Changes In Renal Perfusion Pressure Research Articles

Elastin haploinsufficiency accelerates age-related structural and functional changes in the renal microvasculature and impairment of renal hemodynamics in female mice.

Age-related decline in functional elastin is associated with increased arterial stiffness, a known risk factor for developing cardiovascular disease. While the contribution of elastin insufficiency to the stiffening of conduit arteries is well described, little is known about the impact on the structure and function of the resistance vasculature, which contributes to total peripheral resistance and the regulation of organ perfusion. In this study, we determined how elastin insufficiency impinges on age-related changes in the structure and biomechanical properties of the renal microvasculature, altering renal hemodynamics and the response of the renal vascular bed to changes in renal perfusion pressure (RPP) in female mice. Using Doppler ultrasonography, we found that resistive index and pulsatility index were elevated in young Eln +/- and aged mice. Histological examination showed thinner internal and external elastic laminae, accompanied by increased elastin fragmentation in the medial layer without any calcium deposits in the small intrarenal arteries of kidneys from young Eln +/- and aged mice. Pressure myography of interlobar arteries showed that vessels from young Eln +/- and aged mice had a slight decrease in distensibility during pressure loading but a substantial decline in vascular recoil efficiency upon pressure unloading. To examine whether structural changes in the renal microvasculature influenced renal hemodynamics, we clamped neurohumoral input and increased renal perfusion pressure by simultaneously occluding the superior mesenteric and celiac arteries. Increased renal perfusion pressure caused robust changes in blood pressure in all groups; however, changes in renal vascular resistance and renal blood flow (RBF) were blunted in young Eln +/- and aged mice, accompanied by decreased autoregulatory index, indicating greater impairment of renal autoregulation. Finally, increased pulse pressure in aged Eln +/- mice positively correlated with high renal blood flow. Together, our data show that the loss of elastin negatively affects the structural and functional integrity of the renal microvasculature, ultimately worsening age-related decline in kidney function.

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Analysis of the critical determinants of renal medullary oxygenation.

We have previously developed a three-dimensional computational model of oxygen transport in the renal medulla. In the present study, we used this model to quantify the sensitivity of renal medullary oxygenation to four of its major known determinants: medullary blood flow (MBF), medullary oxygen consumption rate (V̇o2,M), hemoglobin (Hb) concentration in the blood, and renal perfusion pressure. We also examined medullary oxygenation under special conditions of hydropenia, extracellular fluid volume expansion by infusion of isotonic saline, and hemodilution during cardiopulmonary bypass. Under baseline (normal) conditions, the average medullary tissue Po2 predicted for the whole renal medulla was ~30 mmHg. The periphery of the interbundle region in the outer medulla was identified as the most hypoxic region in the renal medulla, which demonstrates that the model prediction is qualitatively accurate. Medullary oxygenation was most sensitive to changes in renal perfusion pressure followed by Hb, MBF, and V̇o2,M, in that order. The medullary oxygenation also became sensitized by prohypoxic changes in other parameters, leading to a greater fall in medullary tissue Po2 when multiple parameters changed simultaneously. Hydropenia did not induce a significant change in medullary oxygenation compared with the baseline state, while volume expansion resulted in a large increase in inner medulla tissue Po2 (by ~15 mmHg). Under conditions of cardiopulmonary bypass, the renal medulla became severely hypoxic, due to hemodilution, with one-third of the outer stripe of outer medulla tissue having a Po2 of <5 mmHg.

