Inhibition Of Tubuloglomerular Feedback Research Articles

Role of the macula densa sodium glucose cotransporter type 1-neuronal nitric oxide synthase-tubuloglomerular feedback pathway in diabetic hyperfiltration

An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus invitro, micropuncture of kidney tubules invivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

Synthetic oleanane triterpenoids: magic bullets or not?

A recent clinical trial in patients with chronic kidney disease (CKD) and diabetic nephropathy demonstrated that bardoxolone methyl (CDDO-ME) increases estimated glomerular filtration rate (eGFR) by an unknown mechanism. The paper by Ding et al. suggests that short-term administration of a CDDO-ME analog increases GFR by increasing glomerular surface area. However, changes in other renal hemodynamic parameters cannot be excluded. Vigorous testing of CDDO-ME and highly purified analogs is warranted to determine their physiology, pharmacology, and efficacy and to exclude serious side effects.

Role of connexin40 in the autoregulatory response of the afferent arteriole

Connexins in renal arterioles affect autoregulation of arteriolar tonus and renal blood flow and are believed to be involved in the transmission of the tubuloglomerular feedback (TGF) response across the cells of the juxtaglomerular apparatus. Connexin40 (Cx40) also plays a significant role in the regulation of renin secretion. We investigated the effect of deleting the Cx40 gene on autoregulation of afferent arteriolar diameter in response to acute changes in renal perfusion pressure. The experiments were performed using the isolated blood perfused juxtamedullary nephron preparation in kidneys obtained from wild-type or Cx40 knockout mice. Renal perfusion pressure was increased in steps from 75 to 155 mmHg, and the response in afferent arteriolar diameter was measured. Hereafter, a papillectomy was performed to inhibit TGF, and the pressure steps were repeated. Conduction of intercellular Ca(2+) changes in response to local electrical stimulation was examined in isolated interlobular arteries and afferent arterioles from wild-type or Cx40 knockout mice. Cx40 knockout mice had an impaired autoregulatory response to acute changes in renal perfusion pressure compared with wild-type mice. Inhibition of TGF by papillectomy significantly reduced autoregulation of afferent arteriolar diameter in wild-type mice. In Cx40 knockout mice, papillectomy did not affect the autoregulatory response, indicating that these mice have no functional TGF. Also, Cx40 knockout mice showed no conduction of intercellular Ca(2+) changes in response to local electrical stimulation of interlobular arteries, whereas the Ca(2+) response to norepinephrine was unaffected. These results suggest that Cx40 plays a significant role in the renal autoregulatory response of preglomerular resistance vessels.

Acute saline expansion increases nephron filtration and distal flow rate but maintains tubuloglomerular feedback responsiveness: role of adenosine A1 receptors

Temporal adaptation of tubuloglomerular feedback (TGF) permits readjustment of the relationship of nephron filtration rate [single nephron glomerular filtration rate (SNGFR)] and early distal tubular flow rate (V(ED)) while maintaining TGF responsiveness. We used closed-loop assessment of TGF in hydropenia and after acute saline volume expansion (SE; 10% body wt over 1 h) to determine whether 1) temporal adaptation of TGF occurs, 2) adenosine A(1) receptors (A(1)R) mediate TGF responsiveness, and 3) inhibition of TGF affects SNGFR, V(ED), or urinary excretion under these conditions. SNGFR was evaluated in Fromter-Wistar rats by micropuncture in 1) early distal tubules (ambient flow at macula densa), 2) recollected from early distal tubules while 12 nl/min isotonic fluid was added to late proximal tubule (increased flow to macula densa), and 3) from proximal tubules of same nephrons (zero flow to macula densa). SE increased both ambient SNGFR and V(ED) compared with hydropenia, whereas TGF responsiveness (proximal-distal difference in SNGFR, distal SNGFR response to adding fluid to proximal tubule) was maintained, demonstrating TGF adaptation. A(1)R blockade completely inhibited TGF responsiveness during SE and made V(ED) more susceptible to perturbation in proximal tubular flow, but did not alter ambient SNGFR or V(ED). Greater urinary excretion of fluid and Na(+) with A(1)R blockade may reflect additional effects on the distal nephron in hydropenia and SE. In conclusion, A(1)R-independent mechanisms adjust SNGFR and V(ED) to higher values after SE, which facilitates fluid and Na(+) excretion. Concurrently, TGF adapts and stabilizes early distal delivery at the new setpoint in an A(1)R-dependent mechanism.

