Is cerebral control of plasma [Na] a major determinant for systemic sodium balance?

To evaluate the role of volume expansion for prandial/postprandial natriuresis, we first determined spontaneous daily NaCl, H2O, and diet turnover and Evans blue and inulin spaces in male Wistar rats on various high-salt diets. Second, we measured the time course of Na and water clearance in chloralose/ketamine anesthetized rats over 270 minutes after a single intragastric Na load (0, 290.4, or 581 micromol/100 g body weight). Finally, similar measurements were made during and after a local [NaCl] increase in the left carotid artery supplying the brain for 60 minutes. Daily NaCl, H2O, and diet intake per rat was 2 to 74 mmol, 13 to 223 ml, and 1.5 to 33 g, respectively. Only inulin space and plasma [Na] correlated with daily Na uptake (X; regressions Y = 0.02X + 15.13, N = 99, r2 = 0.0716, P = 0.02; and Y = 141.7 + 0.1005X, N = 179, r2 = 0.104, P < 0.0001, respectively). Under chloralose/ketamine anesthesia, 86% to 102% of the total (i.v. plus i.g.) Na load and some 50% of the unilaterally administered intracarotid Na were excreted. Chloralose/ketamine anesthesia is thus suitable for studies on Na balance mechanisms. Plasma [Na] is under cerebral control. Because of its immediate onset, this mechanism might be the principal determinant of prandial and postprandial natriuresis and hence for the systemic Na balance.

Sodium balance and blood pressure response to salt ingestion in uninephrectomized rats.

The possible role of extracellular volume (ECV) expansion in prandial/postprandial natriuresis was evaluated in control, sham-operated (SO), and uninephrectomized (UNX) male Wistar rats fed a 0.64 (normal salt, NS) or 8 (high salt, HS) g% NaCl diet for seven days after UNX. We thus determined daily NaCl, diet, and water intake and Evans blue and inulin spaces on day 7. Finally, we determined Na and water clearance after a single i.g. Na load (581 micromol/100 g body weight) under chloralose/ketamine anesthesia in UNX and control HS rats. NaCl, diet, and water intakes were comparable beyond day 5. Plasma volume and ECV were similar in all groups. With NS diet, glomerular filtration rate (GFR) in UNX was compensated but lower than that of SO rats (0.55 vs. 0.74 ml/min per 100 g body weight). Blood pressure (BP) was 111 mm Hg in SO controls and 112 mm Hg in the UNX group. After oral Na loading, BP rose in both groups and remained higher in UNX (134 vs. 126 mm Hg at 15 minutes, 130 vs. 118 mm Hg at 225 minutes). Cumulative Na and water excretions were similar (513 and 610 micromol/100 g body weight, 1.97 and 2.35 ml/100 g body weight in SO and UNX, respectively). Chronically salt-loaded UNX rats seem to maintain dietary Na balance by mechanism(s) other than volume expansion.

Chloralose/ketamine anaesthesia preserves a form of postprandial sodium chloride balance in Wistar rats.

Studies on the mechanisms underlying Na balance in anaesthetized rats are complicated by the fact that the most frequently used barbiturate anaesthetics attenuate or abolish this phenomenon. In the present study we show that a combination of nonbarbiturate anaesthetics: chloralose (140 mg/kg i.v.) and ketamine (30 mg/kg i.m. ), preserve the ability of rats to excrete intragastrically applied NaCl loads dose dependently. Thus rats anaesthetized with this regime excreted 86-102% of in- tragastrically applied NaCl whereas rats anaesthetized with thiobutabarbitone sodium (Inactin) excreted only 20-28%. We conclude that chloralose/ketamine anaesthesia is suitable for studies on Na balance mechanisms.

Carl Friedrich Wilhelm Ludwig: the founder of modern renal physiology.

The revolutionary "Zeitgeist" in the Europe of the 1840s left its mark no less in science than it did in the social and political life of the population. The essence of the scientific revolution was the change in paradigm from a vitalist-inductive to a mechanistic hypothetico-deductive approach, in which the experiment assumed the central role. The initiator of this new approach was a young physiologist in Marburg, Germany-Carl Friedrich Wilhelm Ludwig- and the first document his 1842 Habilitation thesis. Although this thesis was limited to a study on renal function, the impact of this epochal new approach, namely the analysis and explanation of living phenomena solely on the basis of physics and chemistry, went far beyond renal physiology: it revolutionised thinking in all the biological sciences. In this thesis, Carl Ludwig enunciated the principle of glomerular ultrafiltration driven by physical forces alone, i.e., the difference in the hydrostatic and oncotic pressures of the blood in the glomerular capillaries, a concept which remains valid today. Ludwig thus became the first scientist to describe correctly a principal component of renal function, the process of glomerular filtration.

