Autoregulatory Efficiency Research Articles

Regional Differences in Dynamic Cerebral Autoregulation in the Healthy Brain Assessed by Magnetic Resonance Imaging

A novel method is described for mapping dynamic cerebral blood flow autoregulation to assess autoregulatory efficiency throughout the brain, using magnetic resonance imaging (MRI). Global abnormalities in autoregulation occur in clinical conditions, including stroke and head injury, and are of prognostic significance. However, there is limited information about regional variations. A gradient-echo echo-planar pulse sequence was used to scan the brains of healthy subjects at a rate of 1 scan/second during a transient decrease in arterial blood pressure provoked by a sudden release of pressure in bilateral inflated thigh cuffs. The signal decrease and subsequent recovery were analyzed to provide an index of autoregulatory efficiency (MRARI). MRI time-series were successfully acquired and analyzed in eleven subjects. Autoregulatory efficiency was not uniform throughout the brain: white matter exhibited faster recovery than gray (MRARI = 0.702 vs. 0.672, p = 0.009) and the cerebral cortex exhibited faster recovery than the cerebellum (MRARI = 0.669 vs. 0.645, p = 0.016). However, there was no evidence for differences between different cortical regions. Differences in autoregulatory efficiency between white matter, gray matter and the cerebellum may be a result of differences in vessel density and vasodilation. The techniques described may have practical importance in detecting regional changes in autoregulation consequent to disease.

Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26mg/L) for 48h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.

Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib

Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib. Rats were administered sorafenib (20mg/kg per day) alone or in combination with captopril (40mg/kg per day) for 4weeks. Sorafenib administration increased blood pressure, which plateaued by day 10. Concurrent treatment with captopril for 4weeks resulted in a 30mmHg decrease in blood pressure compared with sorafenib alone (155±5 vs 182±6mmHg, respectively; P<0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20±8 vs 42±9mg/day, respectively; P<0.05) and reduced nephrinuria by eightfold (280±96 vs 2305±665μg/day, respectively; P<0.05). Glomerular injury, thrombotic microangiopathy and tubular cast formation were also decreased in captopril-treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity. In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib.

Inhibition of soluble epoxide hydrolase improves the impaired pressure–natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats

In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure-natriuresis relationship in response to stepwise reduction in renal arterial pressure (RAP) in Cyp1a1-Ren-2 transgenic rats. Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration for 11 days of the natural xenobiotic indole-3-carbinol (I3C) which activates the renin gene. Treatment with c-AUCB and losartan was started 48 h before initiating administration of the diet containing I3C. Rats were prepared for renal functional studies to evaluate in-vivo renal autoregulatory efficiency when RAP was gradually decreased by an aortic clamp. I3C administration resulted in the development of severe hypertension which was associated with markedly lower basal RBF and GFR and substantially impaired autoregulatory efficiency as well as a suppression of the pressure-natriuresis relationship when compared with noninduced rats. Treatment with c-AUCB significantly decreased BP, improved autoregulatory efficiency of RBF and GFR and the slope of pressure-natriuresis relationship. Treatment with losartan completely prevented the impaired autoregulation and pressure-natriuresis relationship as well as the development of hypertension in I3C-induced rats. Our present findings indicate that chronic treatment with the sEH inhibitor c-AUCB substantially attenuates the development of malignant hypertension in I3C-induced rats likely via improvement of the renal autoregulatory efficiency and the pressure-natriuresis relationship.

High Salt Diet –Induced Afferent Arteriolar Autoregulatory Dysfunction is Improved by Acute Antioxidant Treatment

High salt (HS) diet reduces myogenic reactivity in resistance arteries and autoregulatory responses of afferent arterioles. Oxidative stress is increased in HS rats. We tested the hypothesis that HS blunts autoregulatory behavior by stimulating accumulation of reactive oxygen species. Rats were fed a normal (NS, 0.4% NaCl) or HS (8% NaCl) diet for a period of 14 days. Baseline arteriolar diameter was similar between the NS and HS groups. Autoregulatory behavior was assessed by measuring diameter changes during step‐wise 15 mmHg increases in perfusion pressure from 65 to 170 mmHg. In NS kidneys, afferent arteriolar diameter decreased by 34 ± 2% (n=6) as perfusion pressure increased from 65 to 170 mmHg. In HS kidneys arteriolar diameter decreased by 6 ± 4% (P &lt; 0.05; n = 8) indicating markedly attenuated pressure induced vasoconstriction. Acute exposure to Tempol (1.0 mM) in the superfusate had no effect on the autoregulatory response in NS rats but markedly improved autoregulation in the HS group. Increasing perfusion pressure from 65 to 170 mmHg in NS kidneys decreased afferent diameter by 32 ± 3% (n=3), whereas diameter decreased by 28 ± 3% (n=6) in kidneys from HS rats exposed to Tempol. These data indicate that reactive oxygen species blunt autoregulatory efficiency in kidneys from HS rats facilitating enhanced excretion of salt by buffering autoregulatory control of glomerular hemodynamics.

