longer lasting hypernatremia than in dogs in water-electrolytes balance. Aldosterone infusion in Series 3 did not change hypokalemic effect of insulin but attenuated hypernatremia. Infusion of insulin in Series 1 elicited increase of sodium excretion and decrease in potassium excretion. These effects were absent in Series 2 and 3. The results indicate that depletion of electrolytes and blood aldosterone elevation modify the effects of insulin on plasma concentration and renal excretion of sodium and potassium.     

Ten days of head down tilt: effects of isotonic and hypertonic saline loads in normal man

The initial response to bed rest involves an increase in central blood volume leading to a an enhanced renal excretion of fluid and electrolytes. Within 24 hours of head-down bed rest a new steady state condition occurs with a sustained reduction of plasma volume, extracellular fluid volume, total body water, and body weight. It was the purpose of the present study to elucidate the volume homeostatic mechanisms during head-down bed rest by investigating the endocrine and renal responses to a load of sodium chloride given as either an isotonic or a hypertonic solution.     

Effect of lysophosphatidylcholine on renal hemodynamics and excretory function in anesthetized rats.

The effect of myristoyl-lysophosphatidylcholine (myristoyl-LPC) on renal hemodynamics, electrolyte and water excretion was examined over a 90 min period in sodium pentobarbital anesthetized male Sprague Dawley rats. Intravenous infusion of myristoyl-LPC at 13 +/- 3 pmol/min resulted in a small fall in systemic blood pressure, a 13% decrease in renal plasma flow without significantly altering glomerular filtration rate and produced a slightly greater excretion of sodium and water than vehicle controls. These results suggest that short term myristoyl-LPC administration can significantly alter renal function producing a weak natriuresis and diuresis which is not dependent on systemic blood pressure and renal hemodynamic changes.     

Studies on the role of the pituitary in the control of atrial natriuretic factor secretion and sodium excretion

Recent work suggests that hypophysectomized (HYPOX) rats show low levels of atrial natriuretic factor (ANF) and an attenuated diuresis and natriuresis to blood volume expansion. The purpose of this was (i) to examine the effect of various hormone replacements on ANF and renal excretion in HYPOX rats and (ii) to compare the renal responses to exogenous ANF in intact and HYPOX rats. Groups of rats received subcutaneous pellet implant of either dexamethasone (DEX), thyroxine (T4), or a placebo. Approximately 1 week later, they were anesthetized and subjected to a 20% blood volume expansion. DEX rats had a higher mean arterial pressure than placebo-treated rats while both MAP and heart rate were higher in T4 rats. Only the DEX rat showed augmented renal responses to volume expansion while no group showed significant changes in plasma ANF concentration during volume expansion. In a second series, groups of HYPOX rats received renal capsular transplants of either six hemi-pituitaries or six pieces of muscle which markedly raised serum prolactin levels in the hemi-pituitary group. The hemi-pituitary rats showed a greater diuresis and natriuresis during volume expansion than the muscle group and also showed a transient increase in plasma ANF. In addition, groups of either intact or HYPOX rats were anesthetized and received intravenous bolus injections of ANF. Both intact and HYPOX rats showed a very similar diuresis and natriuresis to exogenous ANF. However, potassium excretion was markedly reduced in HYPOX rats. The results show that DEX augments the renal responses to volume expansion by some mechanism which does not involve changes in plasma ANF. Thyroxine increases mean arterial pressure and heart rate in HYPOX rats but does not augment the renal or ANF responses to volume expansion. Chronic elevations in prolactin increase the renal response to volume expansion. Finally, the kidneys of HYPOX rats are capable of increasing sodium and water output in response to large doses of exogenous ANF.     

