Impaired Renal Blood Flow Autoregulation due to Compromised Tubuloglomerular Feedback in Mice Lacking Connexin 40

Autoregulation of renal blood flow (RBF) is mediated by a fast myogenic response (MR; ∼5 s), a slower tubuloglomerular feedback (TGF; ∼25 s), and potentially additional mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial nephrons and contribute to overall autoregulation, but the impact on the other autoregulatory mechanisms is unknown. We studied dynamic autoregulatory responses of RBF to rapid step increases of renal artery pressure in mice. MR was estimated from autoregulation within the first 5 s, TGF from that at 5–25 s, and a third mechanism from 25–100 s. Genetic deficiency of A1AR (A1AR−/−) reduced autoregulation at 5–25 s by 50%, indicating a residual fourth mechanism resembling TGF kinetics but independent of A1AR. MR and third mechanism were unaltered in A1AR−/−. Autoregulation in A1AR−/− was faster at 5–25 than at 25–100 s suggesting two separate mechanisms. Furosemide in wild-type mice (WT) eliminated the third mechanism and enhanced MR, indicating TGF-MR interaction. In A1AR−/−, furosemide did not further impair autoregulation at 5–25 s, but eliminated the third mechanism and enhanced MR. The resulting time course was the same as during furosemide in WT, indicating that A1AR do not affect autoregulation during furosemide inhibition of TGF. We conclude that at least one novel mechanism complements MR and TGF in RBF autoregulation, that is slower than MR and TGF and sensitive to furosemide, but not mediated by A1AR. A fourth mechanism with kinetics similar to TGF but independent of A1AR and furosemide might also contribute. A1AR mediate classical TGF but not TGF-MR interaction.

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Spontaneous renal blood flow autoregulation curves in conscious sinoaortic baroreceptor-denervated rats

AJP Renal Physiology ◽

10.1152/ajprenal.0186.2001 ◽

2002 ◽

Vol 282 (1) ◽

pp. F51-F58 ◽

Cited By ~ 10

Author(s):

Silene L. S. Pires ◽

Claude Julien ◽

Bruno Chapuis ◽

Jean Sassard ◽

Christian Barrès

Keyword(s):

Blood Flow ◽

Arterial Pressure ◽

Renal Blood Flow ◽

Coefficient Of Variation ◽

Tubuloglomerular Feedback ◽

Before And After ◽

Renal Blood Flow Autoregulation ◽

Limited Accuracy ◽

Weibull Equation ◽

Intact Rats

These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg · kg−1 · h−1 iv)administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 ± 1.2 vs. 5.4 ± 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 ± 0.6 vs. 6.1 ± 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation ( r 2 = 0.24 ± 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 ± 0.7 ml/min) and a lower limit of RBF autoregulation (PLL = 93 ± 6 mmHg, defined as AP at RBF 5% below the plateau). After furosemide treatment, autoregulation curves ( r 2 = 0.49 ± 0.07) in SAD rats were shifted downward (plateau = 8.6 ± 0.8 ml/min) and rightward (PLL = 102 ± 5 mmHg). In five of six intact rats, PLL became measurable (104 ± 1 mmHg), albeit with limited accuracy ( r 2 = 0.09 ± 0.03). In conclusion, the conscious SAD rat offers the possibility of describing RBF autoregulation curves under dynamic, unforced conditions. The tubuloglomerular feedback and myogenic mechanisms cooperate in setting PLL and thus in stabilizing RBF during spontaneous depressor episodes.

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Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O2− dismutation on renal autoregulation in the time and frequency domains

AJP Renal Physiology ◽

10.1152/ajprenal.00461.2015 ◽

2016 ◽

Vol 310 (9) ◽

pp. F832-F845 ◽

Cited By ~ 6

Author(s):

Nicholas G. Moss ◽

Tayler K. Gentle ◽

William J. Arendshorst

Keyword(s):

