Influence of water-diuresis or saline volume expansion on deep nephron tubuloglomerular feedback

We have recently demonstrated the existence of a tubuloglomerular feedback mechanism in juxtamedullary nephrons in rat kidneys during antidiuresis. In the present experiments, we have investigated the influence of water-diuresis on Munich Wistar rats and in homozygote Brattleboro rats. We have also observed the effect of saline volume expansion on the tubuloglomerular feedback of juxtamedullary nephrons in Munich Wistar rats. For comparison, the feedback mechanism was also studied in surface nephrons during water-diuresis in Munich Wistar rats. Measurements of flow rate in the descending limb of Henle and single nephron glomerular filtration rate (GFR) using micropuncture at the renal papilla were performed, while the ascending limb was microperfused at varying perfusion rates with a modified Ringer solution. In surface nephrons early proximal flow rate, single nephron GFR and stop-flow pressure was measured during microperfusion of the end-proximal loop. No significant changes were measured in surface nephrons during water-diuresis: the tubular flow rates, feedback responses, stop-flow pressure and stop-flow pressure changes were similar to those during anti-diuresis. In juxtamedullary nephrons, Henle loop flow rate increases during water-diuresis but the feedback-mediated flow and single nephron GFR response curves obtained during microperfusion were unaltered compared to controls. Together, these results indicate that the feedback could be more activated during water-diuresis than during control conditions. On the other hand, during saline volume expansion, reduced tubuloglomerular feedback sensitivity was found as shown earlier for surface nephrons. The reduction of tubuloglomerular feedback sensitivity therefore seems to be important in maintaining salt-, but not water-balance.     

Activation of the tubuloglomerular feedback mechanism in dehydrated rats

To study the influence of the tubuloglomerular feedback control (TGF) on the regulation of glomerular filtration rate (GFR) during dehydration, micropuncture experiments were performed on surface nephrons of dehydrated rats. Dehydration was achieved by withdrawal of food and water for 24 h. The urine flow rate decreased to 1.5 μl/min (controls 2.9 μl/min) and GFR decreased in these rats to 0.80 ml/min (controls 1.22). TGF was studied by two different micropuncture procedures. With the first technique the changes in proximal stop-flow pressure in response to changes of the late proximal microperfusion rate were measured. With this technique the perfusion rate necessary to induce a half maximal stop-flow pressure response, the turning point, was also determined. An increased TGF sensitivity was found in dehydrated rats, as indicated by increased stop-flow pressure responses (35 versus 26%) and decreased turning points (16 versus 21 nl/min). With the second micropuncture technique the single nephron GFR (SNGFR) was measured at distal and proximal tubular sites, in the same nephron. Distal SNGFR was decreased during dehydration to 32.2 nl/min, versus 42.7 nl/min in controls. A significant difference between paired SNGFR measurements in the same nephron was observed during dehydration, the proximal value being 5.3 nl/min higher than the distal, whereas this difference was not seen in control rats. This finding indicates that activation of the feedback mechanism takes place to reduce SNGFR. It is concluded that the decrease in whole kidney GFR is partly caused by the observed increase in feedback activity. The present results are also in agreement with our earlier hypothesis that the hydrostatic and oncotic pressure conditions within the interstitial space surrounding the macula densa cells modulate the sensitivity of the tubuloglomerular feedback mechanism.     

Chronic salt loading: Effects on plasma volume and regulation of glomerular filtration rate in Wistar rats

