Effects of insulin on renal interstitial hydrostatic pressure and natriuretic response to volume expansion in diabetic rats

Diabetes mellitus (DM) is characterized by alterations in fluid balance and blood volume homeostasis. Renal interstitial hydrostatic pressure (RIHP) has been shown to play a critical role in mediating sodium and water excretion under various conditions. The objective of this study was to determine the effects of immediate and delayed initiation of insulin treatment on the restoration of the relationship between RIHP, natriuretic, and diuretic responses to acute saline volume expansion (VE) in diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (STZ; 65 mg/kg body wt). Four groups of female Sprague-Dawley rats were studied: normal control group (C), untreated diabetic group (D), immediate insulin-treated diabetic group (DI; treatment with insulin for 2 wk was initiated immediately when diabetes was confirmed, which was 2 days after STZ injection), and delayed insulin-treated diabetic group (DDI; treatment with insulin for 2 wk was initiated 2 wk after STZ injection). RIHP and sodium and water excretions were measured before and during VE (5% body wt/30 min) in the four groups of anesthetized rats. VE significantly increased RIHP, fractional excretion of sodium (FE(Na)), and urine flow rate (V) in all groups of rats. Basal RIHP, RIHP response to VE (Delta RIHP), and FE(Na) and V responses to VE (Delta FE(Na) and Delta V) were significantly lower in the D group compared with the C group of rats. Delta RIHP was significantly higher in both DI and DDI groups compared with D group but was similar to that of the C group of rats. While in the DI group the Delta FE(Na) response to VE was restored, Delta FE(Na) was significantly increased in DDI compared with D group, but it remained lower than that of the C group. In conclusion, insulin treatment initiated immediately after the onset of diabetes restores basal RIHP and RIHP, natriuretic, and diuretic responses to VE; however, delayed insulin treatment restores the basal RIHP and RIHP response to VE but does not fully restore the natriuretic response to VE.     

Regulation of sodium excretion by renal interstitial hydrostatic pressure

Renal interstitial hydrostatic pressure (RIHP) appears to play a crucial role in linking the renal circulation to the rate of tubular reabsorption of sodium and water. Various physiological and pharmacological maneuvers that increase RIHP are associated with increases in sodium excretion. Renal vasodilators that increase RIHP also increase sodium excretion, whereas the vasodilators that do not alter RIHP do not affect sodium excretion. Preventing increases in RIHP during intrarenal infusion of vasodilators markedly attenuates the normal increase in sodium and water excretion. Techniques that directly increase RIHP by renal interstitial volume expansion increase urinary excretion of sodium and water. RIHP may be an important mediator of renal perfusion pressure (RPP) natriuresis. Experimental evidence suggests that the proximal tubule of deep nephrons may be an important nephron site that is sensitive to changes in RPP.     

Atrial natriuretic peptide--cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP)--cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the renin--angiotensin--aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.     

Influence of volume expansion on sodium excretion during parabiotic dialysis.

Dialysis of a saline-infused against a noninfused dog was associated with a significant increase in Na excretion in both animals without a significant change in creatinine clearance or filtered Na. This indicates that there was movement by diffusion of a humoral agent between the two animals. The observed increase in Na excretion in the noninfused animal resulted from gain of a natriuretic hormone, since in a second series of experiments a natriuretic rather than antinatriuretic hormone appeared to be involved.     

Renal excretion of calcium and sodium in acute nephritis

Hypocalciuria was found in the early stages of illness in six patients aged 12 to 30 with acute nephritis. The hypocalciuria does not appear to be due to hypocalcaemia, lowered glomerular filtration rate, or hypoparathyroidism. It is suggested that the hypocalciuria is due in part to decreased intestinal absorption of calcium, though possibly there is also a primary alteration in renal tubular handling of calcium.     