Blood Flow ◽

Frequency Domain ◽

Renal Blood Flow ◽

Renal Perfusion ◽

No Synthase ◽

Tubuloglomerular Feedback ◽

Frequency Range ◽

Stage 1 ◽

Renal Blood Flow Autoregulation

Renal blood flow autoregulation was investigated in anesthetized C57Bl6 mice using time- and frequency-domain analyses. Autoregulation was reestablished by 15 s in two stages after a 25-mmHg step increase in renal perfusion pressure (RPP). The renal vascular resistance (RVR) response did not include a contribution from the macula densa tubuloglomerular feedback mechanism. Inhibition of nitric oxide (NO) synthase [ NG-nitro-l-arginine methyl ester (l-NAME)] reduced the time for complete autoregulation to 2 s and induced 0.25-Hz oscillations in RVR. Quenching of superoxide (SOD mimetic tempol) during l-NAME normalized the speed and strength of stage 1 of the RVR increase and abolished oscillations. The slope of stage 2 was unaffected by l-NAME or tempol. These effects of l-NAME and tempol were evaluated in the frequency domain during random fluctuations in RPP. NO synthase inhibition amplified the resonance peak in admittance gain at 0.25 Hz and markedly increased the gain slope at the upper myogenic frequency range (0.06–0.25 Hz, identified as stage 1), with reversal by tempol. The slope of admittance gain in the lower half of the myogenic frequency range (equated with stage 2) was not affected by l-NAME or tempol. Our data show that the myogenic mechanism alone can achieve complete renal blood flow autoregulation in the mouse kidney following a step increase in RPP. They suggest also that the principal inhibitory action of NO is quenching of superoxide, which otherwise potentiates dynamic components of the myogenic constriction in vivo. This primarily involves the first stage of a two-stage myogenic response.

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A multinephron model of renal blood flow autoregulation by tubuloglomerular feedback and myogenic response

Acta Physiologica Scandinavica ◽

10.1111/j.1748-1716.1991.tb09203.x ◽

1991 ◽

Vol 143 (1) ◽

pp. 71-92 ◽

Cited By ~ 15

Author(s):

A. H. ØIEN ◽

K. AUKLAND

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Myogenic Response ◽

Renal Blood Flow Autoregulation

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Analysis of interaction between TGF and the myogenic response in renal blood flow autoregulation

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.4.f581 ◽

1995 ◽

Vol 269 (4) ◽

pp. F581-F593 ◽

Cited By ~ 23

Author(s):

R. Feldberg ◽

M. Colding-Jorgensen ◽

N. H. Holstein-Rathlou

Keyword(s):

Blood Flow ◽

Smooth Muscle ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Distributed Model ◽

Myogenic Response ◽

Control Mechanisms ◽

Afferent Arteriole ◽

Vascular Effects ◽

Renal Blood Flow Autoregulation

The present study investigates the interaction between the tubuloglomerular feedback (TGF) response and the myogenic mechanism by use of a mathematical model. The two control mechanisms are implemented in a spatially distributed model of the rat renal juxtamedullary afferent arteriole. The model of the afferent arteriole is based on in vivo measurements of the stress-strain relation in muscle strips. Analysis of experimental data shows that the myogenic response can be modeled by a linear relation between the transmural pressure and the level of activation of the vascular smooth muscle cells. The contribution of TGF to smooth muscle activity is assumed to be a linear function of the glomerular capillary pressure. The results show that the myogenic response plays an important role in renal blood flow autoregulation. Without a myogenic response, mechanisms such as TGF that are localized in the distal segments of the microvasculature would not be able to achieve autoregulation because of passive, pressure-mediated effects in the upstream vascular segments. In addition, it is shown that a strong myogenic response may lead to both propagation and enhancement of vascular effects mediated through mechanisms located in the distal part of the afferent arteriole. An ascending myogenic response could enhance the regulatory efficiency of the TGF mechanism by increasing the open-loop gain of the system. However, such a synergistic interaction will only be observed when the two mechanisms operate on more or less separate segments of the afferent arteriole. In the case where they operate on common segments of the arteriole, the outcome of the interaction may well be antagonistic.

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Roles of Superoxide and Nitric Oxide in the Myogenic Control of Renal Blood Flow Autoregulation

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.808.13 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Nicholas Moss ◽

Tayler Gentle ◽

William Arendshorst

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Renal Blood Flow ◽

Renal Blood Flow Autoregulation

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Tubuloglomerular feedback dynamics and renal blood flow autoregulation in rats

AJP Renal Physiology ◽

10.1152/ajprenal.1991.260.1.f53 ◽

1991 ◽

Vol 260 (1) ◽

pp. F53-F68 ◽

Cited By ~ 40

Author(s):

N. H. Holstein-Rathlou ◽

A. J. Wagner ◽

D. J. Marsh

Keyword(s):

Blood Flow ◽

Arterial Pressure ◽

Renal Blood Flow ◽

Slow Component ◽

Broad Band ◽

Experimental Results ◽

Tubuloglomerular Feedback ◽

Single Frequency ◽

Vascular Control ◽

Arterial Blood

To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.

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