Summary Experiments were carried out in Wistar rats to determine whether the loss of sensitivity of the tubuloglomerular feedback mechanism (TGF) which is known to occur in volume expansion is due to a change in the functional characteristics of the juxtaglomerular apparatus or to a change in some property of the tubular fluid which influences the feedback signal at the macula densa. Proximal tubular fluid was collected by means of a microperfusion/suction pump from Wistar rats maintained for a minimum of 10 days on a high salt diet and also from rats fed a control low salt diet. Both fluids were then used to perfuse loops of Henle in rats from both groups and the feedback response assessed from the change in early proximal tubular flow rate (EPF). In high salt rats, perfusion of the loop of Henle with homologous tubular fluid confirmed the loss of sensitivity of the TGF mechanism in volume expansion, the response of EPF was practically absent. In contrast, the low salt rat responded with a 50% decrease in EPF to loop perfusion at 40 nl/min with its homologous fluid. On the other hand, when the loop of Henle in high salt rats was perfused at 40 nl/min with heterologous (low salt) tubular fluid, EPF again decreased by some 50% whereas EPF in low salt rats failed to respond to loop perfusion with high salt fluid. From these results it is concluded that in rats chronically volume expanded by a high salt diet an unknown inhibitory principle occurs in the proximal tubular fluid which reduces the sensitivity of the tubuloglomerular feedback mechanism.     

Renal response to volume depletion and expansion in Milan hypertensive rats

In previous studies on Milan hypertensive (MHS) rats, we found an impaired tubuloglomerular feedback (TGF) response before, during and after development of hypertension. In the present study MHS rats and rats of the Milan normotensive strain (MNS) were investigated after 24 hours of volume depletion (VD) and subsequently after 5% isotonic volume expansion (VE) with respect to whole kidney function, interstitial hydrostatic (P_int) and oncotic (II_int) pressures, stop-flow pressure characteristics of TGF and changes in early proximal flow rate in response to increased loop of Henle flow. MHS rats had higher mean arterial blood pressure (P_a) than MNS rats (129 vs. 101 mmHg) both after VD and after subsequent VE. No difference in glomerular filtration rate (GFR) was found. Both strains had a low urine flow rate (1.5 μl min^-1) during VD, which increased fourfold after VE. The interstitium was significantly more dehydrated in MHS, as indicated by a more negative net interstitial pressure (P_int–±_int t than in MNS (-1.3 ± 0.3 vs. ± 0.0 ± 0.5 mmHg) after VE. The TGF mechanism was more activated in MHS during volume depletion, as indicated by a larger drop in stop-flow pressure (P_sf) in response to loop of Henle perfusion (7.1 ± 0.7 vs. 4.7 ± 0.2 mmHg, P < 0.05). However, during VD the loop of Henle flow that elicited half maximal response in P_sf, the turning point (TP), was equally low in MHS and MNS (13.5 ± 0.6 and 14.3 ± 0.4, respectively). After VE, however, TP increased significantly more in MNS to (32.6 ± 2.1 nl min^-1) then in MHS (to 21.8 ± 0.9 nl min^-1, P < 0.05). It is concluded that the blunting of the TGF resetting in response to VE in MHS rats may well be of importance in the development of hypertension in the MHS strain.     

The early phase of experimental acute renal failure. III. Tubuloglomerular feedback

Summary Experiments were designed to determine whether tubuloglomerular feedback, which modifies nephron filtration rate in response to alterations in the macula densa sodium chloride concentration, was still apparent in the initiation phase of various types of acute renal failure. The response of the glomerulus to changes in the macula densa stimulus was evaluated in haeme pigment, ischaemic and nephrotoxic induced renal damage by measuring early proximal flow rates. The sodium chloride concentration at the macula densa was varied between low values and isotonicity in two ways: firstly, by interruption of flow through the loop of Henle, followed by orthograde perfusion with Ringer's solution; secondly, by retrograde perfusion of the loop of Henle with isosmotic mannitol or Ringer's solution. In all nephrons examined, filtration rate was inversely correlated to the macula densa sodium chloride concentration, except during orthograde perfusion with 10^–4 M furosemide in Ringer's solution, when, despite the high sodium chloride concentration, filtration rate remained high. It is concluded that the mechanism of tubuloglomerular feedback is viable after the onset of compromised renal function, and may, as postulated, account for the reduction in blood flow and nephron filtration rate occurring in acute renal failure.     