Carbon monoxide inhibits tubuloglomerular feedback in vivo by activation of soluble guanylyl cyclase

We have previously shown in vitro that carbon monoxide (CO) inhibits tubuloglomerular feedback (TGF), but how this happens is not known. We hypothesized that CO in vivo inhibits TGF by activating the soluble guanylyl cyclase (sGC)/cyclic guanosine 3′, 5′‐monophosphate (cGMP) system. Renal micropuncture studies were performed in male Sprague Dawley rats. TGF was induced by increasing late proximal perfusion rate (0, 10, 20, 30, 40 nL/min) while measuring stop‐flow pressure (PSF) as an index of single nephron glomerular filtration. We measured the effect of a CO‐donor, CORM‐3 (50 μM) on PSFmax with and without inhibition of sGC using the sGC inhibitor LY83583 (1 μM). First, we demonstrated that the PSF response to increased tubular perfusion rate was reversible and reproducible. Next, we found CORM‐3 blunted the TGF response, as the maximum change in PSF was 6.9 ± 0.2 mmHg in controls, but only 3.9 ± 0.4 mmHg in CORM‐3 treated tubules (p < 0.001). However, with addition of LY83583 to the perfusate, the effect of CORM‐3 was eliminated. Addition of LY83583 potentiated the TGF response by 28% (8.4 ± 0.3 mmHg, p < 0.001), and it also reversed the blunting effect of CORM‐3 (8.3 ± 0.4 mmHg, p < 0.001) to a similar extent. From these data, we conclude that inhibition of TGF by CO in vivo is mediated by activation of the sGC/cGMP system. This study was supported by National Institutes of Health Grant HL‐090550.

Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice

Loop diuretics like furosemide have been shown to cause renal vasodilatation in dogs and humans, an effect thought to result from both a direct vascular dilator effect and from inhibition of tubuloglomerular feedback. In isolated perfused afferent arterioles preconstricted with angiotensin II or N(G)-nitro-L-arginine methyl ester, furosemide caused a dose-dependent increase of vascular diameter, but it was without effect in vessels from NKCC1-/- mice suggesting that inhibition of NKCC1 mediates dilatation in afferent arterioles. In the intact kidney, however, furosemide (2 mg/kg iv) caused a 50.5 +/- 3% reduction of total renal blood flow (RBF) and a 27% reduction of superficial blood flow (SBF) accompanied by a marked and immediate increase of tubular pressure and volume. At 10 mg/kg, furosemide reduced RBF by 60.4 +/- 2%. Similarly, NKCC1-/- mice responded to furosemide with a 45.4% decrease of RBF and a 29% decrease of SBF. Decreases in RBF and SBF and increases of tubular pressure by furosemide were ameliorated by renal decapsulation. In addition, pretreatment with candesartan (2 mg/kg) or indomethacin (5 mg/kg) attenuated the reduction of RBF and peak urine flows caused by furosemide. Our data indicate that furosemide, despite its direct vasodilator potential in isolated afferent arterioles, causes a marked increase in flow resistance of the vascular bed of the intact mouse kidney. We suggest that generation of angiotensin II and/or a vasoconstrictor prostaglandin combined with compression of peritubular capillaries by the expanding tubular compartment are responsible for the reduction of RBF in vivo.

Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback

This rat renal blood flow (RBF) study quantified the impact of nitric oxide synthase (NOS) inhibition on the myogenic response and the balance of autoregulatory mechanisms in the time domain following a 20 mmHg-step increase or decrease in renal arterial pressure (RAP). When RAP was increased, the myogenic component of renal vascular resistance (RVR) rapidly rose within the initial 7-10 s, exhibiting an approximately 5 s time constant and providing approximately 36% of perfect autoregulation. A secondary rise between 10 and 40 s brought RVR to 95% total autoregulatory efficiency, reflecting tubuloglomerular feedback (TGF) and possibly one or two additional mechanisms. The kinetics were similar after the RAP decrease. Inhibition of NOS (by l-NAME) increased RAP, enhanced the strength (79% autoregulation) and doubled the speed of the myogenic response, and promoted the emergence of RVR oscillations ( approximately 0.2 Hz); the strength (52%) was lower at control RAP. An equi-pressor dose of angiotensin II had no effect on myogenic or total autoregulation. Inhibition of TGF (by furosemide) abolished the l-NAME effect on the myogenic response. RVR responses during furosemide treatment, assuming complete inhibition of TGF, suggest a third mechanism that contributes 10-20% and is independent of TGF, slower than the myogenic response, and abolished by NOS inhibition. The hindlimb circulation displayed a solitary myogenic response similar to the kidney (35% autoregulation) that was not enhanced by l-NAME. We conclude that NO normally restrains the strength and speed of the myogenic response in RBF but not hindlimb autoregulation, an action dependent on TGF, thereby allowing more and slow RAP fluctuations to reach glomerular capillaries.

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

Vasopeptidase inhibitors are a novel class of antihypertensive agents that concomitantly inhibit angiotensin converting enzyme and neutral endopeptidase. Our purpose was to investigate the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and tubuloglomerular feedback (TGF) response in anesthetized 9-10-week-old spontaneously hypertensive rats (SHR). Intravenous injection of omapatrilat at 10 micromol/kg decreased systemic blood pressure and renal vascular resistance. Renal plasma flow was unchanged, whereas glomerular filtration rate (GFR) and filtration fraction (FF) were reduced. Increased urinary sodium excretion of tubular origin was observed. These parameters remained unaltered with vehicle treatment. Micropuncture study revealed that the maximal reduction of early proximal flow rate (EPFR) induced by orthograde perfusion of Henle's loop with artificial tubular fluid (ATF) was significantly reduced by omapatrilat treatment (28.5+/-3.1% vs. 72.0+/-2.8% of control) and was not significantly changed in the vehicle-treated group (vehicle 70.8+/-1.7% vs. control 71.0+/-2.1%). EPFR at zero perfusion was comparable between omapatrilat and vehicle treatment (29.7+/-2.2 vs. 31.3+/-2.1 nl/min, respectively). Luminal perfusion of 10(-4) mol/l 7-nitroindazole in ATF abrogated the blunting of TGF response by omapatrilat but elicited no change in the vehicle-treated group. The suppression of the TGF mechanism and the reduction in FF suggest that omapatrilat respectively dilates the afferent and efferent arterioles. Under such conditions, reduction of GFR may indicate a fall in intraglomerular pressure. The restoration of nitric oxide signaling in the juxtaglomerular apparatus of SHR seems to participate in the inhibition of TGF by omapatrilat. These findings suggest that omapatrilat may provide a novel approach to the treatment of systemic and glomerular hypertension.

Dynamics and contribution of mechanisms mediating renal blood flow autoregulation.