Renal autoregulation in medical therapy of renovascular hypertension

IntroductionRenovascular hypertension (RVH) is caused by renal ischaemia associated with haemodynamically significant renal artery stenosis (RAS). The choice of optimal treatment of atherosclerotic RAS is still controversial. Increase in the renal resistive index (RI) value after captopril administration is considered to indicate preserved renal autoregulation. The objective of the study was to assess the effect of medical therapy of RVH on renal autoregulation efficiency in patients with atherosclerotic RAS.Material and methods19 persons (38 kidneys) in 2 groups: 1) study: with RVH and stenosis of 1 renal artery – 8 patients; 2) control: – 11 healthy volunteers. Doppler captopril test with RI measurements and estimation of creatinine clearance (CCr) were performed in both groups at baseline, and after a period of controlled medical therapy (CMT) only in the study group. ABPM was evaluated in controls at baseline, and in the study group at the end of CMT.ResultsIn the study group the mean period of CMT was 8.3 ±2.7 months, the number of antihypertensive drugs was 4.1 ±1.0, and mean 24-hour blood pressure was 138/74 mmHg. Mean CCr was stable during the study. Significant increase of RI after captopril was found only in controls. At baseline, in the group of kidneys with a non-stenotic renal artery, significant lowering of RI was observed, and ΔRI differed significantly from controls. After CMT, ΔRI increased in non-stenotic kidneys in comparison to the baseline, and did not differ from controls.ConclusionsAdequate medical therapy of RVH preserved renal function and improved renal autoregulation efficiency in non-stenotic kidneys.

Impaired pressure‐natriuresis relationship precedes the development of hypertension in Cyp1a1‐Ren‐2 transgenic rats

ObjectiveThe present study was performed to characterize the autoregulatory efficiency of renal blood flow (RBF) and glomerular filtration rate (GFR) and the pressure‐natriuresis relationship in transgenic rats with inducible hypertension (Cyp1a1‐Ren‐2 rats).MethodsThe renin gene was induced in Cyp1a1‐Ren‐2 rats trough dietary administration of the natural xenobiotic indole‐3‐carbinol (I3C, 0.3 %) for 12 hours. Non‐induced rats served as controls. Anesthetized rats were prepared for renal function studies and an aortic clamp was placed on the aorta to regulate the level of renal arterial pressure. ANG II levels were measured by radioimmunoassay.ResultsAdministration of I3C resulted in progressive increases in ANG II levels as compared with non‐induced rats. I3C‐induction for 12 hours did not cause significant changes in blood pressure as compared with non‐induced rats. 12 hours I3C‐induction caused an impairment of the autoregulatory efficiency of RBF and GFR and of the pressure‐natriuresis relationship as compared with non‐induced rats.ConclusionsOur findings indicate that an impairment of the pressure‐natriuresis mechanism precedes the development of ANG II‐dependent hypertension in Cyp1a1‐Ren‐2 transgenic rats.

Impairment of the autoregulation of renal hemodynamics and of the pressure-natriuresis relationship precedes the development of hypertension in Cyp1a1-Ren-2 transgenic rats

The present study was performed to characterize the autoregulatory efficiency of renal blood flow and glomerular filtration rate and the pressure-natriuresis relationship in transgenic rats with inducible angiotensin II (ANG II)-dependent hypertension (Cyp1a1-Ren-2 rats). The renin gene was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3%) for 12 and 24 h, respectively. Noninduced rats served as controls. Anesthetized rats were prepared for renal function studies and an aortic clamp was placed above the junction of the left renal artery to regulate the level of renal arterial pressure. Plasma renin activity, ANG II and aldosterone levels were measured at the end of the experiment by radioimmunoassay. Administration of I3C resulted in progressive increases in plasma renin activity and plasma and kidney ANG II levels; however, it did not significantly alter aldosterone levels as compared with those in noninduced rats. I3C induction for 12 h did not cause significant changes in blood pressure as compared with those in noninduced rats. I3C induction for 24 h elicited a significant rise in blood pressure. Twelve-hour I3C induction caused an impairment of the autoregulatory efficiency of renal blood flow and glomerular filtration rate and of the pressure-natriuresis relationship as compared with that in noninduced rats. In addition, 24 h I3C induction of the renin gene resulted in a marked reduction in renal blood flow and glomerular filtration rate and a further impairment of the pressure-natriuresis mechanism as compared with that in noninduced rats. Our findings indicate that an impairment of the pressure-natriuresis mechanism precedes the development of ANG II-dependent hypertension in Cyp1a1-Ren-2 transgenic rats.