Prostaglandin E2 induced changes in renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat

Prostaglandin E2, when infused into the renal artery of the dog, is a vasodilator and increases both renal interstitial hydrostatic pressure and sodium excretion. Similar studies in the rat, however, have been inconclusive. The present study examined the effect of prostaglandin E2 infusion into the renal interstitium, by means of a chronically implanted matrix, on renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat. Prostaglandin E2 was continuously infused directly into the kidney interstitium to mimic endogenous prostaglandin E2 production by renal cells. The maximum change in each of these parameters occurred when 10(-5) M PGE2 was infused. Renal blood flow increased from 4.70 +/- 0.91 to 5.45 +/- 0.35 ml/min (p less than 0.05) while renal interstitial hydrostatic pressure decreased from 3.9 +/- 0.4 to 2.6 +/- 0.5 mmHg (p less than 0.05) and fractional excretion of sodium decreased from 1.02 +/- 0.20 to 0.61 +/- 0.12% (p less than 0.05). Thus, the present study demonstrates that renal interstitial infusion of prostaglandin E2 increases total renal blood flow but decreases both renal interstitial hydrostatic pressure and urinary sodium excretion in the rat.     

Noninvasive beat-to-beat stroke volume computation during acute hydrostatic pressure changes in parabolic flight

A three-element model of the cardiovascular system was used to monitor stroke volume (SV) changes during parabolic flight. Aortic blood flow was estimated from continuous arterial finger pressure and SV computed by integrating simulated aortic flow during each systole. SV was significantly higher in microgravity (microgravity) compared to 1 G whereas in hypergravity (hG), SV was significantly lower. Exponential SV transients were observed after the transitions to and from microgravity and the succeeding or preceeding hG phases. These SV transients present different time constants, which reflect two different mechanisms of cardiovascular adaptation to sudden gravitational changes. These results show that beat-to-beat computation of SV provides noninvasive information on circulatory adaptation to acute hydrostatic pressure changes.     

Renal reflexes in the regulation of blood pressure and sodium excretion

The rich innervation of the kidney is distributed to all structures of renal parenchyma thus providing important anatomical support to the functional evidence that the renal nerves can control kidney functions and send signals on the kidney environment to the central nervous system. Efferent renal nerve fibres are known to influence renal haemodynamics by modifying arteriolar vascular tone, renin release by a direct action on juxtaglomerular cells, and the excretion of sodium and water by changing tubular reabsorption of sodium and water at the different tubular levels. Mechano- and chemo-receptors have been shown in the kidney. Afferent fibres connected with renal receptors convey signals to the central nervous system both at spinal and supraspinal levels. The central areas receiving inputs from the kidney are those involved in the control of cardiovascular homeostasis and fluid balance. Activation of renal receptors by the electrical stimulation of renal afferent fibres were found to elicit both excitatory and inhibitory sympathetic responses. Although the existence of excitatory renorenal reflexes has been suggested, electrophysiological and functional data demonstrate that neural renorenal reflexes exert a tonic inhibitory influence on the tubular sodium and water reabsorption and on the secretion of renin from the juxtaglomerular cells.     

Prostaglandin E2 induced changes in renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat

Prostaglandin E₂, when infused into the renal artery of the dog, is a vasodilator and increases both renal interstitial hydrostatic pressure and sodium excretion. Similar studies in the rat, however, have been inconclusive. The present study examined the effect of prostaglandin E₂ infusion into the renal interstitium, by means of a chronically implanted matrix, on renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat. Prostaglandin E₂ was continously infused directly into the kidney interstitium to minic endogenous prostaglandin E₂ production by renal cells. The maximum change in each of these parameters occured when 10⁻⁵ M PGE₂ was infused. Renal blood flow increased from 4.70±0.91 to 5.45±0.35 ml/min (p<0.05) while renal interstitial hydrostatic pressure decreased from 3.9±0.4 to 2.6±0.5 mmHg (p<0.05) and fractional excretion of sodium decreased from 1.02±0.20 to 0.61±0.12% (p<0.05. Thus, the present study demonstrates that renal interstitial infusion of prostaglandin E₂ increases total renal blood flow but decreases both renal interstitial hydrostatic pressure and urinary sodium excretion in the rat.     

Urinary cyclic AMP excretion during volume expansion in the rat.

We have studied the effect of volume expansion with 0.9% saline solution (10% body weight in 1 h) on urinary cyclic AMP excretion in rats. In nine normal rats urinary cyclic AMP excretion (picomoles/minute) was 113.9+/-9.9 during the control period, rose significantly to 171+/-20 during the first 10 min of expansion, came back to control levels for the next 20 min, and finally decreased significantly to 48.8+/-13.2 at the end of the expansion period. In nine parathyroidectomized rats control cyclic AMP excretion was 78.0+/-4.5, did not rise during expansion, and decreased significantly (to 33.7+/-4.1) at the end of the expansion period. The transient increase in cyclic AMP excretion observed in normal rats could be due to parathyroid hormone release. Our studies do not allow us to explain the subsequent decrease noted in both groups.     