Functional consequences at the single-nephron level of the lack of adenosine A1 receptors and tubuloglomerular feedback in mice

Mice deficient for adenosine A1 receptors (A1AR) lack tubuloglomerular feedback (TGF). In vivo micropuncture experiments were performed under anesthesia in A1AR-deficient and wild-type littermate mice to study the effects of chronic absence of A1AR on fluid and Na⁺ reabsorption along the nephron, as well as the functional consequences at the single-nephron level of the lack TGF. Evidence is provided for an A1AR-mediated tonic inhibition of Na⁺ reabsorption in a water-impermeable segment of the loop of Henle, possibly the thick ascending limb. In contrast, proximal tubular reabsorption of fluid, Na⁺ and K⁺ was unaffected by the chronic absence of A1AR. Experiments in which artificial tubular fluid was added to free-flowing late-proximal tubules demonstrated an essential role of A1AR/TGF in the stabilization of fluid and Na⁺ delivery to the distal nephron. Further, the occurrence of spontaneous oscillations of hydrostatic pressure in proximal tubule (P _PT) at a frequency of about 32 mHz depended on intact A1AR/TGF. In comparison, the normal, stabilizing reduction in P _PT following the initial rise in P _PT during sustained small increases in proximal tubular flow rate does not require A1AR/TGF; TGF-independent mechanisms appear to compensate in this regard for a lack of TGF under physiological conditions and the lack of TGF is unmasked only when supraphysiological flow rates overwhelm TGF-independent compensation.     

A model study of the tubuloglomerular feedback mechanism: effector site and influence on renal autoregulation

The effector site of the macula densa tubuloglomerular feedback mechanism was determined with a mathematical model of glomerular ultrafiltration. The feedback response was found to be mediated by an increase in the hydraulic resistance of the afferent arteriole, possibly accompanied by a slight decrease in the ultrafiltration coefficient of the glomerular membrane. The contribution of the tubuloglomerular feedback mechanism to the autoregulation of renal blood flow and GFR during increased arterial blood pressure was evaluated with a mathematical model of the kidney. The tubuloglomerular feedback system of the superficial nephron was found to be a less efficient regulator of renal blood flow and GFR than the remainder of the autoregulatory mechanism.     

The early phase of experimental acute renal failure

Experiments were conducted to determine whether suppression of the renin-angiotensin-system and inhibition of the tubuloglomerular feedback response offer protection from acute renal failure, as found in chronically-salt loaded animals. The juxtaglomerular renin activity and tubuloglomerular feedback response were inhibited acutely, by saline expansion, or chronically by DOCA-treatment with saline drinking fluid or salt diet, by high salt diet alone, or by inducing two-kidney Goldblatt hypertension. The chronic pretreatment procedures depressed juxtaglomerular renin to 16, 7, 13 and 4% of control, respectively, inhibited the feedback response to 53, 37, 56, and 38% of control, respectively, but conferred no benefit in the first hours following a nephrotoxin or ischaemia. In contrast, the acute treatment procedure reduced juxtaglomerular renin activity to only 56% and lowered the feedback response to only 71%, but improved renal function after the nephrotoxin, although not after ischaemia. It is concluded that since severe restrictions of renin activity and tubuloglomerular feedback are not protective, neither is primarily involved in generating the functional restrictions early in acute renal failure. The restoration of renal function by saline expansion accompanied only a modest depression of these two systems and suggests that the beneficial effect may result more from volume expansion or diuresis than from suppression of renal renin or inhibition of tubuloglomerular feedback.     

Resetting of tubuloglomerular feedback by interrupting early distal flow

Cell–cell contact between the macula densa and the glomerular arterioles is thought to provide the information pathway for the tubuloglomerular feedback (TGF) mechanism. When concentrations of sodium and chloride in the macula densa segment are increased, a signal is transmitted through the extraglomerular mesangium to contract the afferent arteriole. In addition, some observers have described a second region of contact between a later part of the distal tubule and the afferent arteriole of the same nephron. In this region the connecting tubule (CNT), and sometimes nerves that make contact with the cells of this CNT, were found. This arrangement gives another potential tubular segment, besides the macula densa plaque, in which the composition of tubular fluid may regulate glomerular dynamics. The present study was designed to investigate whether interrupting flow in the distal tubule downstream from the macula densa would influence the TGF mechanism. TGF was examined in rats by orthograde microperfusion, before and after blockade of the distal nephron with castor oil. Two variables were measured: maximum decrease in stop-flow pressure (ΔP_sf), and perfusion rate which elicits half-maximal decrease in ΔP_af (V_1/2). The fluid arriving at the blocking point was collected into a micro-pipette. The results show a significant increase in V_1/2 from 19 to 25 nl min^-1after 30 min of blockade. In conclusion the results support a role of the distal nephron in the control of the TGF mechanism.     