The influence of connexin 45 on renal autoregulation

The kidney maintains constant renal blood flow and glomerular filtration rate despite acute changes in renal perfusion pressure (RPP) via renal autoregulation. Renal autoregulation is made up of the myogenic response and the tubuloglomerular feedback (TGF) mechanism, both acting on the afferent arteriole. Both mechanisms have a conducted component, believed to proceed via gap junctions (GJ). These fluid‐filled pores are made up of two connexons, one from each cell, with connexins (Cx) as building blocks. Several Cx isoforms are expressed in the renal vessel wall, including connexin 45 (Cx45), making it a functional syncytium. Disruption of Cx expression and function in the vasculature reduces myogenic response and causes TGF dysregulation, and is associated with hypertension development. The aim of the study was to explore the influence Cx45 has on renal autoregulation.To investigate the TGF mechanism, experiments were performed using the isolated perfused juxtamedullary nephron preparation. Kidneys were isolated from wild type (WT) and smooth muscle cell knockout (KO) Cx45 mice and perfused with a Tyrode's buffer containing BSA and amino acids mixture, at pH 7.4. Local afferent vasoconstriction was induced by electrical pulse stimulation administered via microelectrode, at the glomerular entrance. RPP was kept constant at 95 mmHg and inner afferent arteriolar diameter was measured locally and at upstream sites to evaluate vascular conduction. Responses between WT and KO were compared.To investigate the myogenic response, arteriolar diameter was measured in response to changes in RPP. Experiments were performed in the same setup as previously mentioned, using a stepwise increase in RPP. Perfusion was initiated at 95 mmHg and increased in steps of 20 mmHg until 195 mmHg is reached. Inner afferent arteriolar diameter was measured 100 μm upstream from the glomerulus, and responses between WT and KO were compared. To eliminate the TGF mechanism and isolate only the myogenic response in the kidneys, papillectomy were performed before repeating the same experimental protocol. Responses between WT and KO were compared.To further investigate the influence of Cx45 in the renal vascular function, interlobar arteries from WT and KO mice were isolated and mounted in a pressure myograph. An experimental protocol consisted of stepwise pressure increases of 25 mmHg, starting at 25 mmHg until 175 mmHg is reached. Inner diameter from both WT and KO were measured and compared. In this set‐up no TGF is present.In both WT and KO mice, electrical stimulation at the glomerular pole of the afferent arteriole reduces the diameter at the local site. The conducted vasoconstriction at upstream sites was attenuated in KO mice. The conducted response is observed at 400 μm in the WT mice and 250 μm in the KO. Preliminary myogenic data shows that pressure increases induce a greater afferent vasoconstriction in WT mice and less so in the Cx45 KO. These results suggest that Cx45 may play a role in TGF signaling and myogenic response in the preglomerular vasculature and thus renal autoregulation.Support or Funding InformationThe work is part of the Dynamical Systems Interdisciplinary Network, University of CopenhagenThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute In Vivo Analysis of ATP Release in Rat Kidneys in Response to Changes of Renal Perfusion Pressure.

BackgroundATP and derivatives are recognized to be essential agents of paracrine signaling. It was reported that ATP is an important regulator of the pressure‐natriuresis mechanism. Information on the sources of ATP, the mechanisms of its release, and its relationship to blood pressure has been limited by the inability to precisely measure dynamic changes in intrarenal ATP levels in vivo.Methods and ResultsNewly developed amperometric biosensors were used to assess alterations in cortical ATP concentrations in response to changes in renal perfusion pressure (RPP) in anesthetized Sprague–Dawley rats. RPP was monitored via the carotid artery; ligations around the celiac/superior mesenteric arteries and the distal aorta were used for manipulation of RPP. Biosensors were acutely implanted in the renal cortex for assessment of ATP. Rise of RPP activated diuresis/natriuresis processes, which were associated with elevated ATP. The increases in cortical ATP concentrations were in the physiological range (1–3 μmol/L) and would be capable of activating most of the purinergic receptors. There was a linear correlation with every 1‐mm Hg rise in RPP resulting in a 70‐nmol/L increase in ATP. Furthermore, this elevation of RPP was accompanied by a 2.5‐fold increase in urinary H2O2.ConclusionsChanges in RPP directly correlate with renal sodium excretion and the elevation of cortical ATP. Given the known effects of ATP on regulation of glomerular filtration and tubular transport, the data support a role for ATP release in the rapid natriuretic responses to acute increases in RPP.

Acute toll-like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour.

Little is known about how toll-like receptor 4 (TLR4) influences the renal microvasculature. We hypothesized that acute TLR4 stimulation with lipopolysaccharide (LPS) impairs afferent arteriole autoregulatory behaviour, partially through reactive oxygen species (ROS). We assessed afferent arteriole autoregulatory behaviour after LPS treatment (1 mg kg-1 ; i.p.) using the in vitro blood-perfused juxtamedullary nephron preparation. Autoregulatory behaviour was assessed by measuring diameter responses to stepwise changes in renal perfusion pressure. TLR4 expression was assessed by immunofluorescence, immunohistochemistry and Western blot analysis in the renal cortex and vasculature. Baseline arteriole diameter at 100 mmHg averaged 15.2 ± 1.2 μm and 12.2 ± 1.0 μm for control and LPS groups (P < 0.05) respectively. When perfusion pressure was increased in 15 mmHg increments from 65 to 170 mmHg, arteriole diameter in control kidneys decreased significantly to 69 ± 6% of baseline diameter. In the LPS-treated group, arteriole diameter remained essentially unchanged (103 ± 9% of baseline), indicating impaired autoregulatory behaviour. Pre-treatment with anti-TLR4 antibody or the TLR4 antagonist, LPS-RS, preserved autoregulatory behaviour during LPS treatment. P2 receptor reactivity was normal in control and LPS-treated rats. Pre-treatment with Losartan (angiotensin type 1 receptor blocker; (AT1 ) 2 mg kg-1 ; i.p.) increased baseline afferent arteriole diameter but did not preserve autoregulatory behaviour in LPS-treated rats. Acute exposure to Tempol (10-3 mol L-1 ), a superoxide dismutase mimetic, restored pressure-mediated vasoconstriction in kidneys from LPS-treated rats. These data demonstrate that TLR4 activation impairs afferent arteriole autoregulatory behaviour, partially through ROS, but independently of P2 and AT1 receptor activation.