We investigated dynamic characteristics of renal blood flow (RBF) autoregulation and relative contribution of underlying mechanisms within the autoregulatory pressure range in rats. Renal arterial pressure (RAP) was reduced by suprarenal aortic constriction for 60 s and then rapidly released. Changes in renal vascular resistance (RVR) were assessed following rapid step reduction and RAP rise. In response to rise, RVR initially fell 5-10% and subsequently increased approximately 20%, reflecting 93% autoregulatory efficiency (AE). Within the initial 7-9 s, RVR rose to 55% of total response providing 37% AE, reaching maximum speed at 2.2 s. A secondary RVR increase began at 7-9 s and reached maximum speed at 10-15 s. Response times suggest that the initial RVR reflects the myogenic response and the secondary tubuloglomerular feedback (TGF). During TGF inhibition by furosemide, AE was 64%. The initial RVR rise was accelerated and enhanced, providing 49% AE, but it represented only 88% of total. The remaining 12% indicates a third regulatory component. The latter contributed up to 50% when the RAP increase began below the autoregulatory range. TGF augmentation by acetazolamide affected neither AE nor relative myogenic contribution. Diltiazem infusion markedly inhibited AE and the primary and secondary RVR increases but left a slow component. In response to RAP reduction, initial vasodilation constituted 73% of total response but was not affected by furosemide. The third component's contribution was 9%. Therefore, RBF autoregulation is primarily due to myogenic response and TGF, contributing 55% and 33-45% in response to RAP rise and 73% and 18-27% to RAP reduction. The data imply interaction between TGF and myogenic response affecting strength and speed of myogenic response during RAP rises. The data suggest a third regulatory system contributing <12% normally but up to 50% at low RAP; its nature awaits further investigation.

Effect of the Selective Adenosine A1Receptor Antagonist KW-3902 on Tubuloglomerular Feedback in Radiocontrast-Media-Induced Nephropathy in Rats With Chronic Nitric Oxide Deficiency

To study the possible mechanism of renoprotective effects of adenosine A1-receptor antagonist against radiocontrast media (RCM)-induced nephropathy, we investigated the effects of adenosine A1-receptor antagonist on tubuloglomerular feedback (TGF) activity prior to and following application of RCM in chronic NO-depleted rats. TGF in NO-depleted rats was significantly enhanced compared with that in normal rats. After RCM application, the enhanced TGF was continued. A selective adenosine A1-receptor antagonist, KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), inhibited the enhanced TGF. These results suggest that KW-3902 could inhibit TGF in chronic NO-depleted rats. Renoprotective effects by adenosine antagonists could be partly due to an inhibition of TGF via the blockade of the adenosine A1-receptor.

Pharmacological modulation of spontaneous renal blood flow dynamics

Two mechanisms contribute to renal autoregulation. The faster system, which is thought to be myogenic, operates at 0.1-0.2 Hz (i.e., 5-10 s/cycle), while the slower one, tubuloglomerular feedback, operates at 0.03-0.05 Hz (i.e., 20-30 s/cycle). Both attenuate spontaneous or induced fluctuations of blood pressure, but it has proven difficult to separate their individual contributions because there is potential for interaction between the two. The present study was designed to examine the dynamics of the faster system during pharmacological blockade of tubuloglomerular feedback. Normotensive and hypertensive rats were studied under isoflurane or halothane anesthesia. Administration of the loop diuretic furosemide plus the angiotensin II (ANGII) AT1 receptor antagonist losartan caused a 10-fold or greater natriuresis, indicating profound inhibition of ascending limb salt transport, and also produced characteristic changes in the transfer function relating blood pressure (input) to renal blood flow (output). Operation of the 0.1-0.2 Hz mechanism was essentially unaltered, as shown by the presence of a peak in phase angle at 0.1-0.2 Hz and reduction of gain at frequencies slower than 0.15 Hz. The 0.03-0.05 Hz mechanism was markedly inhibited, as shown by loss of the second phase angle peak at 0.03-0.05 Hz, loss of the local maximum in gain at 0.05 Hz, and loss of the second gain reduction below 0.05 Hz. Both during control and after inhibition of tubuloglomerular feedback, the 0.1-0.2 Hz system attenuated = 50% of the effects of spontaneous blood pressure fluctuations, suggesting that this mechanism, operating alone, can significantly stabilize renal blood flow in the face of spontaneous fluctuations of blood pressure.

Mechanisms of temporal variation in single-nephron blood flow in rats.