Effects of acute and chronic unilateral renal denervation on the tubuloglomerular feedback mechanism

We recently observed a time-dependent resetting of the tubuloglomerular feedback (TGF) sensitivity to a subnormal level after acute unilateral renal denervation (aDNX). The present investigation compares the effects of aDNX with those of chronic unilateral renal denervation (cDNX), i.e one week after aDNX. All experiments were performed in anaesthetized rats prepared for micropuncture. cDNX led to increases in urine, sodium and potassium excretion in denervated kidneys, while contralateral kidneys showed reduced excretion of these parameters. GFR was increased in denervated kidneys, but unchanged on the contralateral side. TGF activity was determined by measuring the maximal stop-flow pressure response (ΔP_sf) and the tubular flow rate at which 50% of the maximal response occurred (turning point; TP). cDNX decreased TGF sensitivity, as indicated by an increased TP from 19.1 nL/min in sham-DNX to 26.1 nL/min. Concomitantly, TP in contralateral kidneys was significantly decreased to 15.9 nL/min. aDNX led to a greater sensitivity reduction; TP increased from 19.8 to 34.0 nL/min and contralaterally TP decreased to 14.0 nL/min. ΔP_sf in cDNX increased by 63% compared to sham-DNX, while on the contralateral side this was unchanged. No difference in ΔP_sf was found between control, DNX and contralateral kidneys in the aDNX group. In summary, these experiments show that the previously reported decrease in TGF sensitivity in aDNX kidneys still persists after one week, although less pronounced. As a result of the decreased TGF sensitivity, GFR is kept on a high level in cDNX kidneys. Contralateral kidneys show reversed resetting.     

Factors controlling the release of renin

Summary Blood was collected by micropuncture from the efferent arteriole and superficial venules of the cat's kidney. Blood samples were also collected from the femoral artery and the renal vein. The blood renin concentrations (ng Al ml^–1 2 h^–1) in a basal state were 37.2±3.5 (S.E.M.) (n=60) (artery), 32.5±5.2 [7] (efferent arteriole), 53.5±4 (116) (superficial venule), 54.2±5.4 (43) (renal vein). The corresponding values after haemorrhage were 389±98 (21), 345±115(6), 963±208 (37), 907±290 (17), ng Al ml^–1 2 h^–1. The efferent arteriolar renin did not differ from that in the artery but the concentrations in superficial venular blood and renal vein were higher than arterial concentration. Thus renin entered the circulation between the efferent arteriole and the superficial venule. The blood renin concentration of different superficial venules at a steady arterial renin concentration varied markedly. Into certain venules there appeared to be little or no renin secretion, into others a marked renin secretion, suggesting a heterogeneity of renin secretion by the different nephrons.When the flow of tubular fluid to the macula densa of a group of nephrons was blocked, the renin concentration fell and was significantly less than the renin concentration in venules draining non blocked nephrons and less than in the renal vein.These results suggest that the juxtaglomerular apparatus of the nephrons do not release renin in a synchronous fashion. The release appears to be episodic and is inhibited when flow to the macula densa is ceased. This implies that a high sodium concentration at the macula densa stimulates renin release.Supported by the National Heart Foundation of Australia     

The effect of inhibition of prostaglandin synthesis on tubuloglomerular feedback in the rat kidney