Blood flow autoregulation in pedicled flaps

Clinical work on the blood perfusion in skin and muscle flaps has suggested that some degree of blood flow autoregulation exists in such flaps. An autoregulatory mechanism would enable the flap to protect itself from changes in the perfusion pressure. The purpose of the present study was to evaluate if, and to what extent, a tissue flap could compensate a reduction in blood flow due to an acute constriction of the feed artery. Further, we wanted to examine the possible role of smooth muscle L-type calcium channels in the autoregulatory mechanism by pharmacological intervention with the L-type calcium channel blocker nimodipine and the vasodilator papaverine. Pedicled flaps were raised in pigs. Flow in the pedicle was reduced by constriction of the feed artery (n=34). A transit time flow probe measured the effect on blood flow continuously. Following this, three different protocols were followed: (1) Time control (n=10): the procedure described above was repeated in the same flap to determine whether autoregulatory efficiency changed over time. (2) Nimodipine infusion (n=13): continuous intra-arterial infusion of nimodipine (0.2mg/ml, 0.5 ml/min) started when the flow had returned to the initial value. After stabilisation, the flow was reduced. When the flow had been stable for at least 5 min, the constriction was removed. (3) Nimodipine and papaverine (n=8): the infusion of nimodipine was followed by an intra-arterial bolus of papaverine (10mg). After stabilisation, the flow in the pedicle was reduced and the flow was recorded. The flaps showed a strong autoregulatory response with complete compensation for flow reductions of up to 70-80%. Infusion of nimodipine caused a 28+/-10% increase in blood flow and removed the autoregulation. Papaverine caused a further increase in blood flow by 61+/-19%. The time control experiments proved that the experimental procedure was reproducible and stable over time. A tissue flap can nearly completely compensate for repeated flow reductions of up to 70-80%. This is due to a decrease in the peripheral resistance, mediated by a local intrinsic mechanism. Nimodipine (a blocker of L-type voltage-activated calcium channels) abolishes the autoregulation, but a significant vasodilatory reserve exists, as an additional injection of papaverine (a smooth muscle relaxant) results in a further increase in the blood flow. This strongly suggests a direct role for voltage-activated calcium channels in the autoregulatory process.

Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats

The mechanisms underlying the development and prevention of diabetic nephropathy are still not fully understood. In the present study in the Otsuka Long-Evans Tokushima Fatty (OLETF) model of type 2 diabetic rats, we investigated whether renal hemodynamic abnormalities exist and whether they precede the onset of diabetes. Using OLETF rats in both prediabetic and diabetic stages, we assessed autoregulatory responses of total renal blood flow (RBF) and of superficial (SBF) and deep renal cortical (DBF) blood flow to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. During clamp-induced reductions of RPP by 10 or 20 mmHg, RBF fell significantly more in OLETF rats than in lean control [Long-Evans Tokushima Otsuka (LETO)] rats. Whereas SBF showed no significant changes in either OLETF rats or LETO rats during mild clamping, DBF decreased significantly more in OLETF rats than LETO rats. Reduced autoregulatory efficiency in OLETF rats was observed in both prediabetic and diabetic stages. Micropuncture studies showed that tubuloglomerular feedback (TGF) responses of stop flow pressure are reduced in prediabetic (-7.3 vs. -25.7%) as well as in diabetic OLETF rats compared with LETO control rats (-4.4 vs. -18.8%). Renal corticotomy was performed to measure glomerular capillary pressure (Pgc) directly. Pgc of deep cortical glomeruli was higher than superficial glomerular Pgc in both strains of rats, but the difference was especially pronounced in OLETF rats (deep 78 +/- 2 vs. superficial 57 +/- 4 mmHg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region.