Modified laser-Doppler velocimetry was used to determine the number of different mechanisms regulating single-nephron blood flow. Two oscillations were identified in star vessel blood flow, one at 20-50 mHz and another at 100-200 mHz. Tubuloglomerular feedback (TGF) mediates the slower oscillation, and the faster one is probably myogenic in origin. Acute hypertension increased autospectral power in the 20-50 mHz and 100-200 mHz frequency bands to 282 +/- 50 and 248 +/- 64%, respectively, of control even though mean single-nephron blood flow was autoregulated. Mean blood flow increased 24.6 +/- 6.1% when TGF was inhibited by intratubular perfusion with furosemide, and it decreased 42.8 +/- 3.9% when TGF was saturated by tubular perfusion with artificial tubular fluid at high rates. Autospectral power in the low-frequency band decreased 50.5 +/- 9.6% during furosemide and decreased 74.9 +/- 5.9% during TGF saturation, consistent with a TGF origin of the slow oscillation. In contrast, autospectral power of the high-frequency oscillation increased 75.4 +/- 23.9% during TGF inhibition and decreased 35.8 +/- 11% when TGF was saturated, suggesting interactions between the two spontaneously oscillating components in efferent arteriole blood flow.

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.

Tubuloglomerular feedback dependence of autoregulation in rat juxtamedullary afferent arterioles

Experiments were performed in blood-perfused juxtamedullary nephrons in vitro to evaluate the tubuloglomerular feedback (TGF) dependence of autoregulatory vasoconstriction in mid-to-late (mAA) and juxtaglomerular (jAA) afferent arterioles. Videometric measurements were made of perfusion pressure (PP) dependent changes in lumen diameter of superficial vessels before and after acute inhibition of the TGF mechanism by direct microinfusion of 0.1 mM furosemide solution into the macula densa (MD) segment. When PP was raised from 60 to 123 +/- 7 mm Hg in seven vessels, jAA diameter decreased by 29 +/- 3% (SEM, N = 7). During furosemide infusion with the same change in PP, jAA diameter decreased only 7 +/- 2%. After calcium channel blockade with 1 micromolar nimodipine, jAA lumen diameter increased by 21 +/- 7%. A similar pattern of responses was observed in eight jAA where TGF was inhibited with an oil block at the MD. mAA autoregulatory responses were also blunted by TGF inhibition. Raising PP from 60 to 120 mm Hg resulted in 15 +/- 2% and 7 +/- 2% decreases in mAA luminal diameter before and after TGF inhibition. These results demonstrate that the autoregulatory responses in mid- and juxtaglomerular afferent arteriolar segments are mediated by both TGF and a TGF-independent myogenic mechanism.

Inhibition of tubuloglomerular feedback during adenosine1 receptor blockade

Experiments were performed in anesthetized rats to study the effect of the selective adenosine1 (A1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) on tubuloglomerular feedback (TGF) responses assessed as the maximum change of stop-flow pressure (PSF). Compared with control, PSF responses were reduced during luminal application of CPX at 10(-4) and 10(-5)M (-4.9 +/- 0.44 vs. + 0.9 +/- 0.42 mmHg and -6.8 +/- 0.69 vs. -1.4 +/- 0.7 mmHg, respectively), during peritubular administration of CPX at 10(-4)M (-6.2 +/- 0.44 vs. -2.8 +/- 0.42 mmHg), and during infusion of CPX at 10(-4) M into the lumen of a neighboring nephron (-5.6 +/- 0.6 vs. -1.98 +/- 0.51 mmHg). Selectivity of CPX was tested by studying its effect on the PSF reduction produced by the A1-receptor agonist N6-cyclohexyladenosine (CHA). CHA at 10(-5)M reduced PSF when infused into the peritubular blood (-11.8 +/- 3.7 mmHg), and this effect was blunted by luminal application of CPX (-1.5 +/- 0.6 mmHg). CHA also reduced PSF when infused into a neighboring nephron, and this effect was blunted by infusing CPX at 10(-4)M into the same neighboring nephron, a different neighboring nephron, or a peritubular capillary. These results are consistent with the concept that activation of A1-receptors on vascular cells of the afferent arterioles participates in the mediation of TGF responses.