To further clarify the mechanism mediating the reduction of nephron filtration rate in response to an increase of loop of Henle flow rate we have studied the effect of prostaglandin inhibition on tubuloglomerular feedback in rats. Following inravenous administration of 2 or 5 mg/kg indomethacin feedback responses expressed as the percent reduction of early proximal flow rate (EPFR) during flow elevation from 0–40 nl/min decreased from control values of –54.3±4.3% (mean ± S.E.) and –39.5±3.9% to –27.9±2.8% (P<0.001) and –5.0±4.9% (P<0.001) respectively. A significant reduction in the feedback response was also seen following intravenous administration of 2 or 5 mg/kg Ro 20-5720 (–28.8±5.8% and –7.8±3.8% respectively), 10 mg/kg meclofenamate (–15±4%), and 2 mg/kg eicosa-5,8,11,14-tetraynoic acid (–16.2±4.8%). In contrast to control animals injection of 5 mg/kg indomethacin had no effect on the feedback response in rats kept on a low salt diet. After applying a single dose of 5 mg/kg indomethacin or Ro 20-5720 feedback responses were reduced to –5.4±4.3% and –3.0±4.36% in the period 0–80 min, but were normal in the period 81–160 min after injection (–36.1±2.83% and –44.3±2.82% respectively). A dose dependent inhibition of the feedback response was also noted when indomethacin was applied intraluminally with full inhibition being established at a concentration of 0.5 mM. Urinary excretion rates of PGE₂ and PGF₂ fell from control values of 286.1±73.7 and 143.5±25.9 pg/min to 31.2±9.9 and 23.6±9 pg/min following 2 mg/kg indomethacin and to 36.8±4.4 and 8.9±1.9 pg/min following 5 mg/kg Ro 20-5720. Reduction of PG excretion was not reversible during the time of the experiment. Our results demonstrate a consistent decrease of tubuloglomerular feedback responses during inhibition of prostaglandin biosynthesis.Supported by the Deutsche Forschungsgemeinschaft     

Tubular sodium handling and tubuloglomerular feedback in compensatory renal hypertrophy

Tubular sodium handling and tubuloglomerular feedback (TGF) activity were assessed in established compensatory renal hypertophy in Sprague Dawleys rats. Hyperfiltration at the level of the single nephron was confirmed 4–6 weeks following a reduction in renal mass. TGF activity, determined as the difference between late proximal and early distal measurements of single-nephron glomerular filtration rate (SNGFR), was significantly increased in compensatory renal hypertrophy, being 7.8±1.0 vs 23.3±1.9 vs 25.5±2.6 nl/min (P for analysis of variance <0.05) following sham operation, unilateral nephrectomy, and 1 1/3 nephrectomy, respectively. Enhanced net tubular Na transport was also observed, with total Na reabsorption up to the late proximal site being 1.8±0.2 vs 2.7±0.1 vs 3.1±0.3 nmol/min (P<0.05), and to the early distal site being 3.4±0.5 vs 5.8±0.6 vs 7.9±0.8 nmol/min (P<0.05) in the three animal groups respectively. Comparison of proximal tubular length demonstrated a 71.9±8.1% increase in uninephrectomised vs sham-operated animals. This increase was proportionately greater than the increase in proximal Na reabsorption (50.0±4.0%) observed in the corresponding animal groups. Concurrent electron microprobe experiments in uninephrectomised and sham-operated animals demonstrated that the proximal tubular intracellular Na concentration was significantly lower following uninephrectomy (16.8±0.6 vs 18.9±0.5 mmol/kg wet weight, P<0.01), in association with evidence of reduced basolateral Na/K-ATPase activity. In summary, these data indicate that total Na transport in individual nephrons is increased in the proximal tubule and in the loop of Henle in compensatory renal hypertrophy, although the net amount of Na reabsorbed per unit proximal tubular length is actually reduced. The cell composition data suggest that the site of inhibition of transcellular transport is at the apical cell membrane. The elevated SNGFR is under the regulatory influence of an appropriately activated TGF system, which serves to limit the hyperfiltration.     