Renal and single-nephron function is comparable in thiobutabarbitone- and thiopentone-anaesthetised rats.

The thiobutabarbitone(TB, Inactin)-anaesthetised rat is an extremely widely used preparation for the study of renal function at the whole-organ and nephron levels. The recent withdrawal of TB from the market has made it essential to find an anaesthetic producing experimental conditions as similar as possible to TB to allow comparison of past and future data. Blood gas analysis, clearance and micropuncture studies were therefore performed in rats anaesthetised with TB or the related thiobarbiturate thiopentone (TP) (both 100 mg/kg body weight) to establish whether the latter meets this requirement. Both barbiturates caused similar transient respiratory depression and acidosis. Mean values (TP versus TB) over the total 8-h observation period for glomerular filtration rate (0.94 versus 1.05 ml/min), urine flow (3.8 versus 4.4 microliters/min) and K+ excretion (0.98 versus 1.18 mumol/min) were slightly lower (P < 0.05) in TP rats, whereas renal blood flow (6.26 versus 6.24 ml/min), filtration fraction (0.31 versus 0.34) and Na+ excretion (0.11 versus 0.098 mumol/min) did not differ. The single-nephron filtration rate (SNGFR) (42.1 versus 41.1 nl/min) and fractional reabsorption (42% versus 47%), both measured in the proximal tubule, did not differ, although in the TP group SNGFR rose with time (4.4%/h) whereas the fractional reabsorption did not change significantly; in the TB group SNGFR was constant but fractional reabsorption declined with time (1.5%/h). Fractional reabsorption up to the distal convoluted tubule declined with time, this was more pronounced in the TP group. SNGFR measured at this site did not differ between TP and TB (30.3 versus 30.1 nl/min) but increased with time with TP (2.7%/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of tubuloglomerular feedback by the D1 agonist fenoldopam in chronically salt-loaded rats.

1. Chronic dietary NaCl loading in rats is paralleled by an increase of the dopamine concentration in the tubular fluid and humorally mediated inhibition of the tubuloglomerular feedback mechanism at the macula densa. Since these two phenomena are causally linked, the alterations in the tubuloglomerular feedback response by the luminal application of dopamine, the D1 agonist fenoldopam, the D2 agonist bromocriptine and the D1 and D2 antagonists SCH 23390 and metoclopramide were further investigated using the micropuncture technique. 2. Very similar, concentration-dependent inhibition of the tubuloglomerular feedback response was observed for dopamine and fenoldopam. Half-maximal inhibition was achieved at 10(-11) M and the slope factors of the sigmoid concentration-response curves were comparable. Bromocriptine was ineffective. 3. The inhibition of TGF by both agonists could be antagonized very similarly and concentration dependently by the D1 antagonist SCH 23390. At equimolar concentrations of 10(-9) M the inhibition was reduced by approximately 50%. Raising the SCH 23390 concentration to 10(-6) M completely abolished the TGF inhibition. In contrast, TGF inhibition by 10(-9) M-fenoldopam or dopamine was not significantly affected by an equimolar concentration of the D2 antagonist metoclopramide. Increasing metoclopramide concentration to 10(-6) M attenuated tubuloglomerular feedback inhibition by approximately 55%. 4. It is concluded that the inhibition of tubuloglomerular feedback seen during chronic dietary salt loading can be ascribed to the binding of endogenous dopamine to luminal D1 receptors on the macula densa cells.

Renal blood flow control by tubuloglomerular feedback (TGF) in normal and spontaneously hypertensive rats--a role for dopamine and adenosine.