Renal P2 receptors and hypertension.

The regulation of extracellular fluid volume is a key component of blood pressure homeostasis. Long-term blood pressure is stabilized by the acute pressure natriuresis response by which changes in renal perfusion pressure evoke corresponding changes in renal sodium excretion. A wealth of experimental evidence suggests that a defect in the pressure natriuresis response contributes to the development and maintenance of hypertension. The mechanisms underlying the relationship between renal perfusion pressure and sodium excretion are incompletely understood. Increased blood flow through the vasa recta increases renal interstitial hydrostatic pressure, thereby reducing the driving force for transepithelial sodium reabsorption. Paracrine signalling also contributes to the overall natriuretic response by inhibiting tubular sodium reabsorption in several nephron segments. In this brief review, we discuss the role of purinergic signalling in the renal control of blood pressure. ATP is released from renal tubule and vascular cells in response to increased flow and can activate P2 receptor subtypes expressed in both epithelial and vascular endothelial/smooth muscle cells. In concert, these effects integrate the vascular and tubular responses to increased perfusion pressure and targeting P2 receptors, particularly P2X7, may prove beneficial for treatment of hypertension.

Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.

The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, KCa channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys. BLSL and AR were moderately hypertensive without kidney disease while ARSL developed severe hypertension and renal failure. In the four groups, methacholine induced biphasic endothelium-dependent responses, a transient decrease in RPP followed by a cyclooxygenase-dependent increase in RPP. In the presence or not of indomethacin, the vasodilatations were poorly sensitive to NO synthase inhibition. However, in the presence of cyclooxygenase and NO synthase inhibitors, apamin, and/or TRAM-34, blockers of KCa2.3 and KCa3.1, respectively, abolished the decrease in RPP in response to either methacholine or the two activators of KCa2.3/KCa3.1, NS309, and SKA-31. Thus, KCa2/3 channels play a major role in the regulation of murine kidney perfusion and this mechanism is maintained in hypertension, even when severe and associated with kidney damage.

Role of connexin40 in the autoregulatory response of the afferent arteriole

Connexins in renal arterioles affect autoregulation of arteriolar tonus and renal blood flow and are believed to be involved in the transmission of the tubuloglomerular feedback (TGF) response across the cells of the juxtaglomerular apparatus. Connexin40 (Cx40) also plays a significant role in the regulation of renin secretion. We investigated the effect of deleting the Cx40 gene on autoregulation of afferent arteriolar diameter in response to acute changes in renal perfusion pressure. The experiments were performed using the isolated blood perfused juxtamedullary nephron preparation in kidneys obtained from wild-type or Cx40 knockout mice. Renal perfusion pressure was increased in steps from 75 to 155 mmHg, and the response in afferent arteriolar diameter was measured. Hereafter, a papillectomy was performed to inhibit TGF, and the pressure steps were repeated. Conduction of intercellular Ca(2+) changes in response to local electrical stimulation was examined in isolated interlobular arteries and afferent arterioles from wild-type or Cx40 knockout mice. Cx40 knockout mice had an impaired autoregulatory response to acute changes in renal perfusion pressure compared with wild-type mice. Inhibition of TGF by papillectomy significantly reduced autoregulation of afferent arteriolar diameter in wild-type mice. In Cx40 knockout mice, papillectomy did not affect the autoregulatory response, indicating that these mice have no functional TGF. Also, Cx40 knockout mice showed no conduction of intercellular Ca(2+) changes in response to local electrical stimulation of interlobular arteries, whereas the Ca(2+) response to norepinephrine was unaffected. These results suggest that Cx40 plays a significant role in the renal autoregulatory response of preglomerular resistance vessels.