Renal effects of dopamine and ANP in high volume expanded rats

Both dopamine (DA) and atrial natriuretic peptide (ANP) have been postulated to exert similar effects on the kidney, participating in the regulation of body fluid and sodium homeostasis. In the present study, experiments were performed in anesthetized and isotonic sodium chloride volume expanded rats. After acute volume expansion at 15 % of body weight during 30 min, glomerular filtration rate, urine output, sodium excretion, fractional sodium excretion, proximal and distal sodium excretion and blood pressure were measured. In additional groups we administered ANP or haloperidol or the combination of both to volume expanded animals. Blockade of DA receptors with haloperidol, attenuated diuretic and natriuretic responses to volume load. Proximal sodium excretion was not modified by haloperidol in all experimental groups of rats. Reduction in distal tubular excretion was induced by haloperidol in saline infusion expanded rat but not in ANP treated expanded animals. In conclusion, when exaggerated volume expansion is provoked, both DA and ANP exert renal tubular events, but ANP have a major central role in the regulation of renal sodium handling.     

Effects of 30 day simulated microgravity and recovery on fluid homeostasis and renal function in the rat

Transition from a normal gravitational environment to that of microgravity eventually results in decreased plasma and blood volumes, increasing with duration of exposure to microgravity. This loss of vascular fluid is presumably due to negative fluid and electrolyte balance and most likely contributes to the orthostatic intolerance associated with the return to gravity. The decrease in plasma volume is presumed to be a reflection of a concurrent decrease in extracellular fluid volume with maintenance of normal plasma-interstitial fluid balance. In addition, the specific alterations in renal function contributing to these changes in fluid and electrolyte homeostasis are potentially responding to neuro-humoral signals that are not consistent with systemic fluid volume status. We have previously demonstrated an early increase in both glomerular filtration rate and extracellular fluid volume and that this decreases towards control values by 7 days of simulated microgravity. However, longer duration studies relating these changes to plasma volume alterations and the response to return to orthostasis have not been fully addressed. Male Wistar rats were chronically cannulated, submitted to 30 days head-down tilt (HDT) and followed for 7 days after return to orthostasis from HDT. Measurements of renal function and extracellular and blood volumes were performed in the awake rat.     

Effect of mineralocorticoid deficiency on ion and urea transporters and aquaporin water channels in the rat

Mineralocorticoid deficiency is associated with impaired urinary concentration and dilution. The present investigation was undertaken to determine the effects of selective mineralocorticoid deficiency on renal sodium and urea transporters and aquaporin water channels and whether these perturbations can be reversed by maintenance of extracellular fluid volume. Mineralocorticoid deficiency was induced by bilateral adrenalectomies with glucocorticoid replacement. Mineralocorticoid deficient rats receiving plain drinking water (MDW) were compared with mineralocorticoid deficient rats receiving saline-drinking water (MDS) in order to maintain extracellular fluid volume, and with controls (CTL). In MDW rats, there was a significant decrease in renal outer medulla Na-K-2Cl co-transporter and outer medulla Na-K-ATPase as well as an increase in inner medulla aquaporins 2 and 3. There were no significant changes in aquaporin-1, aquaporin-4, or urea transporters. These alterations were reversed with maintenance of extracellular fluid volume in MDS rats. Our findings indicate that mineralocorticoid deficiency in the rat is associated with alterations in factors involved in the countercurrent concentrating mechanism (Na-K-2Cl, Na-K-ATPase) and osmotic water equilibration in the collecting duct (AQP2, AQP3). Maintenance of sodium balance and extracellular fluid volume is associated with normalization of these perturbations.     

Interaction between the natriuretic effects of renal perfusion pressure and the antinatriuretic effects of angiotensin and aldosterone in control of sodium excretion

Aldosterone has been recognized as an important sodium retaining hormone for many years. Recently we have demonstrated that angiotensin II has a much more powerful antinatriuretic effect than that of aldosterone. The importance of angiotensin II in regulation of sodium excretion has been observed in experiments in which angiotensin II has been infused intravenously or into the renal artery in acute and chronic situations, and in studies involving blockade of angiotensin II formation. In other experiments we have studied the effects of changes in renal perfusion pressure on sodium excretion. While earlier work by others indicated that an acute 10 mm Hg increase in perfusion pressure would increase sodium excretion 60%-70% we observed that a chronic 10 mm Hg change in perfusion pressure would result in a 300% change in sodium excretion. In view of evidence suggesting that changes in the ability of the kidney to excrete sodium normally at normal arterial pressure is an important element in hypertension we studied the effects of aldosterone and angiotensin II on arterial pressure regulation in normal dogs. High physiological levels of each hormone were infused intravenously for several weeks. Both produced sustained hypertension. Aldosterone hypertension was a typical volume loading type with sodium retention, increased blood volume and extracellular fluid volume and a slow rise in arterial pressure. Angiotensin hypertension was a typical vasoconstrictor type with high peripheral resistance, normal or decreased blood volume, decreased cardiac output, a rapid rise in arterial pressure and only initial sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective Chronic Sodium or Chloride Depletion Specifically Modulates Subfornical Organ Atrial Natriuretic Peptide Receptor Number in Young Rats