Morphometric studies of the extraglomerular mesangial cell field in volume expanded and volume depleted rats

Summary The extraglomerular mesangial cell field was studied by morphometric techniques in volume expanded and volume depleted rats. The volume density of the extraglomerular mesangial interstitium was found to be significantly different between the two conditions, 16.9±3.7% in volume depletion and 29.0±4.1% in volume expansion. No difference in the volume density of the peritubular interstitium could be detected under the same conditions. These findings are interpreted as indicating a specific sensitivity of the extraglomerular mesangial interstitium to changes in body fluid content, a phenomenon which may play a role in the mechanism of resetting the tubulo-glomerular feedback control.     

Renal interstitial pressure and tubuloglomerular feedback control in rats during infusion of atrial natriuretic peptide (ANP)

Atrial natriuretic peptide (ANP), injected at physiological concentrations, is known to induce both natriuresis and diuresis. It has been suggested by some investigators that these changes result from an increasing glomerular filtration rate (GFR), but others have been unable to demonstrate an increased GFR. The tubuloglomerular feedback (TGF) mechanism is an important regulator of GFR, and the sensitivity of TGF is decreased during ANP administration. Furthermore, resetting of TGF is, in most instances, related to changes in renal interstitial hydrostatic and oncotic pressures. It is also known that ANP may increase capillary permeability which may change renal interstitial pressure. The present study was performed to examine renal interstitial pressures and the TGF mechanism during ANP infusion. In accordance with previous studies, TGF sensitivity was found to be decreased. The tubular flow rate which elicited half the maximal drop in stop-flow pressure (P_sf) was increased from 18.5 to 25.7 nl min^-1. In contrast, ANP infusion resulted in a decreased interstitial hydrostatic pressure and an increased interstitial oncotic pressure. From previous experiments, such changes in interstitial pressures would be expected to increase TGF sensitivity. The changes in interstitial pressure cannot, therefore, directly explain the resetting of the feedback mechanism. In conclusion, the present paper shows a decreased renal net interstial pressure after intravenous administration of ANP.     

Further evidence for an inverse relationship between macula densa NaCl concentration and filtration rate

It has been concluded that tubulo-glomerular feedback mechanism is triggered by changes in NaCl concentration ([NaCl]) at the macula densa. This conclusion is based on the demonstration that changes in filtration rate produced during retrograde perfusion of the loop of Henle depend upon the perfusate [NaCl]. Experiments were performed to evaluate whether the effect on glomerular function of orthograde perfusion of the loop of Henle is consistent with this conclusion. Early proximal flow rate ( ), stop-flow pressure (P _SF), early distal chloride concentration ([Cl]), and flow rate were measured during perfusion of the loop of Henle with mannitol solution (300 mosm kg^–1), 30 mM NaCl+mannitol (300 mosm kg^–1), 140 mM Na isethionate and artificial tubular fluid. When distal flow exceeded 10 nl min^–1, the magnitude of the glomerular response was predictable from the [Cl]. The linear regression line, , did not differ from that obtained previously with the retrograde technique. Retrograde perfusion with 140 mM Na isethionate was without effect on . We conclude that the effect on glomerular function of perfusion of the loop of Henle in either an orthograde or a retrograde direction with these solutions depends upon the chloride concentration at the macula densa.     

Exercise-induced plasma volume expansion and post-exercise parasympathetic reactivation

The purpose of this study was to investigate the effect of exercise-induced plasma volume expansion on post-exercise parasympathetic reactivation. Before (D₀) and 2 days after (D₊₂) a supramaximal exercise session, 11 men (21.4 ± 2.6 years and BMI = 23.0 ± 1.4) performed 6-min of submaximal running where heart rate (HR) recovery (HRR) and HR variability (HRV) indices were calculated during the first 10 min of recovery. Relative plasma volume changes (∆PV) were calculated using changes in hematocrit and hemoglobin measured over consecutive mornings from D₀ to D₊₂. Parasympathetic reactivation was evaluated through HRR and vagal-related indexes calculated during a stationary period of recovery. Compared with D₀, ∆PV (+4.8%, P < 0.01) and all vagal-related HRV indices were significantly higher at D₊₂ (all P < 0.05). HRR was not different between trials. Changes in HRV indices, but not HRR, were related to ∆PV (all P < 0.01). HRR and HRV indices characterize distinct independent aspects of cardiac parasympathetic function, with HRV indices being more sensitive to changes in plasma volume than HRR.     