Tubuloglomerular feedback and blood flow autoregulation during DA1-induced renal vasodilation

The effect of renal vasodilation produced by the dopamine DA1-receptor agonist, fenoldopam (SKF-82526), on tubuloglomerular feedback (TGF) activity and the autoregulation of renal blood flow (RBF) was determined in euvolemic rats. Fenoldopam (2.5 micrograms.kg-1.min-1 iv) increased RBF by 17% (electromagnetic flow probe) while glomerular filtration rate (GFR) was unchanged; mean arterial pressure was decreased by 6%. Superficial cortical blood flow was increased by 12% (laser-Doppler flowmetry) while single-nephron GFR (SNGFR) and estimated glomerular capillary pressure (stop-flow pressure, Psf) were stable. SNGFR measured at proximal and distal sites along the same nephron was not affected by fenoldopam. Partial inhibition of TGF was indicated by the constancy of distal SNGFR and the proximal-distal SNGFR difference in the presence of increased distal delivery of native fluid. However, fenoldopam did not affect feedback control of Psf evaluated by perfusing artificial fluid through Henle's loop at 0-62 nl/min. Despite the decrease in renal vascular resistance over an arterial pressure range of 130 to 70 mmHg, RBF was autoregulated efficiently during fenoldopam infusion. These results indicate that DA1-receptor activation dilates the preglomerular and efferent arterioles without affecting GFR or glomerular pressure. However, this vasodilatory mechanism operates independent of autoregulation and TGF-induced changes in glomerular pressure such that preglomerular vessels remain responsive to the appropriate signals from these intrinsic control systems. The ability of fenoldopam to blunt feedback control of SNGFR may depend on changes in the filtration coefficient independent of glomerular pressure and/or a constituent of natural tubular fluid.

Native tubular fluid attenuates ANF-induced inhibition of tubuloglomerular feedback

The effect of atrial natriuretic factor [ANF-(1-28); 0.25 microgram.kg-1.min-1] on tubuloglomerular feedback (TGF) and the efficiency of renal blood flow (RBF) autoregulation was determined in anesthetized euvolemic rats. In microperfusion studies, ANF dramatically inhibited (greater than 80%) feedback-mediated decreases in single-nephron glomerular filtration rate (SNGFR) and stop-flow pressure (Psf) when Henle's loop was perfused at 0-48 nl/min with artificial fluid. The sigmoidal relationship between Psf and loop perfusion during control was shifted to a linear relation during ANF; reactivity was almost nonexistent and no inflection point could be discerned. ANF almost completely blocked maximum Psf and SNGFR responses to loop perfusion at rates greater than 24 nl/min. In contrast 30 nl/min loop perfusion with native proximal tubular fluid obtained during ANF infusion restored maximum TGF activity to 70% of control levels. During ANF administration, the paired Psf responses to native and artificial perfusate were significantly different (-5.3 vs. -0.8 mmHg, P less than 0.001), compared with similar responses during control conditions (-7.6 vs. -8.3 mmHg, P greater than 0.1). In free-flow studies, ANF increased proximally and distally measured SNGFR equally. The constancy of the proximal-distal SNGFR difference (10.3 vs. 9.3 nl/min) in the presence of increased distal fluid delivery suggests partial inhibition of TGF during ANF administration. ANF elevated Psf but did not affect basal RBF or the RBF autoregulatory index over an arterial pressure range of 130-70 mmHg. These results indicate that 1) RBF autoregulation is efficiently maintained during ANF infusion when preglomerular vessels are vasodilated and TGF is inhibited by approximately 30%; 2) an endogenous factor(s) in native proximal tubular fluid may attenuate ANF-induced inhibition of TGF; and 3) microperfusion studies using artificial fluid significantly overestimate the net in vivo effect of ANF on TGF.

