A novel mechanism of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice

2007 ◽  
Vol 293 (5) ◽  
pp. F1489-F1500 ◽  
Author(s):  
Armin Just ◽  
William J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Adenosine Receptors ◽  
Time Course ◽  
Tubuloglomerular Feedback ◽  
The Third ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Renal Blood Flow Autoregulation

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.

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.

Role of A1 adenosine receptors in regulation of vascular tone

2005 ◽  
Vol 288 (3) ◽  
pp. H1411-H1416 ◽  
Author(s):  
Huda E. Tawfik ◽  
J. Schnermann ◽  
Peter J. Oldenburg ◽  
S. Jamal Mustafa
Keyword(s):  
Adenosine Receptors ◽  
Vascular Tone ◽  
Receptor Subtypes ◽  
Vascular Relaxation ◽  
Response Curves ◽  
Cgs 21680 ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Regulation Of Vascular Tone

The vascular response to adenosine and its analogs is mediated by four adenosine receptors (ARs), namely, A1, A2A, A2B, and A3. A2AARs and/or A2BARs are involved in adenosine-mediated vascular relaxation of coronary and aortic beds. However, the role of A1ARs in the regulation of vascular tone is less well substantiated. The aim of this study was to determine the role of A1ARs in adenosine-mediated regulation of vascular tone. A1AR-knockout [A1AR(−/−)] mice and available pharmacological tools were used to elucidate the function of A1ARs and the impact of these receptors on the regulation of vascular tone. Isolated aortic rings from A1AR(−/−) and wild-type [A1AR(+/+)] mice were precontracted with phenylephrine, and concentration-response curves for adenosine and its analogs, 5′- N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro- N6-cyclopentyladenosine (CCPA, A1AR selective), 2-(2-carboxyethyl)phenethyl amino-5′- N-ethylcarboxamido-adenosine (CGS-21680, A2A selective), and 2-chloro- N6-3-iodobenzyladenosine-5′- N-methyluronamide (Cl-IBMECA, A3 selective) were obtained to determine relaxation. Adenosine and NECA (0.1 μM) caused small contractions of 13.9 ± 3.0 and 16.4 ± 6.4%, respectively, and CCPA at 0.1 and 1.0 μM caused contractions of 30.8 ± 4.3 and 28.1 ± 3.9%, respectively, in A1AR(+/+) rings. NECA- and CCPA-induced contractions were eliminated by 100 nM of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, selective A1AR antagonist). Adenosine, NECA, and CGS-21680 produced an increase in maximal relaxation in A1AR(−/−) compared with A1AR(+/+) rings, whereas Cl-IBMECA did not produce contraction in either A1AR(+/+) or A1AR(−/−) rings. CCPA-induced contraction at 1.0 μM was eliminated by the PLC inhibitor U-73122. These data suggest that activation of A1ARs causes contraction of vascular smooth muscle through PLC pathways and negatively modulates the vascular relaxation mediated by other adenosine receptor subtypes.

scholarly journals Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

2009 ◽  
Vol 20 (7) ◽  
pp. 1577-1585 ◽  
Author(s):  
Armin Just ◽  
Lisa Kurtz ◽  
Cor de Wit ◽  
Charlotte Wagner ◽  
Armin Kurtz ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Connexin 40 ◽  
Renal Blood Flow Autoregulation

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

2002 ◽  
Vol 282 (1) ◽  
pp. F51-F58 ◽  
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.

scholarly journals Dynamic characteristics and underlying mechanisms of renal blood flow autoregulation in the conscious dog

2001 ◽  
Vol 280 (6) ◽  
pp. F1062-F1071 ◽  
Author(s):  
Armin Just ◽  
Heimo Ehmke ◽  
Lira Toktomambetova ◽  
Hartmut R. Kirchheim
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
Vascular Resistance ◽  
Time Course ◽  
External Iliac Artery ◽  
Tubuloglomerular Feedback ◽  
Step Response ◽  
Myogenic Response ◽  
Pressure Step

The time course of the autoregulatory response of renal blood flow (RBF) to a step increase in renal arterial pressure (RAP) was studied in conscious dogs. After RAP was reduced to 50 mmHg for 60 s, renal vascular resistance (RVR) decreased by 50%. When RAP was suddenly increased again, RVR returned to baseline with a characteristic time course (control; n = 15): within the first 10 s, it rose rapidly to 70% of baseline ( response 1), thus already comprising 40% of the total RVR response. Thereafter, it increased at a much slower rate until it started to rise rapidly again at 20–30 s after the pressure step ( response 2). After passing an overshoot of 117% at 43 s, RVR returned to baseline values. Similar responses were observed after RAP reduction for 5 min or after complete occlusions for 60 s. When tubuloglomerular feedback (TGF) was inhibited by furosemide (40 mg iv, n = 12), response 1 was enhanced, providing 60% of the total response, whereas response 2 was completely abolished. Instead, RVR slowly rose to reach the baseline at 60 s ( response 3). The same pattern was observed when furosemide was given at a much higher dose (>600 mg iv; n = 6) or in combination with clamping of the plasma levels of nitric oxide ( n = 6). In contrast to RVR, vascular resistance in the external iliac artery after a 60-s complete occlusion started to rise with a delay of 4 s and returned to baseline within 30 s. It is concluded that, in addition to the myogenic response and the TGF, a third regulatory mechanism significantly contributes to RBF autoregulation, independently of nitric oxide. The three mechanisms contribute about equally to resting RVR. The myogenic response is faster in the kidney than in the hindlimb.