Enalapril treatment restores the decreased proximal tubule reabsorption in response to acute volume expansion in diabetic rats

The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid and electrolyte homeostasis. The RAS is activated and renal interstitial hydrostatic pressure (RIHP) is decreased in diabetic rats. The objective of this study was to evaluate the roles of proximal tubule reabsorption and RAS in the decreased RIHP and blunted natriuretic and diuretic responses to acute saline volume expansion (VE) in diabetic rats. Enalapril was utilized to inhibit angiotensin II (AII) formation. Diabetes mellitus (DM) was induced by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 65 mg/kg). RIHP was measured by a polyethylene (PE) matrix that was chronically implanted in the left kidney. Fractional excretion of phosphate (FE(Pi)) and fractional excretion of lithium (FE(Li)) were used as indexes for proximal tubule reabsorption. VE significantly increased both FE(Li) and FE(Pi) in all groups of rats studied. However, the increase in FE(Li) (DeltaFE(Li)=17.26+/-3.83%) and FE(Pi) (DeltaFE(Pi)=7.38+/-2.37%) in diabetic rats (DC, n=12) were significantly lower as compared with those in nondiabetic control rats (NC, n=8; DeltaFE(Li)=32.15+/-4.71% and DeltaFE(Pi)=20.62+/-3.27%). The blunted increases in FE(Li) and FE(Pi) were associated with an attenuated increase in RIHP (DeltaRIHP) in DC (1.8+/-0.4 mm Hg) compared with NC rats (4.3+/-0.3 mm Hg). Enalapril treatment (25 mg/kg/day in drinking water) had no effect on nondiabetic rats (NE, n=8) as compared with untreated NC rats, but significantly improved RIHP response (DeltaRIHP) to VE in diabetic rats (DE, n=9; 2.8+/-0.5 mm Hg). Both DeltaFE(Li) and DeltaFE(Pi) were restored by enalapril treatment in diabetic rats and no significant differences were found in DeltaFE(Li) and DeltaFE(Pi) between DE (DeltaFE(Li)=26.81+/-4.94% and DeltaFE(Pi)=10.45+/-4.67%) and NC groups of rats in response to VE. These data suggest that the activated RAS and the decrease in RIHP may play an important role in the increased proximal tubule reabsorption, and the attenuated natriuretic and diuretic responses to acute volume expansion in diabetic rats.     

Renal excretion and saline intake during post-stress immobilization period in rats

An experiment in which the rats access either to 0.5% or 1.5% saline was designed in order to further characterise the relationship between sodium intake and renal excretion after acute immobilization stress. A saline solution for 3 days was provided to the rats previous to the experimental day. On that day, after finishing acute immobilization stress, all variables under observation were measured every 6 h for 24 h. These periods were denominated as follows: T1 (12.00 to 18.00 h), T2 (18.00 to 24.00 h), T3 (24.00 to 06.00 h) and T4 (06.00 to 12.00 h). Acute immobilization stress reduced sodium renal excretion in both T1 and T2. Sodium intake in acute immobilization stress rats was lower than in control rats during all observed periods, while the urine volume was only reduced in the stressed animals in T1. These results were similar in both saline solution concentrations. A good correlation was observed between sodium intake and sodium excretion in control rats having access to either 0.5% or 1.5% saline as well as in stressed rats having access to 0.5% saline, this correlation was not observed in stressed rats with 1.5% saline. This suggests that stress impaired the renal capability of rats to handle high sodium but not a slight sodium overload. The inability of the kidney to excrete sodium may be critical to reduce sodium intake after acute immobilization stress.     

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.     

Effect of extracellular volume expansion on erythrocyte sodium transport in rats.