Following the elementary laws of hemodynamics and the functional characteristics of the renal myogenic and macula densa-mediated (TGF) vascular resistance control mechanisms, TGF-mediated changes of renal vascular resistance are amplified by cooperative changes of the myogenic mechanism. Myogenically induced changes, on the other hand, would be antagonized by TGF. Resetting of renal vascular flow resistance by alterations to the TGF mechanisms might thus be more effective than alterations to the myogenic mechanism. Dopamine and adenosine, two autacoids occurring normally in the tubular fluid, may play a key role in operating such a resetting mechanism. Dopamine and adenosine were found in proximal tubular fluid at concentrations of 10(-8) and 0.5 10(-6) M respectively. Dopamine inhibits the tubuloglomerular feedback mechanism, this inhibition is antagonized concentration-dependently by adenosine. These effects most likely occur via D1 and A1 receptors and hence by regulation of the adenyl cyclase activity in the macula densa cells. The balance between adenosine and dopamine in tubular fluid appears to be under the control of extrarenal parameters. In normal rats, high dietary salt intake, by influencing the secretion of an unknown adrenal hormone, and inhibition of Na-K-ATPase might be of importance. In spontaneously hypertensive rats unknown genetic parameters may also play a role.

Blood pressure and tubuloglomerular feedback mechanism in chronically salt-loaded spontaneously hypertensive rats.

Experiments were performed to qualitatively characterize the effects of tubuloglomerular feedback (TGF) inhibition by chronic salt loading on salt sensitivity of blood pressure in spontaneously hypertensive rats (SHR). After two weeks of salt loading, systolic blood pressure (SBP) was significantly exacerbated and plasma volume (PV) was expanded in salt-loaded SHR compared with those in control SHR (SBP: 182 +/- 1 vs. 159 +/- 2 mm Hg; PV: 4.38 +/- 0.06 vs. 4.04 +/- 0.03 ml/100 g body wt, respectively). Plasma volume of WKY was also but only transiently expanded by salt loading, whereas plasma volume expansion in SHR had persisted over the entire dietary treatment period. TGF activity was assessed as the maximal reduction of single nephron GFR (SNGFR) on increasing loop of Henle perfusion rate from 0 to 40 nl/min using previously collected tubular fluid from salt-loaded rats (TFs) or control rats (TFc). Maximal TGF response in salt-loaded SHR with TFs was 14.9 +/- 2.9% and 57.8 +/- 2.6% with TFc. In control SHR the responses were 16.9 +/- 2.5% with TFs and 52.7 +/- 2.9% with TFc. In salt-loaded WKY the response with TFs were 3.1 +/- 1.6% and 37.4 +/- 2.8% with TFc. And in control WKY, the response with TFs were 8.2 +/- 1.9% and 40.8 +/- 2.8% with TFc, respectively. These results indicate the TGF resetting in chronically salt-loaded SHR and WKY is caused by the activation of humoral TGF inhibitory factor. The suppression of TGF in SHR was, however, far more variable and, on average, less than in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic dietary salt loading: resetting of tubuloglomerular feedback control of renal hemodynamics by an adrenal hormone.

Experiments were performed in chronically salt loaded rats (4 g% NaCl diet for 2 weeks) to determine whether the resetting of tubuloglomerular feedback (TGF) by a humoral inhibitor in tubular fluid is caused by a humoral factor from the adrenal glands. TGF response was assessed by measuring NGFR in the absence of loop of Henle perfusion and during perfusion at 40 nl/min with tubular fluid from normal or salt loaded rats and expressed as NGFR40/NGFR0. (1) Loop of Henle perfusion with tubular fluid from normal rats elicited a TGF response of 50.3% +/- 7.9% (mean +/- SEM) in normal rats and 57.2% +/- 7.9% in salt loaded rats. With tubular fluid from high salt rats, TGF response in normal rats was 97.4% +/- 6.3% and in salt loaded rats 98.0% +/- 1.6%. Participation of adrenal steroids in the inhibition is suggested by the following results: (2) Acute adrenalectomy (ADX) in high salt rats abolished the TGF inhibitory potency of high salt tubular fluid. TGF response in salt loaded rats with high salt tubular fluid from high salt ADX rats was 62.3% +/- 3.0%. Substitution of high salt ADX rats with matching adrenal venous blood from high salt rats restored TGF inhibition. (3) With cross over experiments the effect of heterologous adrenal venous blood substitution on TGF inhibitory activity was studied. The TGF response in high salt rats with high salt tubular fluid and tubular fluid from normal ADX rats substituted with adrenal venous blood collected from high salt rats was 88.9% +/- 5.5% and 91.7% +/- 6.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperreactivity of tubuloglomerular feedback in chronically salt-loaded spontaneous hypertensive rats.