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Impaired renal blood flow autoregulation and renal damage in a mouse model of reduced βENaC

Previous studies from our laboratory indicate β Epithelial Na+ Channel (βENaC) mediates myogenic constriction in small renal arteries. Although studies suggest myogenic constriction contributes to renal blood flow (RBF) autoregulation (AR) and protects the kidney from injury, the importance of myogenic constriction in AR and renal injury has not been tested. Thus, the aim of this study was to test the hypothesis that suppression of βENaC impairs RBF‐AR and leads to renal damage. We evaluated steady state changes in RBF in response to step increases in renal perfusion pressure (RPP) in anesthetized mice with reduced levels of βENaC (m/m) and littermate controls (+/+ and +/‐). The autoregulatory index (AI) was calculated as: AI=[(RBF2‐RBF1)/RBF1]/[(RPP2‐RPP1)/RPP1]. AR to step changes in RPP was impaired in m/m compared with control mice, as indicated by higher AI (m/m=1.8±0.2, n=4 vs. control=0.2±0.07, n=3). 24‐hour urine albumin excretion and macrophage infiltration, markers of renal injury, were assessed. Urinary albumin excretion was higher in m/m (12.8 [0]± 1.4 μg/day, n=13) than in +/+ mice (9.3 ± 1.2, n=9, p=0.04). Furthermore, macrophage infiltration was higher in the renal cortex of m/m vs. +/+ mice (33 ± 1.4 cells, n=3; 9.3 ± 1.1, n=3, respectively). These data suggest that reduction in βENaC expression impairs RBF‐AR and may predispose the kidney to hypertension‐related injury. Supported by: NIH‐NHLBI, AHA

C014 Endothelial dysfunction in isolated perfused kidneys of L-NAME-treated spontaneous hypertensive rats

In hypertensive humans, the development of end-stage renal disease is often associated with an endothelial dysfunction attributed to a decrease in the bioavailability of nitric oxide (NO). An early endothelial dysfunction is also reported in most animal models of hypertension and profound alterations in renal function are observed in aged hypertensive animals. As kidneys play an important role in blood pressure regulation, the purpose of the present study was to determine whether a chronic treatment with a NO synthase inhibitor, L-NAME (Nω- nitro-L-arginine methyl ester) accelerates the renal dysfunction in younger adult spontaneously hypertensive rats (SHR). Indeed, in this model, the alterations in cardiac function mimic those observed in aging SHR. Male SHR were subjected to chronic L-NAME-treatment (6 mg/ kg/day) for two weeks. At 19 weeks, the kidneys were isolated, perfused with oxygenated physiological salt solution and changes in renal perfusion pressure continuously recorded. During a sustained constriction caused by methoxamine, bolus injections of acetylcholine and of the NO donor sodium nitroprusside caused dose-dependent dilatations in both groups of SHR. The responses to acetylcholine were not affected by the L-NAME treatment while those to sodium nitroprusside were significantly augmented. In the two groups, indomethacin, a cyclooxygenase inhibitor, did not affect the vasodilatation caused by acetylcholine. However, an acute treatment with another NO synthase inhibitor, L-nitroarginine, produced a major inhibition of the acetylcholine response in the SHR while it did not affect it in the kidney of SHR chronically treated with L-NAME. In the presence of indomethacin plus L-nitro-arginine, TRAM-34, an inhibitor of Ca2+-activated K+ channels of intermediate conductance, IK(Ca), blocked the responses to acetylcholine in both groups of SHR. These data show that in SHR, the acetylcholine-induced vasodilatation involves both NO release and an endothelium-derived hyperpolarizing factor (EDHF)-mediated component while in the L-NAME-treated SHR, the NO-component is abolished and the EDHF-mediated component becomes the major contributor to this vasodilatation. In the kidney of L-NAME-treated SHR, EDHF-mediated responses are a compensatory mechanism that sustain endothelium-dependent dilatations when NO activity is impaired. The responses involve IK(Ca), activation and must be further characterized.

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 …

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.