The effects of extracellular volume expansion (EVE) on the major sodium transport systems and sodium and potassium contents in rat erythrocytes have been examined in the present study. Study has been performed in anesthetized Wistar rat weighing about 300 g. Acute extracellular volume expansion (EVE) was induced by a constant intravenous saline infusion (3% body wt, 3 hours). Rats anaesthetized and catheterized but not expanded were used as controls. Arterial blood samples from control and expanded rats were obtained at the same time, and assayed immediately. Intracellular sodium and potassium concentration and ouabain sensitive (Na(+)-K(+)-pump) and bumetanide sensitive (Na(+)-K(+)-cotransport system) outward Na+ fluxes in erythrocytes were measured. The effect of plasma on erythrocyte transport was also analyzed by measuring 86Rb uptake. Neither of two plasma cations (Na+ and K+) were modified by the EVE. Also intracellular Na+ and K+ levels remained unvariable. Total Na+ efflux was not modified by EVE, but pump-mediated Na+ efflux was smaller after than before EVE. The ouabain-inhibible Na+ efflux rate constant decreased after EVE (from 687 +/- 81 to 525 +/- 29 h-1 x 10(-3); P less than 0.05). Both Na(+)-K(+)cotransport-mediated Na+ efflux and passive permeability increased significantly after EVE. The incubation with plasma from saline-infused animals induced a significant decrease in Rb uptake rate constant, that was not observed after incubation with plasma from non-expanded rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between interstitial fluid volume and pressure (compliance) in hypothyroid rats

There is clinical and experimental evidence that lack of thyroid hormones may affect the composition and structure of the interstitium. This can influence the relationship between volume and pressure during changes in hydration. Hypothyrosis was induced in rats by thyroidectomy 8 wk before the experiments. Overhydration was induced by infusion of acetated Ringer, 5, 10, and 20% of the body weight, while fluid was withdrawn by peritoneal dialysis with hypertonic glucose. Interstitial fluid pressure (P(i)) in euvolemia (euvolemic control situation) and experimental situation was measured with micropipettes connected to a servocontrolled counterpressure system. The corresponding interstitial fluid volume (V(i)) was found as the difference between extracellular fluid volume measured as the distribution volume of (51)Cr-labeled EDTA and plasma volume measured using (125)I-labeled human serum albumin. In euvolemia, V(i) was similar or lower in the skin and higher in skeletal muscle of hypothyroid than in euthyroid control rats, whereas the corresponding P(i) was higher in all tissues. During overhydration, P(i) rose to the same absolute level in both types of rats, whereas during peritoneal dialysis there was a linear relationship between volume and pressure in all tissues and types of rats. Interstitial compliance (C(i)), calculated as the inverse value of the slope of the curve relating changes in volume and pressure in dehydration, did not differ significantly in the hindlimb skin of hypothyroid and euthyroid rats. However, in skeletal muscle, C(i) was 1.3 and 2.0 ml. 100 g(-1). mmHg(-1) in hypothyroid and euthyroid rats (P < 0.01), with corresponding numbers for the back skin of 2.7 and 5.0 ml. 100 g(-1). mmHg(-1) (P < 0.01). These experiments suggest that lack of thyroid hormones in rats changes the interstitial matrix, again leading to reduced C(i) and reduced ability to mobilize fluid from the interstitium.     

Plasma parathyroid hormone during acute volume expansion in the rat

Various studies have suggested the possibility that volume expansion may increase parathyroid hormone (PTH) secretion. PTH appears to have renal effects consistent with the actions of a natriuretic and diuretic and the possibility exists that PTH may play a physiological role in volume homeostasis. The present studies were designed to examine whether PTH levels in plasma from rats was influenced by acute volume expansion and whether such effects were independent of alterations in plasma ionized calcium concentration. Volume expansion with calcium-free bicarbonate Ringers (10% of body weight, IV) led to a drop in plasma ionized calcium from 1.08 to 0.92 mMol/l (p less than 0.01) while plasma PTH concentration was increased from 67.2 to 114.2 pMol/l. Volume expansion with bicarbonate Ringers solution (also 10% of body wt, IV) which contained 1.8 mM CaCl2 was not associated with any significant change in either plasma ionized calcium or plasma PTH concentration. However, measurements of blood packed cell volume (PCV) revealed that infusion resulted in a drop in PCV from 49.7 to 41.1% (p less than 0.01). This represents a dilution of plasma of approximately 42%. The absence of any drop in plasma PTH during isocalcemic volume expansion suggests an underlying stimulus to PTH secretion during volume expansion independent of plasma ionized calcium levels.     

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 pressures were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.