Abstract 490: Constrictor Mechanism of the Afferent Arteriole Initiated by Na/H Exchanger in the Nephron

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hong Wang ◽  
Martin A D'Ambrosio ◽  
YiLin Ren ◽  
Jeffrey L Garvin ◽  
Oscar A Carretero
Keyword(s):  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Na Channel ◽  
Afferent Arteriole ◽  
Renal Vasculature ◽  
Connecting Tubule ◽  
Flow Pressure ◽  
Stop Flow ◽  
Epithelial Na Channel

The afferent arteriole (Af-Art) accounts for most of renal vasculature resistance, thus controlling glomerular filtration rate and renal function. Two mechanisms have been described in which the nephron helps control Af-Art resistance, namely tubuloglomerular feedback (TGF), and connecting tubule glomerular feedback (CTGF). TGF is a constrictor mechanism initiated at the macula densa by the Na/K/2Cl cotransporter (NKCC2), while CTGF is a dilator mechanism initiated at the connecting tubule by the epithelial Na channel (ENaC). However, when NKCC2 is blocked by furosemide, CTGF-induced Af-Art dilation is not evident, thus we hypothesize that there is a constrictor mechanism that is furosemide-insensitive and counters CTGF. To test this, we used in vivo micropuncture of single nephrons. Stop-flow pressure (P SF ) was measured as an index of glomerular capillary pressure (which decreases when the Af-Art constricts). Two consecutive P SF curves were generated by raising nephron perfusion from 0 to 40 nL/min while adding drugs to the tubular perfusate. The decrease in P SF induced by increasing nephron perfusion was blocked by furosemide 10 -4 M (control: 7.9±0.2 mmHg, furosemide: 0.4±0.2 mmHg, P <0.001, n=6), but was partially restored when blocking CTGF with the ENaC inhibitor benzamil 10 -6 M (furosemide: 0.2±0.1 mmHg, furosemide+benzamil: 4.3±0.3 mmHg, P <0.001, n=6). A possible explanation for these observations is that TGF may be activated to some degree by Na/H exchanger (NHE)-mediated Na entry at the macula densa when NKCC2 is blocked. When we added the NHE blocker dimethylamiloride (DMA, 10 -4 M) in the presence of furosemide and benzamil, the decrease in PSF was significantly prevented (furosemide+benzamil: 4.6±0.3 mmHg, furosemide+benzamil+DMA: 1.1±0.2 mmHg, P <0.001, n=6). Therefore, we conclude that a constrictor mechanism of the Af-Art is initiated by NHE in the nephron and is observable when NKCC2-mediated TGF and ENaC-mediated CTGF have been blocked.

scholarly journals Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo

2010 ◽  
Vol 299 (6) ◽  
pp. F1374-F1378 ◽  
Author(s):  
H. Wang ◽  
J. L. Garvin ◽  
M. A. D'Ambrosio ◽  
Y. Ren ◽  
O. A. Carretero
Keyword(s):  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
In Vitro Experiments ◽  
Nacl Transport ◽  
Connecting Tubule ◽  
Vasoconstrictor Effect ◽  
Flow Pressure ◽  
Stop Flow

In vitro experiments showed that the connecting tubule (CNT) sends a signal that dilates the afferent arteriole (Af-Art) when Na+ reabsorption in the CNT lumen increases. We call this process CNT glomerular feedback (CTGF) to differentiate it from tubuloglomerular feedback (TGF), which is a cross talk between the macula densa (MD) and the Af-Art. In TGF, the MD signals the Af-Art to constrict when NaCl transport by the MD is enhanced by increased luminal NaCl. CTGF is mediated by CNT Na+ transport via epithelial Na+ channels (ENaC). However, we do not know whether CTGF occurs in vivo or whether it opposes the increase in Af-Art resistance caused by TGF. We hypothesized that CTGF occurs in vivo and opposes TGF. To test our hypothesis, we conducted in vivo micropuncture of individual rat nephrons, measuring stop-flow pressure (PSF) as an index of glomerular filtration pressure. To test whether activation of CTGF opposes TGF, we used benzamil to block CNT Na+ transport and thus CTGF. CTGF inhibition with the ENaC blocker benzamil (1 μM) potentiated the decrease in PSF at 40 and 80 nl/min. Next, we tested whether we could augment CTGF by inhibiting NaCl reabsorption in the distal convoluted tubule with hydrochlorothiazide (HCTZ, 1 mM) to enhance NaCl delivery to the CNT. In the presence of HCTZ, benzamil potentiated the decrease in PSF at 20, 40, and 80 nl/min. We concluded that in vivo CTGF occurs and opposes the vasoconstrictor effect of TGF.