GFR regulation and flow-dependent electrophysiology of early distal tubule in Amphiuma.

Tubuloglomerular feedback (TGF) in mammals and amphibians senses flow-dependent concentration changes in tubular fluid of the distal tubule and signals to arterioles to initiate changes in glomerular filtration rate. The distal tubules and afferent arterioles are situated on the surface of the kidney of Amphiuma means. Micropuncture techniques were used to measure luminal and intracellular chloride concentrations and the associated electrical potential differences, while tubular perfusion rate was varied. Transepithelial potential difference (PDte) and basolateral potential difference (PDbl) became more positive at increased tubular flow rates. Intratubular and intracellular chloride concentrations also increased significantly with perfusion rate. Single-nephron glomerular filtration rate decreased when perfusion rate was increased but this response was eliminated by the inclusion of furosemide in the perfusion solution; the drug also inhibited the flow dependence of PDte. The results suggest that local changes in PD and Cl- activity result from flow-dependent changes in the rate of hypertonic NaCl transport propagated along the length of the perfused segment; they establish a correlation between the rate of transport and the magnitude of the TGF inhibition; and, because transport and TGF can be jointly inhibited, they suggest a causal link between the two.

Interaction between renal prostaglandins and angiotensin II in controlling glomerular filtration in the dog.

Although previous studies suggest that the renal vasoconstrictor effects of angiotensin II (ANG II) are normally confined to the efferent arterioles, the mechanisms that prevent ANG II from constricting preglomerular vessels are still unclear. In the present study, the role of prostaglandins (PG) in protecting preglomerular vessels from ANG II constriction was examined in dogs with normal or non-filtering kidneys in which ANG II formation was blocked with captopril and renal artery pressure was servo-controlled at 75-80 mmHg. Before PG blockade (n = 6), ANG II infusion (20 ng min-1 kg-1) decreased renal blood flow (RBF) by 54 +/- 4%, but did not change glomerular filtration rate (GFR) significantly. After PG blockade (n = 6), ANG II infusion decreased GFR by 37 +/- 7% and RBF by 56 +/- 6%, while increasing calculated preglomerular resistance much more than before PG blockade. In another group of dogs, secondary changes in renal resistances, due to tubuloglomerular feedback, were prevented by occluding the ureter during mannitol diuresis until glomerular filtration ceased. After inhibition of tubuloglomerular feedback in non-filtering kidneys (n = 7), ANG II decreased RBF by 40 +/- 3% and increased glomerular hydrostatic pressure, estimated from stop-flow ureteral pressure and plasma colloid osmotic pressure, by 8.7 +/- 1.7 mmHg. Postglomerular resistance increased by 91 +/- 12% while preglomerular resistance was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubuloglomerular feedback control of distal fluid delivery: effect of extracellular volume.

A closed-feedback loop micropuncture method was used to examine tubuloglomerular feedback (TGF) and the regulation of distal fluid delivery in hydropenic rats (CON), moderately hemorrhaged rats (HEM), and rats given desoxycorticosterone (DOC) and 0.6% saline to drink. Distal delivery and TGF response curves were measured with four samples per nephron: a spontaneous early distal collection, two distal collections during moderate (7.5 nl/min) and saturating (30 nl/min) perturbations in nephron fluid load, and a proximal collection to measure single-nephron glomerular filtration rate (SNGFR) during TGF inhibition. Arterial pressure, predistal volume reabsorption, SNGFR, and early distal flow were significantly higher in DOC than in HEM; the CON group exhibited intermediate values. Except for a greater maximum TGF response in HEM, the normalized TGF responses were similar in all three groups, as was the regulation of distal fluid delivery. However, the TGF onset threshold and the TGF operating point, defined by the spontaneous rates of early distal flow and SNGFR, were reset such that distal fluid delivery and SNGFR were higher in DOC than in HEM, as was renal sodium excretion. The results show that the level around which TGF stabilizes distal fluid delivery is reset when extracellular fluid volume is altered.