1. We studied the effects of selective chronic sodium depletion of chloride depletion on atrial natriuretic peptide receptor number in the subfornical organ and paraventricular nucleus of young rats.2. Sodium or chloride depletion decreased plasma levels of atrial natriuretic peptide, increased plasma renin activity, and induced extracellular fluid volume contraction. Chloride depletion induced more significant changes in extracellular fluid volume contraction than sodium depletion.3. In the subfornical organ, atrial natriuretic peptide receptor number significantly decreased (30%) after sodium depletion, while chloride depletion induced a smaller, not statistically significant decrease. Conversely, atrial natriuretic peptide receptors located in the paraventricular nucleus of young rats were not significantly affected by sodium or chloride depletion.4. Water deprivation reversed the decrease in atrial natriuretic peptide receptors produced by sodium depletion. Water-deprived sodium-depleted rats actually had higher numbers of atrial natriuretic peptide receptors in the subfornical organ than control rats. These changes were associated with severe extracellular fluid volume contraction and up regulation of brain vasopressin mRNA steady-state levels. Thus, the direction of change in the number of subfornical organ atrial natriuretic peptide receptors was dependent on the degree of extracellular fluid volume contraction.5. Our results suggest that atrial natriuretic peptide receptors located in the subfornical organ, and not in the paraventricular nucleus, are selectively regulated by sodium depletion and extracellular fluid volume contraction.     

ENaC, renal sodium excretion and extracellular ATP

Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension) represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis relationship) represents the key element in defining the BP homeostatic set point. The renin–angiotensin–aldosterone system (RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy over the molecular targets for released ATP, although the P2Y₂ receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion.     

Influence of Medetomidine on Acid-base Balance and Urine Excretion in Goats

Seven goats were given medetomidine 5 μg/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion.     

Effects of tilting and volume loading on plasma levels and urinary excretion of relaxin, NT-pro-ANP, and NT-pro-BNP in male volunteers.

The polypeptide relaxin (RLX) has been suggested to play a role in cardiorenal integration and to be related to the natriuretic peptide system. We hence examined the effects of variations in thoracic blood volume and intravenous volume loading on plasma and urinary RLX levels and associated changes in natriuretic peptide levels in healthy men. Two groups of eight subjects were randomly tilted into a 15 degrees feet-down or a 15 degrees head-down position. Ten volunteers were crossover subjected to an infusion of 15 ml/kg of 0.9% NaCl (over 60 min) or control during an observation period of 10 h. Blood and urine were sampled at timed intervals. RLX, NH(2)-terminal prohormones of atrial natriuretic peptide (NT-pro-ANP), and NH(2)-terminal prohormones of brain natriuretic peptide (NT-pro-BNP) were determined by enzyme, radio-, and electrochemoluminescence immunoassays, respectively. NT-pro-ANP levels (in percentage of baseline levels) were higher (P < 0.05) during the head-down (124 +/- 13%) than during the feet-down position (82 +/- 6%). NT-pro-BNP and RLX were not affected by tilting. Volume loading induced a short-lasting increase in plasma NT-pro-ANP, a delayed increase in plasma NT-pro-BNP, had no effect on plasma RLX, and induced a parallel increase in urine flow, renal excretion of sodium, RLX, and NT-pro-BNP. It is concluded that variations in thoracic blood volume in healthy men are not associated with variations in plasma RLX. Increased urinary RLX and NT-pro-BNP excretion during volume loading suggest renal production and a possible role of kidney-derived RLX and brain natriuretic peptide in sodium homeostasis in men.