Abstract P325: Enhanced Afferent Arteriole Dilatation in Dahl Salt-sensitive Rats (dahlss): Role of Connecting Tubule Glomerular Feedback (ctgf)

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hong Wang ◽  
Cesar A Romero ◽  
Branislava Janic ◽  
Edwards Peterson ◽  
Oscar A Carretero
Keyword(s):  
Indirect Measurement ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
High Salt Diet ◽  
Connecting Tubule ◽  
Simultaneous Inhibition ◽  
Flow Pressure ◽  
Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by 2 intrinsic nephron feedbacks: the vasoconstrictor tubuloglomerular feedback (TGF) and the vasodilator CTGF. TGF is mediated by NKCC2 channel in the macula densa and blocked by furosemide; and CTGF is mediated by ENaC in the connecting tubule and blocked by benzamil. Previously we measured CTGF indirectly, by differences between TGF response with and without CTGF blocker benzamil. Thus, using this indirect measurement we reported that Dahl SS have greater CTGF than Dahl salt-resistant rats (Dahl SR). We have recently developed a new method to measure CTGF more directly and we found that when we simultaneously blocked TGF with furosemide and CTGF with benzamil, the increasing tubular perfusion caused Af-Art constriction (TGF-like) that is mediated by the NHE. W e hypothesize that in vivo during simultaneous inhibition of NKCC2 and the NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (P SF ) and that is greater in Dahl SS than in Dahl SR in a high salt diet. In the presence of furosemide alone, increasing nephron perfusion did not change the P SF in neither Dahl SS nor Dahl SR. When we blocked both, NKCC2 with furosemide and NHE with DMA, increase in tubular flow caused Af-Art dilation that was demonstrated by an increase in P SF . This increase was greater in Dahl SS (5.1±0.4 mmHg) than in Dahl SR (2.9±0.3 mmHg; P < 0.01), (Fig).We confirm that CTGF causes this vasodilation, since benzamil completely blocked this effect. We conclude that during inhibition of NKCC2 and NHE in the nephron CTGF (Af-Art dilatation) is enhanced in Dahl SS as compared to Dahl SR.

scholarly journals Connecting tubule glomerular feedback mediates acute tubuloglomerular feedback resetting

2012 ◽  
Vol 302 (10) ◽  
pp. F1300-F1304 ◽  
Author(s):  
Hong Wang ◽  
Martin A. D'Ambrosio ◽  
Jeffrey L. Garvin ◽  
Yilin Ren ◽  
Oscar A. Carretero
Keyword(s):  
Carbonic Anhydrase ◽  
Proximal Tubule ◽  
Sodium Channels ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Epithelial Sodium Channels ◽  
Connecting Tubule ◽  
Before And After ◽  
Flow Pressure ◽  
Stop Flow

Tubuloglomerular feedback (TGF) and connecting tubule glomerular feedback (CTGF) are mechanisms that control afferent arteriole (Af-Art) tone. TGF, initiated by increased NaCl at the macula densa, causes Af-Art constriction. Prolonged activation of TGF leads to an attenuation or “resetting” of its constrictor effect. The mechanisms of TGF resetting remain incompletely understood. CTGF is initiated by increased NaCl in the connecting tubule and Na+ entry via epithelial sodium channels (ENaC). Contrary to TGF, CTGF dilates the Af-Art. Here, we hypothesize that CTGF, in part, mediates TGF resetting. We performed micropuncture of individual rat nephrons while measuring stop-flow pressure (PSF), an index of glomerular filtration pressure and Af-Art tone. Increases in Af-Art tone cause PSF to decrease. TGF responses, measured as the decrease in PSF induced by switching late proximal tubule perfusion from 5 to 40 nl/min, were elicited before and after a 30-min period of sustained perfusion of the late proximal tubule at a rate of 40 nl/min designed to induce TGF resetting. TGF responses were 7.3 ± 0.3 and 4.9 ± 0.2 mmHg before and after resetting was induced ( P < 0.001, n = 6). When CTGF was inhibited with the ENaC blocker benzamil (1 μM), TGF responses were 9.5 ± 0.3 and 8.8 ± 0.6 mmHg (NS, n = 6), thus resetting was abolished. In the presence of the carbonic anhydrase inhibitor acetazolamide (10 mM), TGF responses were 8.8 ± 0.6 and 3.3 ± 0.4 mmHg before and after resetting ( P < 0.001, n = 6). With both acetazolamide and benzamil, TGF responses were 10.4 ± 0.2 and 8.4 ± 0.5 mmHg ( P < 0.01, n = 6), thus resetting was attenuated. We conclude that CTGF, in part, mediates acutely induced TGF resetting.

Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sumit R Monu ◽  
Mani Maheshwari ◽  
Hong Wang ◽  
Ed Peterson ◽  
Oscar Carretero
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Connecting Tubule ◽  
Single Nephron ◽  
Renal Micropuncture ◽  
The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

scholarly journals Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

2013 ◽  
Vol 304 (9) ◽  
pp. R726-R733 ◽  
Author(s):  
Yiling Fu ◽  
Yan Lu ◽  
Eddie Y. Liu ◽  
Xiaolong Zhu ◽  
Gouri J. Mahajan ◽  
...  
Keyword(s):  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Sprague Dawley ◽  
Mediated Effects ◽  
Sprague Dawley Rats ◽  
Flow Pressure ◽  
Laser Capture ◽  
Stop Flow ◽  
Dependent Pathway

Males have higher prevalence of hypertension and renal injury than females, which may be attributed in part to androgen-mediated effects on renal hemodynamics. Tubuloglomerular feedback (TGF) is an important mechanism in control of renal microcirculation. The present study examines the role of testosterone in the regulation of TGF responses. TGF was measured by micropuncture (change of stop-flow pressure, ΔPsf) in castrated Sprague-Dawley rats. The addition of testosterone (10−7 mol/l) into the lumen increased the ΔPsf from 10.1 ± 1.2 to 12.2 ± 1.2 mmHg. To determine whether androgen receptors (AR) are involved, mRNA of AR was measured in the macula dense cells isolated by laser capture microdissection from kidneys, and a macula densa-like cell line (MMDD1). AR mRNA was expressed in the macula densa of rats and in MMDD1 cells. We next examined the effects of the AR blocker, flutamide (10−5 mol/l) on the TGF response. The addition of flutamide blocked the effects of testosterone on TGF. The addition of Tempol (10−4 mol/l) or polyethylene glycol-superoxide dismutase (100 U/ml) to scavenge superoxide blocked the effect of testosterone to augment TGF. We then applied apocynin to inhibit NAD(P)H oxidase and oxypurinol to inhibit xanthine oxidase and found the testosterone-induced augmentation of TGF was blocked. In additional experiments in MMDD1 cells, we found that testosterone increased O2− generation. Apocynin or oxypurinol blocked the testosterone-induced increases of O2−, while blockade of COX-2 with NS-398 had no effect. These findings suggest that testosterone enhances TGF response by stimulating O2− production in macula densa via an AR-dependent pathway.

Native tubular fluid attenuates ANF-induced inhibition of tubuloglomerular feedback

1990 ◽  
Vol 258 (1) ◽  
pp. F189-F198 ◽  
Author(s):  
D. M. Pollock ◽  
W. J. Arendshorst
Keyword(s):  
Atrial Natriuretic Factor ◽  
Filtration Rate ◽  
Pressure Range ◽  
Tubuloglomerular Feedback ◽  
Fluid Delivery ◽  
Single Nephron ◽  
Proximal Tubular ◽  
Flow Pressure ◽  
Stop Flow

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.

Modulation of tubuloglomerular feedback responsiveness by extracellular ATP

1993 ◽  
Vol 264 (3) ◽  
pp. F458-F466 ◽  
Author(s):  
K. D. Mitchell ◽  
L. G. Navar
Keyword(s):  
Saline Solution ◽  
Isotonic Saline ◽  
Tubuloglomerular Feedback ◽  
Peritubular Capillary ◽  
Arterial Blood ◽  
Transient Decrease ◽  
Peritubular Capillaries ◽  
Flow Pressure ◽  
Stop Flow

Experiments were performed in pentobarbital sodium-anesthetized rats to determine the effects of activation of P2 purinoceptors sensitive to ATP on glomerular capillary pressure, as estimated from proximal tubule stop-flow pressure (SFP) measurements, and on the magnitude of maximal tubuloglomerular feedback-mediated reductions in SFP. To selectively expose nephrons in vivo to ATP without influencing arterial blood pressure, we infused ATP directly into the surrounding peritubular capillaries. Peritubular capillary infusion, at a rate of 20 nl/min, of an isotonic saline solution containing 10(-3) M ATP elicited a transient decrease in resting SFP. However, subsequent infusion of 10(-3) M ATP together with the adenosine receptor (P1 purinoceptor) antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX, 10(-3) M) into the same vascular sites elicited a sustained decrease in resting SFP. Peritubular infusion of the slowly metabolizable ATP analogue, beta,gamma-methylene-ATP (10(-3) M), at a rate of 20 nl/min, also elicited a transient decrease in SFP, but this was not converted to a sustained response by PSPX. The SFP feedback responses to a late proximal perfusion rate of 40 nl/min were markedly attenuated during peritubular infusion of either 10(-3) M ATP (8.7 +/- 1.2 vs. 1.8 +/- 0.9 mmHg; P < 0.01, n = 9) or 10(-3) M beta,gamma-methylene-ATP (8.2 +/- 1.3 vs. 2.2 +/- 1.2 mmHg; P < 0.01, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Natriuretic and Diuretic Actions of a Highly Selective Adenosine A1 Receptor Antagonist