Mysteries of Renal Autoregulation

Autoregulation is an important renal regulatory mechanism that provides an important protective role in glomerular hemodynamics.1 The phenomenon of autoregulatory behavior has been recognized for many decades, but a clear understanding of the underlying mechanisms involved in mediating resistance adjustments remains to be established. As illustrated in Figure 1, pressure-mediated autoregulatory behavior operates by recognizing a change in renal perfusion pressure, or renal vascular transmural pressure, and initiating induction of autoregulatory resistance changes intended to stabilize renal blood flow and/or glomerular filtration rate. The net result is that renal blood flow and glomerular filtration rate remain relatively stable over a wide range of renal perfusion pressures. Autoregulatory behavior is exquisitely sensitive in healthy normal kidneys but significantly less efficient in pathological settings, such as diabetes mellitus and some forms of hypertension. Complete loss of autoregulatory control results in renal blood flow that behaves more passively, thus increasing variability and rendering flow more directly determined by renal perfusion pressure.1,2 Figure 1. Outline of the pressure-induced signaling scheme postulated for autoregulatory adjustments in the afferent arteriolar diameter. Whole kidney autoregulation reflects regulatory input from the myogenic and tubuloglomerular feedback mechanisms at the very least.3–7 Recently, contributions of a third and possibly a fourth mechanism have been suggested.6,7 Consequently, with continued study, the mechanisms underlying renal autoregulatory resistance adjustments are slowly becoming clearer. In addition to the P1 receptor hypothesis put forth to explain signal transduction for tubuloglomerular feedback-dependent resistance changes, we have explored the hypothesis that pressure-mediated autoregulatory responses are mediated by extracellular ATP and activation of P2X1 receptors.3,8,9 Conclusive identification of the signaling molecules that mediate autoregulation remains a point of debate, but it appears clear that the release of a purine-based moiety is required for autoregulatory adjustments in afferent arteriolar resistance.3–5,8–10 This …

Continuously measured renal blood flow does not increase in diabetes if nitric oxide synthesis is blocked.

This study used 16 h/day measurement of renal blood flow (RBF) and arterial pressure (AP) to determine the role of nitric oxide (NO) in mediating the renal vasodilation caused by onset of type 1 diabetes. The AP and RBF power spectra were used to determine the autoregulatory efficiency of the renal vasculature. Rats were instrumented with artery and vein catheters and a Transonic flow probe on the left renal artery and were divided randomly into four groups: control (C), diabetes (D), control plus nitro-L-arginine methyl ester (L-NAME; CL), and diabetes plus L-NAME (DL). Mean AP averaged 90 +/- 1 and 121 +/- 1 mmHg in the D and DL groups, respectively, during the control period, and RBF averaged 5.9 +/- 1.2 and 5.7 +/- 0.7 ml/min, respectively. Respective C and CL groups were not different. Onset of diabetes (streptozotocin 40 mg/kg iv) in D rats increased RBF gradually, but it averaged 55% above control by day 14. In DL rats, on the other hand, RBF remained essentially constant, tracking with RBF in the nondiabetic C and CL groups for the 2-wk period. Diabetes did not change mean AP in any group. Transfer function analysis revealed impaired dynamic autoregulation of RBF overall, including the frequency range of tubuloglomerular feedback (TGF), and L-NAME completely prevented those changes as well. These data strongly support a role for NO in causing renal vasodilation in diabetes and suggest that an effect of NO to blunt RBF autoregulation may play an important role.

The Role of Reactive Oxygen Species in Renal Blood Flow Autoregulation

Autoregulation of renal blood flow (RBF) is mediated by a myogenic response (MR), tubuloglomerular feedback (TGF) and by a third mechanism that is slower than MR and TGF. Reactive oxygen species (ROS) are known to contribute to acute agonist‐induced renal vasoconstriction and to enhance TGF. Little is known about the role of ROS in RBF autoregulation and underlying mechanisms.Autoregulatory mechanisms were assessed from the response of RBF to a rapid step‐increase in renal artery pressure in rats. MR was derived from resistance changes within the first 5 s, TGF from those between 5 and 25 s, and the third mechanism from 25–100 s. During control, overall autoregulation was 85±6% of perfect. MR provided autoregulatory efficiency of 63±6%, TGF 41±5% and the 3rd mechanism 5±6%. Inhibition of NAD(P)H oxidase by apocynin attenuated overall autoregulation to 62±7% (p&lt;0.05) and MR to 39±4% (p&lt;0.001) but barely affected TGF and 3rd mechanism (32±3 and 14±4%, p&gt;0.06). Inhibition of nitric oxide synthase by LNAME markedly augmented MR (130±16%, p&lt;0.001) leaving little room for TGF and 3rd mechanism. During LNAME, apocynin strongly blunted MR (to 56±11%, p&lt;0.01), reversing the effect of LNAME. The superoxide dismutase (SOD) mimetic tempol tended to diminish MR similar to apocynin (38 vs. 52%, p&gt;0.08).We conclude that ROS contribute to RBF autoregulation by strengthening MR in the normal kidney. This effect is mainly due to superoxide rather than H2O2 and does not require NO but instead is blunted by NO. Superoxide plays a major role in facilitating the modulation of MR by NO in the renal microcirculation.Supported by NIH (HL‐02334) and Arthur C Guyton Award.