In order to investigate the mechanisms of the hyperreactivity of the tubuloglomerular feedback (TGF) mechanism in spontaneous hypertensive rats (SHR) the resetting of TGF by chronic dietary NaCl loading was studied in SHR and normotensive Wistar Kyoto rats (WKY). This treatment is known to reset the TGF by an inhibitory factor in tubular fluid and not by alterations of the intrinsic characteristics of the juxtaglomerular apparatus (JGA). TGF reactivity, and its resetting, were determined by loop of Henle perfusion with artificial late proximal tubular fluid and with harvested endogenous tubular fluid respectively. Dietary effects of the high sodium intake were measured by means of the systolic blood pressure (SBP), plasma volume (PV), and renal sodium excretion. The 4-week dietary treatment had no significant influence on SBP in WKY, whereas it accelerated the rise of SBP in SHR significantly. After 1 week of treatment, PV was increased in both WKY and SHR as compared with the control groups kept on the normal diet. Whereas PV in WKY declined to control values over the next 3 weeks, SHR remained expanded. GFR was similar in all groups, whereas urinary sodium excretion was significantly increased in salt-loaded SHR and WKY. Dietary salt loading was paralleled by the appearance of a TGF-inhibiting substance in the tubular fluid in SHR and WKY. However, when assayed with artificial late proximal tubular fluid, hyperreactivity was similar in normal and salt-loaded SHR as compared with WKY. Thus, in SHR TGF hyperreactivity is maintained in spite of volume expansion and TGF resetting by a humoral factor in tubular fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoregulation of the glomerular filtration rate and the single-nephron glomerular filtration rate despite inhibition of tubuloglomerular feedback in rats chronically volume-expanded by deoxycorticosterone acetate.

Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer's solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.

Glomerular tubular balance: mediation by luminal hypotonicity.

Late proximal rat tubular segments were microperfused with slightly hypo- or hypertonic artificial late proximal tubular fluid (ATF) at low (11-13 nl/min) or high (30-38 nl/min) perfusion rates. Volume reabsorption, net chloride and solute reabsorption were measured as a function of length. In addition, the transepithelial resistance and voltage (Vte) were measured as a function of the applied osmotic gradient. Hypertonic solutions equilibrated to isotonicity by solute outflow rather than water influx. With hypertonic ATF the lumen positive Vte was decreased compared with free flow or with hypotonic ATF. The resistance was not significantly different between the different groups. In contrast to hypotonic ATF, hypertonic or isotonic ATF was not significantly reabsorbed. In addition, hypotonic ATF maintained its hypotonicity along the perfused segments. Its reabsorption was flow-dependent. Hypotonicity appeared to enhance solute reabsorption.

Hemodynamic interactions between intrinsic blood flow control mechanisms in the rat kidney.

In order to reconcile the controversial concepts of myogenically and tubuloglomerular-feedback (TGF)-mediated control of renal vascular resistance, a hypothesis is advanced according to which both mechanisms interact hemodynamically because of their serial arrangement. Whereas the myogenic mechanism is suggested to be localized in the more upstream segments of the preglomerular resistance vessels, the TGF mechanism is assumed to control the pre- and/or postglomerular vascular segment(s), close to the glomerular vascular pole. The efferent vascular resistance, however, is assumed to function generally akin to a 'passive' flow resistor. These assumptions together with elementary hemodynamic considerations, allow formulation of a simple renal hemodynamic model whose quantitative predications regarding the characteristics of RBF, GFR and TGF control are remarkably consistent with the literature: (1) the magnitude of TGF response is mainly dependent upon the myogenic cooperative amplification and (2) although the TGF mechanism is not involved in the autoregulative control of RBF and GFR, changes of the TGF function may shift the autoregulation curve to higher or lower RBF and blood pressure levels.

The control of glomerular filtration rate and renal blood flow in chronically volume-expanded rats.