scholarly journals Gender Difference in Renal Blood Flow Response to Angiotensin II Administration after Ischemia/Reperfusion in Rats: The Role of AT2 Receptor

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maryam Maleki ◽  
Mehdi Nematbakhsh
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Renal Blood Flow ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Female Rats ◽  
Male Rats ◽  
Ang Ii ◽  
The Impact

Background. Renal ischemia/reperfusion (I/R) is one of the major causes of kidney failure, and it may interact with renin angiotensin system while angiotensin II (Ang II) type 2 receptor (AT2R) expression is gender dependent. We examined the role of AT2R blockade on vascular response to Ang II after I/R in rats.Methods.Male and female rats were subjected to 30 min renal ischemia followed by reperfusion. Two groups of rats received either vehicle or AT2R antagonist, PD123319. Mean arterial pressure (MAP), and renal blood flow (RBF) responses were assessed during graded Ang II (100, 300, and 1000 ng/kg/min, i.v.) infusion at controlled renal perfusion pressure (RPP).Results.Vehicle or antagonist did not alter MAP, RPP, and RBF levels significantly; however, 30 min after reperfusion, RBF decreased insignificantly in female treated with PD123319 (P=0.07). Ang II reduced RBF and increased renal vascular resistance (RVR) in a dose-related fashion (Pdose<0.0001), and PD123319 intensified the reduction of RBF response in female (Pgroup<0.005), but not in male rats.Conclusion.The impact of the AT2R on vascular responses to Ang II in renal I/R injury appears to be sexually dimorphic. PD123319 infusion promotes these hemodynamic responses in female more than in male rats.

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

2016 ◽  
Vol 310 (9) ◽  
pp. F832-F845 ◽  
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.

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

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Armin Just ◽  
Lisa Kurtz ◽  
Charlotte Wagner ◽  
Cor Wit ◽  
Armin Kurtz ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Connexin 40 ◽  
Renal Blood Flow Autoregulation

scholarly journals Detection of low-frequency oscillations in renal blood flow

2009 ◽  
Vol 297 (1) ◽  
pp. F155-F162 ◽  
Author(s):  
K. L. Siu ◽  
B. Sung ◽  
W. A. Cupples ◽  
L. C. Moore ◽  
K. H. Chon
Keyword(s):  
Blood Flow ◽  
Transfer Function ◽  
Renal Blood Flow ◽  
Experimental Approach ◽  
Low Frequency ◽  
Tubuloglomerular Feedback ◽  
Resonant Peak ◽  
The Third ◽  
Transfer Function Analysis ◽  
Autoregulatory Mechanism

Detection of the low-frequency (LF; ∼0.01 Hz) component of renal blood flow, which is theorized to reflect the action of a third renal autoregulatory mechanism, has been difficult due to its slow dynamics. In this work, we used three different experimental approaches to detect the presence of the LF component of renal autoregulation using normotensive and spontaneously hypertensive rats (SHR), both anesthetized and unanesthetized. The first experimental approach utilized a blood pressure forcing in the form of a chirp, an oscillating perturbation with linearly increasing frequency, to elicit responses from the LF autoregulatory component in anesthetized normotensive rats. The second experimental approach involved collection and analysis of spontaneous blood flow fluctuation data from anesthetized normotensive rats and SHR to search for evidence of the LF component in the form of either amplitude or frequency modulation of the myogenic and tubuloglomerular feedback mechanisms. The third experiment used telemetric recordings of arterial pressure and renal blood flow from normotensive rats and SHR for the same purpose. Our transfer function analysis of chirp signal data yielded a resonant peak centered at 0.01 Hz that is greater than 0 dB, with the transfer function gain attenuated to lower than 0 dB at lower frequencies, which is a hallmark of autoregulation. Analysis of the data from the second experiments detected the presence of ∼0.01-Hz oscillations only with isoflurane, albeit at a weaker strength compared with telemetric recordings. With the third experimental approach, the strength of the LF component was significantly weaker in the SHR than in the normotensive rats. In summary, our detection via the amplitude modulation approach of interactions between the LF component and both tubuloglomerular feedback and the myogenic mechanism, with the LF component having an identical frequency to that of the resonant gain peak, provides evidence that 0.01-Hz oscillations may represent the third autoregulatory mechanism.

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