Atrial natriuretic factor,urinary catechol compounds and electrolyte excretion in rats during normal hydration and isotonic volume expansion. Influence of dopamine receptor blockade.

To investigate the influence of acute isotonic volume expansion (VE) on the plasma concentration of atrial natriuretic factor (ANF), the excretion of catechol compounds and electrolytes and the whole kidney glomerular filtration rate (GFR), these variables were measured before and during 60 min of VE (2% of body weight per hour). Atrial natriuretic factor was measured at the end of the experiment. In a control group (n= 7) without volume expansion, plasma ANF was 58 ± 4 pg ml^-1. The excretion of sodium, dopamine (DA), 3 ,4–dihydroxyphenylacetic acid (DOPAC), noradrenaline (NA) and GFR did not change during the control study. In VE animals (n= 7) plasma ANF was 82 ± 7pg ml^-1, significantly higher than in the control group. Sodium excretion increased more than 17–fold. The excretion of the DA increased by 38% and that of DOPAC by 30%. Noradrenaline excretion remained unchanged while GFR increased by 20%. In haloperidol-pretreated animals subjected to VE (n = 7). plasma ANF was 81± 8 pg ml^-1 during VE, significantly higher than in the control animals. Although the sodium excretion increased more than ninefold in this group during VE, this increase was only 55 % of that in the VE group not given haloperidol. The DA and DOPAC excretion was increased by haloperidol, indicating a feedback effect of receptor blockade. DOPAC excretion was not increased further by VE, hut the excretion of DA increased by 15% and GFR increased by 19%. In conclusion, haloperidol reduced the natriuretic response to VE without impairing either the VE-induced release of ANF or the increase in GFR. The results indicate an important involvement of ANF and DA in the natriuretic response to VE.     

Distal tubule [Na+] and juxtaglomerular apparatus renin activity in uranyl nitrate induced acute renal failure in the rat

Summary It has been previously demonstrated that single nephron filtration rate, whole kidney glomerular filtration rate and total renal blood flow decreased by 30–35% 6 h after uranyl nitrate induced acute renal failure in the rat. In order to evaluate a role of the renin-angiotensin system in the initiating phase (0–6 h) of this model of acute renal failure, determinations of plasma renin activity, superficial (S) and deep (D) juxtaglomerular apparatus (JGA) renin activity and distal nephron [Na⁺] were obtained. Plasma renin activity increased from the control value of 1.5±0.3 (S.E.M.) to 2.9±0.4 ng/ml/h (P<0.005) at 6 h. Mean renin activity in S- and D-JGA's of control rats was 6.99±0.41 and 2.67±0.21 ng/JGA/h, respectively. After uranyl nitrate, renin activity in S-JGA's increased to 13.62±0.80 ng/JGA/h (P<0.001) at 2 h and remained elevated, 12.56±0.90 and 12.75±0.87 ng/JGA/h at 4 and 6 h. D-JGA renin activity increased (P<0.05) to 7.04±0.53, 6.23±0.31 and 3.44±0.33 ng/JGA/h at 2, 4 and 6 h after uranyl nitrate. Distal tubule [Na⁺], 27 samples in 6 rats, increased from a mean control value of 53.7±1.2 mEq/l to 116.9±2.5 mEq/1, 24 samples in 6 rats (P<0.001).Prompt increases in JGA renin activity were observed in the initiating phase of acute renal failure, suggesting a role for the renin-angiotensin system in the pathophysiology of this nephrotoxic model. The association of increased JGA renin activity and increased distal [Na⁺] is consistent with a role for the tubuloglomerular feedback mechanism in the initiating phase of uranyl nitrate induced acute renal failure in the rat.