Adenosine A2 Receptor Activation Attenuates Afferent Arteriolar Autoregulation During Adenosine Receptor Saturation in Rats

Adenosine is an important paracrine agent regulating renal hemodynamics via adenosine A1 and A2 receptors. To determine the interactions between adenosine A1 and A2 receptors and the possible role of adenosine as a modulator of afferent arteriolar autoregulatory responses, videomicroscopic measurements of afferent arteriolar dimensions were performed at different perfusion pressures (from 100 to 125 and 150 mm Hg) using the isolated-blood-perfused rat juxtamedullary nephron preparation. Single afferent arterioles were visualized and superfused with low or high concentrations of adenosine, either alone or with the adenosine A1 receptor antagonist 8-noradamantan-3-yl-1,3-dipropylxanthine (10 micromol/L) or the adenosine A2 receptor antagonist dimethyl-1-propargylxanthine (10 micromol/L). Adenosine (20 micromol/L) decreased afferent arteriolar diameter by -9.0+/-0.9%, and this effect was enhanced by dimethyl-1-propargylxanthine (10 micromol/L) to -16.1+/-1.2%. However, autoregulatory capability was maintained. Adenosine-induced vasoconstriction was prevented by 8-noradamantan-3-yl-1,3-dipropylxanthine (10 micromol/L) with diameter increasing by 9.6+/-1.2%. Adenosine receptor saturation with a high concentration of adenosine (120 micromol/L) or blocking A1 receptors with 8-noradamantan-3-yl-1,3-dipropylxanthine in the presence of adenosine resulted in marked vasodilation and marked impairment of autoregulatory responses to increases in perfusion pressure (-1.5+/-1.1% and -3.5+/-0.9%). However, afferent arteriolar autoregulatory responses to elevations in perfusion pressure were restored after blockade of A2 receptors alone or in combination with A1 receptor blockade. During treatment with dimethyl-1-propargylxanthine in the presence of adenosine receptor saturation (120 micromol/L), afferent arteriolar autoregulatory responses were intact (-16.5+/-1.6% and -26.4+/-2.1%). These results indicate that the interactions between adenosine A1 and A2 receptors exert important modulatory influences on afferent arteriolar tone and autoregulatory capability. Activation of A2 receptors abrogates the counteracting influences of A1 receptors leading to marked vasodilation and decreased afferent arteriolar autoregulatory efficiency.

Purinoceptors in the Kidney

The multiple roles of extracellular ATP and its metabolite adenosine include broad areas, such as regulating vascular tone and inducing inflammation. This review will discuss purinoceptor-induced effects on renal vascular resistance, highlighting the key experiments providing a significant contribution to our current understanding of autoregulatory mechanisms. Emphasis will be placed on the purinoceptor subtypes involved in autoregulatory control by ATP and adenosine. Additionally, the role of purinoceptors in hypertension-associated impairment of autoregulatory efficiency will be discussed.

Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L‐arginine and antioxidants

Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. Nomega-nitro-l-arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 +/- 4 vs. 33 +/- 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 +/- 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.