1. Chronic volume expansion by dietary salt loading practically abolishes tubuloglomerular feed-back (TGF) by means of a humoral inhibitor in tubular fluid. Elimination of the vasoconstrictor influence of feed-back does not, however, increase glomerular filtration rate (GFR) and renal blood flow (RBF), implying that chronic salt loading induces additional preglomerular vasoconstriction. This being so, the feed-back response which, although absent in free-flowing nephrons, can still be elicited by loop of Henle perfusion with Ringer solution, should be essentially normal, except that nephron GFR at any loop perfusion rate should be lower than in controls. Persistence of RBF, GFR and nephron GFR autoregulation would imply that autoregulation is achieved by a preglomerular resistance control system independent of feed-back. 2. These hypotheses were tested by clearance and micropuncture experiments in rats chronically fed a diet containing 40 g NaCl (kg food)-1. 3. RBF and GFR autoregulation indeed persisted, the former down to 90 mmHg compared with 105 mmHg in controls. In controls, nephron GFR measured distally was autoregulated down to 90 mmHg whereas that measured proximally was autoregulated only above 105 mmHg. In high-salt rats nephron GFR from both sites was autoregulated to 90 mmHg. 4. Loop of Henle perfusion with homologous tubular fluid in high-salt rats confirmed attenuation of feed-back. Loop perfusion with Ringer solution yielded a response comparable to that in controls (maximal reduction of nephron GFR to 57%, compared with 56% in controls). Absolute nephron GFR at any loop perfusion rate was lower in high-salt rats than in controls. 5. These observations confirm the initial hypotheses. Considering feed-back and autoregulation as independent, preglomerular resistance control mechanisms, together with elementary haemodynamic considerations, allows formulation of a renal haemodynamics model whose quantitative predictions regarding characteristics of RBF, GFR and feed-back control are remarkably consistent with the literature.

Resetting of tubuloglomerular feedback in acute volume expansion in rats.

Loss of sensitivity or "resetting" of tubulo-glomerular feedback has been reported after both acute and chronic volume expansion in rats. In chronic volume expansion due to dietary salt loading, resetting was found to result from the appearance of an inhibitory factor in tubular fluid. The aim of the present study was to test the possibility that resetting after acute isooncotic volume expansion may also be due to such an inhibitor. Rats were acutely volume expanded (4.5% of body weight) by infusion of a solution of fresh plasma and Ringer's solution. Tubuloglomerular feedback activity was assessed in expanded and control animals by measuring early proximal flow (EPF) rate during perfusion of the loop of Henle at varying rates with proximal tubular fluid harvested from the control (control TF) and expanded animals (AVE TF). When loops of Henle in control animals were perfused with control TF at 10, 20 or 40 nl min-1, EPF fell from (mean +/- SD) 29.8 +/- 5.6 at zero loop flow to 27.5 +/- 7.5, 21.1 +/- 4.2 and 15.5 +/- 4.5 nl min-1 gKW-1 respectively. Perfusion at the same rates with control TF in expanded animals reduced EPF from 39.5 +/- 9.6 (at zero loop flow) to 35.9 +/- 11.3, 31.6 +/- 4.3 and 22.9 +/- 6.8 nl min-1 gKW-1 respectively. When loops of Henle in control animals were perfused with AVE TF, EPF fell from 28.6 +/- 9.5 (zero loop flow) to 23.5 +/- 8.6, 19.9 +/- 8.2 and 15.6 +/- 6.5 nl min-1 gKW-1 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased tubuloglomerular feed-back mediated suppression of glomerular filtration during acute volume expansion in rats.