N-Terminal-Pro-B–Type Natriuretic Peptide

Plasma brain-type natriuretic peptide (BNP) and amino-terminal proBNP (NTproBNP) provide prognostic information on cardiovascular morbidity and mortality beyond that provided by standard risk factors. Clinical applications of B-type peptides under ongoing research include their use in diagnosing acute heart failure (HF), in risk stratification in both acute and established HF, in acute coronary syndromes (ACS), in asymptomatic populations at cardiovascular risk (older adults and people with hypertension), and as part of a screening strategy for detection of left ventricular impairment and prediction of cardiovascular risk in the general population.1,2 In this issue of Circulation , Campbell and colleagues3 assess the ability of NTproBNP to predict myocardial infarction (MI) in subjects who have experienced a cerebrovascular event. NTproBNP (reflecting cardiac distension) is compared with C-reactive protein (a systemic marker of inflammation) and renin (a marker of sodium status regulated by renal perfusion and delivery of sodium to the renal glomerulus). See p 110 The nested case-control study is from the 6105 participants in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of converting enzyme inhibitor–based therapy in patients with previous cerebrovascular events.4 Within PROGRESS, 206 subjects incurred an MI during 3.9 years of follow-up. The investigators matched those incurring an MI with control PROGRESS patients avoiding MI from time of randomization to time of case ascertainment. Cases and controls were matched for age, gender, treatment allocation, region, and cerebrovascular qualifying event. The form of matching meant that individual patients may have been controls initially and subsequently became cases on incurring an MI during further follow-up. Matching in this fashion may confuse the interpretation of the nonconditioned analysis of baseline variables. Comparing the 206 cases with 412 controls at randomization, the investigators report that in addition to higher systolic blood pressure, more frequent known coronary disease, …

THE ‘BODY FLUID PRESSURE CONTROL SYSTEM’ RELIES ON THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM: BALANCE STUDIES IN FREELY MOVING DOGS

1. The physiological role of the 'renal body fluid pressure control system', including the intrarenal mechanism of 'pressure natriuresis', is uncertain. 2. Balance studies in freely moving dogs address the following questions: (i) what is the physiological contribution of pressure natriuresis to the control of total body sodium (TBS); (ii) to what extent is long-term mean arterial blood pressure (MABP) determined by TBS and total body water (TBW); and (iii) during Na accumulation, is Na stored in an osmotically inactive form? 3. Diurnal time-courses of Na excretion (U(Na)V) and MABP reveal no correlation. Spontaneous MABP changes do not affect U(Na)V. The long-term 20% reduction of renal perfusion pressure (RPP) results in Na retention via pressure-dependent stimulation of the renin-angiotensin-aldosterone system (RAAS), not via a pressure natriuresis mechanism. Prevention of pressure natriuresis does not result in ongoing Na retention when the RAAS is operative. The long-term 20% elevation of RPP induced by sustained TBS elevation facilitates Na excretion via pressure natriuresis, but does not restore TBS to normal. 4. Changes in TBW correlate well with changes in TBS (r(2) = 0.79). This correlation is even closer when concomitant changes in total body potassium are also considered (r(2) = 0.91). 5. With normal or elevated TBW, long-term MABP changes correlate well with TBW changes (r(2) = 0.69). At lowered TBW, no correlation is found. 6. In conclusion, the physiological role of pressure natriuresis is limited. Pressure natriuresis does not appear to be operative when RPP is changed from -20 to +10% and neurohumoral control of U(Na)V is unimpeded. Within this range, pressure-dependent changes in the RAAS mediate the effects of changes in RPP on U(Na)V. Pressure natriuresis may constitute a compensating mechanism under pathophysiological conditions of substantial elevation of RPP. A large portion of the long-term changes in MABP are attributable to changes in TBW. The notion of osmotically inactive Na storage during Na accumulation appears to be invalid.

The step response: a method to characterize mechanisms of renal blood flow autoregulation.

Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow (RBF) is mediated by the rapid myogenic response, by the slower tubuloglomerular feedback (TGF) mechanism, and, possibly, by an even slower third mechanism. To evaluate the individual contribution of these mechanisms to RBF autoregulation, we analyzed the response of RBF to a step increase in RPP. In anesthetized rats, the suprarenal aorta was occluded for 30 s, and then the occlusion was released to induce a step increase in RPP. Three dampened oscillations were observed; their oscillation periods ranged from 9.5 to 13 s, from 34.2 to 38.6 s, and from 100.5 to 132.2 s, respectively. The two faster oscillations correspond with previously reported data on the myogenic mechanism and the TGF. In accordance, after furosemide, the amplitude of the intermediate oscillation was significantly reduced. Inhibition of nitric oxide synthesis by Nomega-nitro-l-arginine methyl ester significantly increased the amplitude of the 10-s oscillation. It is concluded that the parameters of the dampened oscillations induced by the step increase in RPP reflect properties of autoregulatory mechanisms. The oscillation period characterizes the individual mechanism, the dampening is a measure for the stability of the regulation, and the square of the amplitudes characterizes the power of the respective mechanism. In addition to the myogenic response and the TGF, a third rather slow mechanism of RBF autoregulation exists.