Assessment of renal autoregulation

The kidney displays highly efficient autoregulation so that under steady-state conditions renal blood flow (RBF) is independent of blood pressure over a wide range of pressure. Autoregulation occurs in the preglomerular microcirculation and is mediated by two, perhaps three, mechanisms. The faster myogenic mechanism and the slower tubuloglomerular feedback contribute both directly and interactively to autoregulation of RBF and of glomerular capillary pressure. Multiple experiments have been used to study autoregulation and can be considered as variants of two basic designs. The first measures RBF after multiple stepwise changes in renal perfusion pressure to assess how a biological condition or experimental maneuver affects the overall pressure-flow relationship. The second uses time-series analysis to better understand the operation of multiple controllers operating in parallel on the same vascular smooth muscle. There are conceptual and experimental limitations to all current experimental designs so that no one design adequately describes autoregulation. In particular, it is clear that the efficiency of autoregulation varies with time and that most current techniques do not adequately address this issue. Also, the time-varying and nonadditive interaction between the myogenic mechanism and tubuloglomerular feedback underscores the difficulty of dissecting their contributions to autoregulation. We consider the modulation of autoregulation by nitric oxide and use it to illustrate the necessity for multiple experimental designs, often applied iteratively.

Interactive modulation of renal myogenic autoregulation by nitric oxide and endothelin acting through ET-B receptors

In rats, nitric oxide modulates renal autoregulation in steady-state experiments and the myogenic mechanism in dynamic studies. Interactive modulation of autoregulation by nitric oxide and endothelin-1, predominantly involving endothelin B receptors, has been reported although it remains unclear whether the interaction is synergistic or obligatory or whether it affects the myogenic component of autoregulation. Nonselective inhibition of nitric oxide synthase (L(omega)-nitro-l-arginine methyl-ester; l-NAME) with endothelin A and B selective receptor antagonists BQ-123 and BQ-788, all infused into the renal artery, plus time series analysis were used to test the interactive actions of nitric oxide and endothelin on renal vascular conductance and on autoregulation. Nonselective endothelin receptor antagonism blunted the constrictor response to subsequent l-NAME but had no effect on previously established l-NAME-induced vasoconstriction. BQ-123 did not affect conductance and caused only minor reduction in myogenic autoregulatory efficiency. Responses to BQ-123 and l-NAME were additive and not interactive. BQ-788 and l-NAME each caused strong vasoconstriction alone and in the presence of the other, indicating that coupling between nitric oxide- and endothelin B-mediated events is not obligatory. l-NAME augmented myogenic autoregulation, and subsequent BQ-788 did not alter this response. However, BQ-788 infused alone also enhanced myogenic autoregulation but resulted in significant impairment of myogenic autoregulation by subsequent l-NAME. Thus the interaction between nitric oxide and endothelin is clearly nonadditive and, because it is asymmetrical, cannot be explained simply by convergence on a common signal pathway. Instead one must postulate some degree of hierarchical organization and that nitric oxide acts downstream to endothelin B activation.

Making sense of the sensor: Mysteries of the macula densa

Increases in luminal NaCl concentration at the macula densa (MD), the sensing element, activate tubuloglomerular feedback (TGF). MD cell volume increases when increments are isosmotic and shrinks if osmolality increases. This interesting finding introduces additional complexity to the role of the MD in TGF.

Mechanisms for Renal Blood Flow Control Early in Diabetes as Revealed by Chronic Flow Measurement and Transfer Function Analysis

The purpose of this study was to establish the roles of the myogenic response and the TGF mechanism in renal blood flow (RBF) control at the very earliest stages of diabetes. Mean arterial pressure (MAP) and RBF were measured continuously, 18 h/d, in uninephrectomized control and diabetic rats, and transfer function analysis was used to determine the dynamic autoregulatory efficiency of the renal vasculature. During the control period, MAP averaged 91 +/- 0.5 and 89 +/- 0.4 mmHg, and RBF averaged 8.0 +/- 0.1 and 7.8 +/- 0.1 ml/min in the control and diabetic groups, respectively. Induction of diabetes with streptozotocin caused a marked and progressive increase in RBF in the diabetic rats, averaging 10 +/- 6% above control on day 1 of diabetes and 22 +/- 3 and 34 +/- 1% above control by the end of diabetes weeks 1 and 2. MAP increased approximately 9 mmHg during the 2 wk in the diabetic rats, and renal vascular resistance decreased. Transfer function analysis revealed significant increases in gain to positive values over the frequency ranges of both the TGF and myogenic mechanisms, beginning on day 1 of diabetes and continuing through day 14. These very rapid increases in RBF and transfer function gain suggest that autoregulation is impaired at the very onset of hyperglycemia in streptozotocin-induced type 1 diabetes and may play an important role in the increase in RBF and GFR in diabetes. Together with previous reports of decreases in chronically measured cardiac output and hindquarter blood flow, this suggests that there may be differential effects of diabetes on RBF versus nonrenal BF control.