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Armin Just

Publications and source records attributed to Armin Just.

12 recordsLinked to original sources
PubMed2006

Mechanisms of renal blood flow autoregulation: dynamics and contributions.

Autoregulation of renal blood flow (RBF) is caused by the myogenic response (MR), tubuloglomerular feedback (TGF), and a third regulatory mechanism that is independent of TGF but slower than MR. The underlying cause of the third regulatory mechanism remains unclear; possibilities include ATP, ANG II, or a slow component of MR. Other mechanisms, which, however, exert their action through modulation of MR and TGF are pressure-dependent change of proximal tubular reabsorption, resetting of RBF and TGF, as well as modulating influences of ANG II and nitric oxide (NO). MR requires < 10 s for completion in the kidney and normally follows first-order kinetics without rate-sensitive components. TGF takes 30-60 s and shows spontaneous oscillations at 0.025-0.033 Hz. The third regulatory component requires 30-60 s; changes in proximal tubular reabsorption develop over 5 min and more slowly for up to 30 min, while RBF and TGF resetting stretch out over 20-60 min. Due to these kinetic differences, the relative contribution of the autoregulatory mechanisms determines the amount and spectrum of pressure fluctuations reaching glomerular and postglomerular capillaries and thereby potentially impinge on filtration, reabsorption, medullary perfusion, and hypertensive renal damage. Under resting conditions, MR contributes approximately 50% to overall RBF autoregulation, TGF 35-50%, and the third mechanism < 15%. NO attenuates the strength, speed, and contribution of MR, whereas ANG II does not modify the balance of the autoregulatory mechanisms.

Animals↗
PubMed2006

Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide.

NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved in vasoconstriction and vascular remodeling during hypertension produced by chronic angiotensin II (ANG II) infusion. These effects are thought to be mediated largely through superoxide anion (O(2)(-)) scavenging of nitric oxide (NO). Little is known about the role of ROS in acute vasoconstrictor responses to agonists. We investigated renal blood flow (RBF) reactivity to ANG II (4 ng), norepinephrine (NE, 20 ng), and alpha(1)-adrenergic agonist phenylephrine (PE, 200 ng) injected into the renal artery (ira) of anesthetized Sprague-Dawley rats. The NOX inhibitor apocynin (1-4 mg.kg(-1).min(-1) ira, 2 min) or the superoxide dismutase mimetic Tempol (1.5-5 mg.kg(-1).min(-1) ira, 2 min) rapidly increased resting RBF by 8 +/- 1% (P < 0.001) or 3 +/- 1% (P < 0.05), respectively. During NO synthase (NOS) inhibition (N(omega)-nitro-l-arginine methyl ester, 25 mg/kg iv), the vasodilation tended to increase (apocynin 13 +/- 4%, Tempol 10 +/- 1%). During control conditions, both ANG II and NE reduced RBF by 24 +/- 4%. Apocynin dose dependently reduced the constriction by up to 44% (P < 0.05). Similarly, Tempol blocked the acute actions of ANG II and NE by up to 48-49% (P < 0.05). In other animals, apocynin (4 mg.kg(-1).min(-1) ira) attenuated vasoconstriction to ANG II, NE, and PE by 46-62% (P < 0.01). During NOS inhibition, apocynin reduced the reactivity to ANG II and NE by 60-72% (P < 0.01), and Tempol reduced it by 58-66% (P < 0.001). We conclude that NOX-derived ROS substantially contribute to basal RBF as well as to signaling of acute renal vasoconstrictor responses to ANG II, NE, and PE in normal rats. These effects are due to O(2)(-) rather than H(2)O(2), occur rapidly, and are independent of scavenging of NO.

Angiotensin II↗
PubMed2005

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.

Animals↗
PubMed2004

NO and NO-independent mechanisms mediate ETB receptor buffering of ET-1-induced renal vasoconstriction in the rat.