1999 ◽  
Vol 10 (4) ◽  
pp. 714-720
Author(s):  
CHRISTOPHER S. WILCOX ◽  
WILLIAM J. WELCH ◽  
GEORGE F. SCHREINER ◽  
LUIZ BELARDINELLI
Keyword(s):  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
New Class ◽  
Direct Measurements ◽  
Single Nephron ◽  
A1 Receptor ◽  
Flow Pressure ◽  
Dose Dependent ◽  
Stop Flow ◽  
Distal Delivery

Abstract. The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6 ± 0.1 to 2.5 ± 0.2 ml/min; P < 0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26 ± 3 to 20 ± 2 nl/min; P < 0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42 ± 5 to 44 ± 4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60 ± 3 to 46 ± 4%; P < 0.05). Despite increasing distal tubular fluid flow rate (5.4 ± 0.7 to 9.7 ± 0.9 nl/min; P < 0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4 ± 1.0 versus during CVT-124: 4.6 ± 1.5 nl/min; P < 0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; ▵PSF with vehicle: 8.3 ± 0.6 versus CVT-124: 6.5 ± 0.3 mmHg; n = 9; P < 0.01). In conclusion, A1AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.

scholarly journals Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF)

2017 ◽  
Vol 313 (6) ◽  
pp. F1209-F1215 ◽  
Author(s):  
Hong Wang ◽  
Cesar A. Romero ◽  
J. X. Masjoan Juncos ◽  
Sumit R. Monu ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Tubuloglomerular Feedback ◽  
Connecting Tubule ◽  
High Salt Intake ◽  
Simultaneous Inhibition ◽  
Flow Pressure ◽  
Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by two intrinsic nephron feedbacks: 1) the vasoconstrictor tubuloglomerular feedback (TGF) mediated by Na+-K+-2Cl− cotransporters (NKCC2) in the macula densa and blocked by furosemide and 2) the vasodilator connecting tubule glomerular feedback (CTGF), mediated by epithelial Na+ channels (ENaC) in the connecting tubule and blocked by benzamil. High salt intake reduces Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly, by differences between TGF responses with and without CTGF inhibition. We recently developed a new method to measure CTGF more directly by simultaneously inhibiting NKCC2 and the Na+/H+ exchanger (NHE). We hypothesize that in vivo during simultaneous inhibition of NKCC2 and NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (PSF) in Dahl SS and that is enhanced with a high salt intake. In the presence of furosemide alone, increasing nephron perfusion did not change the PSF in either Dahl salt-resistant rats (Dahl SR) or Dahl SS. When furosemide and an NHE inhibitor, dimethylamiloride, were perfused simultaneously, an increase in tubular flow caused Af-Art dilatation that was demonstrated by an increase in PSF. This increase was greater in Dahl SS [4.5 ± 0.4 (SE) mmHg] than in Dahl SR (2.5 ± 0.3 mmHg; P < 0.01). We confirmed that CTGF causes this vasodilation, since benzamil completely blocked this effect. However, a high salt intake did not augment the Af-Art dilatation. We conclude that during simultaneous inhibition of NKCC2 and NHE in the nephron, CTGF induces Af-Art dilatation and a high salt intake failed to enhance this effect.

scholarly journals Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron

2015 ◽  
Vol 308 (9) ◽  
pp. F1026-F1031 ◽  
Author(s):  
Hong Wang ◽  
Martin A. D'Ambrosio ◽  
YiLin Ren ◽  
Sumit R. Monu ◽  
Pablo Leung ◽  
...  
Keyword(s):  
Capillary Pressure ◽  
Tubuloglomerular Feedback ◽  
Na Channels ◽  
Epithelial Na Channels ◽  
Transport Inhibitors ◽  
Flow Pressure ◽  
Tubular Flow ◽  
Stop Flow

Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (−7.9 ± 0.2 mmHg) was blocked by furosemide (−0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: −0.2 ± 0.1 vs. furosemide+benzamil: −4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: −1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors.

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