1. Volume expansion is currently believed to change the intrinsic properties of the juxtaglomerular apparatus such that the sensitivity of the tubuloglomerular feedback (TGF) mechanism is reduced, thus allowing glomerular filtration rate, and hence salt and water excretion, to rise. Recent studies conflict with this view and indeed the older literature reveals that the rise in glomerular filtration rate (GFR) under these conditions is far more modest than would be expected if TGF control were eliminated. 2. To investigate this problem, TGF control of filtration rate was examined by measuring single-nephron glomerular filtration rate (SNGFR) during loop of Henle perfusion at varying rates in rats under control conditions, after acute, moderate (4% of body weight), iso-oncotic volume expansion and in rats treated with antibodies to atrial natriuretic peptide (ANP) prior to the acute volume expansion. 3. With TGF control of filtration interrupted by filtrate collection from the proximal tubule, SNGFR in the expanded rats was massively increased compared with controls, although SNGFR measured in the distal tubule, and hence with TGF control intact, was only modestly increased, as was whole-kidney filtration rate. Loop perfusion at increasing rates up to 30 nl min-1 progressively decreased SNGFR in controls, and in the expanded rats the range over which control was exerted extended up to 60-80 nl min-1. For changes in loop flow around the spontaneous operating point, the sensitivity of the TGF mechanism, defined as delta SNGFR/delta loop flow, was similar in both groups. Treatment of rats with ANP antibodies prior to volume expansion substantially blunted the changes in renal salt and water excretion and the increase in SNGFR seen in the absence of loop perfusion. 4. These results are not consistent with a diminution of TGF function after volume expansion, rather with an enhancement. The latter is best accounted for by vasodilation of preglomerular resistance vessels on volume expansion, a result predicted by calculations from a model based on the serial arrangement of preglomerular and TGF-controlled vascular resistance elements and the established pharmacological actions of ANP.

The site of action of nitrendipine in the rat kidney.

Ample evidence suggests that Ca2+ antagonists like nitrendipine are capable of inducing mild diuresis and natriuresis in states predisposing to natriuresis, although there is disagreement on common possible sites or mechanisms of action. To clarify this situation, clearance, micropuncture, and microperfusion studies were undertaken on rats to establish whether nitrendipine inhibits sodium and fluid reabsorption in strict hydropenia, and if so, in which nephron segments this occurs. The clearance studies failed to show any specific effect on glomerular filtration rate, urine flow, or sodium excretion; mean arterial blood pressure was, however, dose-dependently depressed. Single nephron filtration rate, measured in the distal tubule, was also not altered, but fractional salt and water reabsorption up to that site were modestly reduced. Since microperfusion studies failed to show any inhibition of thick ascending limb transport, this implies a proximal inhibitory action, a conclusion confirmed by proximal microperfusion studies. Thus, in strict hydropenia, nitrendipine inhibits proximal salt and water reabsorption, but the increased distal load is completely compensated by distal tubular and collecting duct mechanisms such that urinary electrolyte excretion is unaltered.

The effect of muzolimine on the tubuloglomerular feedback mechanism in the rat kidney.

Inhibition of tubuloglomerular feedback (TGF) by loop diuretics can enhance the diuretic response by attenuating the fall in GFR to be expected with the diuretic-induced rise in distal salt delivery. To establish whether such a mechanism contributes to muzolimine (M)-induced diuresis, TGF activity was tested in male Wistar rats by measuring early proximal flow rate in nephrons, the loops of Henle of which were perfused with M at various concentrations in the presence or absence of M systemically. Since M inhibited TGF only at concentrations far in excess of those adequate to produce substantial diuresis, it is concluded that TGF inhibition by M plays no significant role in the diuretic response to this agent.

Resetting of tubuloglomerular feedback: evidence for a humoral factor in tubular fluid.

Experiments were performed on chronically salt-loaded rats to determine whether resetting of tubuloglomerular feedback is caused by changes in the sensitivity of the juxtaglomerular apparatus itself or by changes of tubular fluid composition. The feedback response was quantified in both salt-loaded and salt-deplete rats by measuring early proximal flow rate (EPF) during loop perfusion at 40, 10, and 0 nl/min using tubular fluid harvested from both groups and with Ringer solution. In salt-loaded rats endogenous tubular fluid produced only a small feedback response (EPF40-0 = 1.9 +/- 1.5 nl/min), whereas exogenous tubular fluid from salt-deplete rats or Ringer solution produced normal feedback responses (EPF40-0 = 15.4 +/- 2.0 and 10.6 +/- 1.7 nl/min, respectively). In salt-deplete rats, endogenous tubular fluid and Ringer solution produced feedback responses of similar magnitude (EPF40-0 = 14.2 +/- 1.8 and 13.0 +/- 2.0 nl/min, respectively) but exogenous tubular fluid from salt-loaded rats elicited only a small feedback response (EPF40-0 = 1.5 +/- 1.6 nl/min), indistinguishable from that seen in salt-loaded rats with endogenous tubular fluid. It is concluded that an inhibitory factor in the tubular fluid of chronically salt-loaded rats causes a reduction in tubuloglomerular feedback response.