Vascular endothelin (ET) type B (ET(B)) receptors exert dilator and constrictor actions in a complex interaction with ET(A) receptors. We aimed to clarify the presence and relative importance of nitric oxide (NO) and other mechanisms underlying the dilator effects of ET(B) receptors in rat kidneys. Complete inhibition of NO production with Nomega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg iv) enhanced the renal vasoconstriction elicited by ET-1 injected into the renal artery from -15 to -30%. Additional infusion of the NO donor nitroprusside (NP) into the renal artery did not reverse this effect (-29%) but effectively buffered ANG II-mediated vasoconstriction. Similarly, ET-1 responses were enhanced after a smaller intrarenal dose of L-NAME (-22 vs. -15%) and were unaffected by subsequent NP infusion (-21%). These results indicate that the responsiveness to ET-1 is buffered by ET(B) receptor-stimulated phasic release of NO, rather than its static mean level. Infusion of the ET(B) receptor antagonist BQ-788 into the renal artery further enhanced the ET-1 constrictor response to NP+L-NAME (-92 vs. -49%), revealing an NO-independent dilator component. In controls, vasoconstriction to ET-1 was unaffected by vehicle (-27 vs. -20%) and markedly enhanced by BQ-788 (-70%). The same pattern was observed when indomethacin (Indo) was used to inhibit cyclooxygenase (-20% for control, -22% with Indo, and -56% with ET(B) antagonist) or methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MS-PPOH) or miconazole+Indo was used to inhibit epoxygenase alone (-10% for control, -11% with MS-PPOH, and -35% with ET(B) antagonist) or in combination (-14% for control, -20% with Indo + miconazole, and -43% with ET(B) antagonist). We conclude that phasic release of NO, but not its static level, mediates part of the dilator effect of ET(B) receptors and that an NO-independent mechanism, distinct from prostanoids and epoxyeicosatetraenoic acids, perhaps ET(B) receptor clearance of ET-1, plays a major buffering role.

Animals↗
PubMed2004

Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice.

Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA(2)) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPS-induced sepsis. This study tested whether TxA(2) receptor blockade, with the use of TxA(2) receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P < 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA(2) on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P < 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P < 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P < 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P < 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P < 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.

Acute Kidney Injury↗
PubMed2003

Dual constrictor and dilator actions of ET(B) receptors in the rat renal microcirculation: interactions with ET(A) receptors.

The vascular actions of endothelin-1 (ET-1) reflect the combination of vasoconstrictor ET(A) and ET(B) receptors on smooth muscle cells and vasodilator ET(B) receptors on endothelial cells. The present study investigated the contribution of ET receptor subtypes using a comprehensive battery of agonists and antagonists infused directly into the renal artery of anesthetized rats to evaluate the actions of each receptor class alone and their interactions. ET-1 (5 pmol) reduced renal blood flow (RBF) 25+/-1%. ET(A) antagonist BQ-123 attenuated this response to a 15+/-1% decrease in RBF (P < 0.01), indicating net constriction by ET(B) receptors. Combined receptor blockade (BQ-123+BQ-788) resulted in a renal vasoconstriction of 7+/-1% (P = 0.001 vs. BQ-123), supporting a constrictor action of ET(B) receptors. In marked contrast, the ET(B) antagonist BQ-788 enhanced the ET-1 RBF response to 60+/-5% (P < 0.001), suggesting ET(B)-mediated net dilation. Consistent with ET(A) blockade, the ET(B) agonist sarafotoxin 6C (S6C) produced vasoconstriction, reducing RBF by 23+/-5%. Dose-response curves for ET-1 and S6C showed similar degrees of constriction between 0.2 and 100 pmol. Both antagonists (BQ-123, BQ-788) were equally effective at threefold lower than the standard doses, suggesting complete inhibition. We conclude that ET(B) receptors alone exert a net constrictor effect but cause a net dilator influence when costimulated with ET(A) receptors. Such opposing actions indicate more complex than additive interaction between receptor subtypes. Model analysis suggests ET(A)-mediated constriction is appreciably greater without than with costimulation of ET(B) receptors. Possible explanations include ET-1 clearance by ET(B) receptors and/or a dilator ET(B) receptor function that counteracts constriction.

Animals↗
PubMed2003

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.

Acetazolamide↗
PubMed2003

Quantification of renal perfusion using an intravascular contrast agent (part 1): results in a canine model.

In this work absolute values of regional renal blood volume (rRBV) and flow (rRBF) are assessed by means of contrast-enhanced (CE) MRI using an intravascular superparamagnetic contrast agent. In an animal study, eight foxhounds underwent dynamic susceptibility-weighted MRI upon injection of contrast agent. Using principles of indicator dilution theory and deconvolution analysis, parametric images of rRBV, rRBF, and mean transit time (MTT) were computed. For comparison, whole-organ blood flow was determined invasively by means of an implanted flow probe, and the weight of the kidneys was evaluated postmortem. A mean rBV value of 28 ml/100 g was found in the renal cortex, with a corresponding mean rBF value of 524 ml/100 g/min and an average MTT of about 3.4 s. Although there was a systematic difference between the absolute blood flow values determined by MRI and the ultrasonic probe, a significant correlation (r(s) = 0.72, P < 0.05) was established. The influence of the arterial input function (AIF), T(1) relaxation effects, and repeated measurements on the precision of the perfusion quantitation is discussed.

Animals↗
PubMed2003

Quantification of renal perfusion abnormalities using an intravascular contrast agent (part 2): results in animals and humans with renal artery stenosis.