α2-Adrenoceptors Potentiate Angiotensin II- and Vasopressin-Induced Renal Vasoconstriction in Spontaneously Hypertensive Rats

Hypertension in spontaneously hypertensive rats (SHRs) is due in part to enhanced effects of vasoactive peptides on the renal vasculature. We hypothesize that the G(i) signal transduction pathway enhances renovascular responses to vasoactive peptides in SHRs more so than in normotensive Wistar-Kyoto (WKY) rats. To test this hypothesis, we examined in isolated perfused kidneys from SHRs and WKY rats the renovascular responses (assessed as changes in renal perfusion pressure in mm Hg) to angiotensin II (10 nM) and vasopressin (3 nM) in the presence and absence of UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; an agonist that selectively activates the G(i) pathway by stimulating alpha(2)-adrenoceptors]. In SHR, but not WKY, kidneys, UK-14,304 (10 nM) enhanced (P < 0.05) renovascular responses to angiotensin II (control WKY, 43 +/- 6; UK-14,304-treated WKY, 52 +/- 19; control SHR, 66 +/- 17; UK-14,304-treated SHR, 125 +/- 16) and vasopressin (control WKY, 42 +/- 17; UK-14,304-treated WKY, 36 +/- 11; control SHR, 16 +/- 8; UK-14,304-treated SHR, 83 +/- 17). Pretreatment of SHRs with pertussis toxin (30 microg/kg, intravenously, 3-4 days before study) to inactivate G(i) blocked the effects of UK-14,304. Western blot analysis of receptor expression in whole kidney and preglomerular microvessels revealed similar levels of expression of AT(1), V(1a), and alpha(2A) receptors in SHRs compared with WKY rats. We conclude that activation of alpha(2)-adrenoceptors selectively enhances renovascular responses to angiotensin II and vasopressin in SHRs via an enhanced cross talk between the G(i) signal transduction pathway and signal transduction pathways activated by angiotensin II and vasopressin.

Influence of progressive renal dysfunction in chronic heart failure.

Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.

Blood flow-dependent changes in renal interstitial guanosine 3',5'-cyclic monophosphate in rabbits.

We examined responses of renal interstitial guanosine 3',5'-cyclic monophosphate (cGMP) to changes in renal perfusion pressure (RPP) within and below the range of renal blood flow (RBF) autoregulation. A microdialysis method was used to monitor renal cortical and medullary interstitial cGMP levels in anesthetized rabbits. RPP was reduced in two steps: from ambient pressure (89 +/- 3 mmHg) to 70 +/- 2 mmHg (step 1) and then to 48 +/- 3 mmHg (step 2). RBF was maintained in step 1 but was significantly decreased in step 2 from 2.94 +/- 0.23 to 1.47 +/- 0.08 ml x min(-1) x g(-1). Basal interstitial concentrations of cGMP were significantly lower in the cortex than in the medulla (12.1 +/- 1.4 and 19.9 +/- 0.4 nmol/l, respectively). Cortical and medullary cGMP did not change in step 1 but were significantly decreased in step 2, with significantly less reduction in cGMP concentrations in the medulla than in the cortex (-25 +/- 3 and -44 +/- 3%, respectively). Over this pressure range, changes in cortical and medullary cGMP were highly correlated with changes in RBF (r = 0.94, P < 0.005 for cortex; r = 0.82, P < 0.01 for medulla). Renal interstitial nitrate/nitrite was not changed in step 1 but was significantly decreased in step 2 (-38 +/- 2% in cortex and -20 +/- 2% in medulla). Nitric oxide synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg bolus, 50 mg x kg(-1) x h(-1) i.v. infusion) significantly decreased RBF (by -46 +/- 4%) and interstitial concentrations of cGMP (-27 +/- 4% in cortex and -22 +/- 4% in medulla, respectively). During L-NAME treatment, renal interstitial concentrations of cGMP in the cortex and medulla were similarly not altered in step 1. However, L-NAME significantly attenuated cGMP responses to a reduction in RPP in step 2. These results indicate that acute changes in RBF result in alterations in nitric oxide-dependent renal interstitial cGMP levels, with differential effects in the medulla compared with the cortex.