The interrelation between the morphologic degree of renal artery stenosis and changes in parenchymal perfusion is assessed using an intravascular contrast agent. In seven adult foxhounds, different degrees of renal artery stenosis were created with an inflatable clamp implanted around the renal artery. Dynamic susceptibility-weighted gradient-echo imaging was used to measure signal-time curves in the renal artery and the renal parenchyma during administration of 1.5 mg/kg BW of an intravascular ultrasmall particle iron oxide (USPIO) contrast agent. From the dynamic series, regional renal blood volume (rRBV), regional renal blood flow (rRBF), and mean transit time (MTT) were calculated. The morphologic degree of stenosis was measured in the steady state using a high-resolution 3D contrast-enhanced (CE) MR angiography (MRA) sequence (voxel size = 0.7 x 0.7 x 1 mm(3)). Five patients with renoparenchymal damage due to long-standing renal artery stenosis were evaluated. In the animal stenosis model, cortical perfusion remained unchanged for degrees of renal artery stenosis up to 80%. With degrees of stenoses > 80%, cortical perfusion dropped to 151 +/- 54 ml/100 g of tissue per minute as compared to a baseline of 513 +/- 76 ml/100 g/min. In the patients, a substantial difference in the cortical perfusion of more than 200 +/- 40 ml/100 g/min between the normal and the ischemic kidneys was found. The results show that quantitative renal perfusion measurements in combination with 3D-CE-MRA allow the functional significance of a renal artery stenosis to be determined in a single MR exam. Differentiation between renovascular and renoparenchymal disease thus becomes feasible.

Angiography, Digital Subtraction↗
PubMed2002

Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog.

The influence of angiotensin II (ANGII) on the dynamic characteristics of renal blood flow (RBF) was studied in conscious dogs by testing the response to a step increase in renal artery pressure (RAP) after a 60 s period of pressure reduction (to 50 mmHg) and by calculating the transfer function between physiological fluctuations in RAP and RBF. During the RAP reduction, renal vascular resistance (RVR) decreased and upon rapid restoration of RAP, RVR returned to baseline with a characteristic time course: within the first 10 s, RVR rose rapidly by 40 % of the initial change (first response, myogenic response). A second rise began after 20-30 s and reached baseline after an overshoot at 40 s (second response, tubuloglomerular feedback (TGF)). Between both responses, RVR rose very slowly (plateau). The transfer function had a low gain below 0.01 Hz (high autoregulatory efficiency) and two corner frequencies at 0.026 Hz (TGF) and at 0.12 Hz (myogenic response). Inhibition of angiotensin converting enzyme (ACE) lowered baseline RVR, but not the minimum RVR at the end of the RAP reduction (autoregulation-independent RVR). Both the first and second response were reduced, but the normalised level of the plateau (balance between myogenic response, TGF and possible slower mechanisms) and the transfer gain below 0.01 Hz were not affected. Infusion of ANGII after ramipril raised baseline RVR above the control condition. The first and second response and the transfer gain at both corner frequencies were slightly augmented, but the normalised level of the plateau was not affected. It is concluded that alterations of plasma ANGII within a physiological range do not modulate the relative contribution of the myogenic response to the overall short-term autoregulation of RBF. Consequently, it appears that ANGII augments not only TGF, but also the myogenic response.

Angiotensin II↗
PubMed2000

Correlation of hemodynamic impact and morphologic degree of renal artery stenosis in a canine model.

In a noninvasive comprehensive magnetic resonance (MR) examination, the morphologic degree of renal artery stenosis was correlated to corresponding changes in renal artery flow dynamics. Different degrees of stenosis were created with the use of a chronically implanted inflatable arterial cuff in seven dogs. For each degree of stenosis, an ultrafast three-dimensional gadolinium MR angiography with high spatial resolution was performed, followed by cardiac-gated MR flow measurements with high temporal resolution for determination of pulsatile flow profiles and mean flow. Flow was also measured by a chronically implanted flow probe. In three of the dogs, trans-stenotic pressure gradients (DeltaP) also were measured via implanted catheters. Five different degrees of stenosis could be differentiated in the MR angiograms (0%, 30%, 50%, 80%, >90%). The MR flow data agreed with the flow probe within +/-20%. Stenoses between 30 and 80% gradually reduced the early systolic peak (Max(1)) of the flow profile but only minimally affected the midsystolic peak (Max(2)) or mean flow. Stenoses of more than 90% significantly depressed mean flow by more than 50%. The ratio between Max(1) and Max(2) (Rmax(1/2)) gradually fell with the degree of stenosis. The onset of significant mean flow reduction and DeltaP was indicated by a drop of Rmax(1/2) below 1 to 1.2. Thus, the analysis of high-resolution flow profiles allows detection of early hemodynamic changes even at degrees of stenoses not associated with a reduction of mean flow. Rmax(1/2) allows differentiation of the grade of hemodynamic compromise for a given morphologic stenosis independent of mean flow in a single comprehensive MR examination.

Angiotensin II↗