© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Kinins modulate the sodium-dependent autoregulation of renal medullary blood flow
Institut für Physiologie der Charité, Humboldt Universität, Tucholskystrasse 2, D-10117 Berlin, Germany
* Corresponding author. Tel.: +49-(30)-2802-6623; fax: +49-(30)-2802-6662.
Received 19 January 1998; accepted 27 April 1998
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Abstract |
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Objective: In the recent past it has become clear that the kallikrein–kinin system is closely intertwined with long-term blood pressure regulation. It was shown that a kinin B2 receptor blockade leads to a sodium-dependent rise in blood pressure. The underlying mechanisms of this phenomenon, however, remain unclear. The osmotic gradient of the renal medulla is a prerequisite for the preservation of volume and sodium by the kidney. We thus hypothesized, that a kinin dependent modulation of medullary blood flow accounts for the influence of sodium on blood pressure. Methods: In 39 urethane anaesthetized rats pressure dependent regulation of whole kidney blood flow and cortical and medullary blood flow were estimated via laser-Doppler flux by a stepwise reduction of renal perfusion pressure to 30 mm Hg. Results: In controls (n=15), a reduction in renal perfusion pressure to 30 mm Hg lead to a concomitant reduction in whole kidney blood flow (25±3% of baseline) and cortical laser-Doppler flux (36±5% of baseline). In contrast, medullary laser-Doppler flux decreased only to 79±8% of the baseline level. Providing a 2% sodium chloride solution as drinking water over 5 days (n=12), resulted in a significantly lower capability to autoregulate medullary flow (50±6% of baseline, P<0.05). Acute subcutaneous administration of Hoe 140, a bradykinin B2 receptor antagonist (300 µg/kg bwt), restored autoregulation of medullary flow to almost normal levels (93±12% of baseline, P<0.01 versus high sodium diet alone, n=12). Conclusions: Our results indicate that B2 receptor blockade restores the attenuated autoregulation of medullary Doppler flux during sodium enriched diet. This, suggests that the kinin dependent impact of sodium on blood pressure regulation is mediated by modulations of medullary blood flow autoregulation.
KEYWORDS Hoe 140; Renal hemodynamics; Blood flow; Blood pressure; Rat
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Bradykinin is a peptide, which constitutes a major component of the kallikrein–kinin system. It is released by proteolytic enzymes, the kallikreins, from its precursors, the kininogens. Beside plasmatic kallikreins, nearly all components of the kallikrein–kinin system have been localized at the distal tubules of the kidney [1, 2]. Furthermore, it is widely accepted that intrarenal infusions of pharmacological doses of bradykinin increase sodium excretion as well as renal fluid loss [3–5], and cause acute vasodilation [6]. It seems, therefore, not surprising that several investigators observed a close relationship between urinary kallikrein levels and systemic blood pressure [7–10]. In addition, it has been shown that a high sodium intake causes a fall in active urinary kallikrein and prokallikrein excretion [10]. In the same study the authors observed that a sodium loading (2% NaCl diet) over 4 weeks can be well compensated for by normal rats, i.e., the animals showed only minor changes in arterial blood pressure. In contrast to healthy rats, kininogen deficient Brown Norway Katholiek rats, which underwent the same treatment, developed a time dependent hypertension, showing a maximum in systolic blood pressure of about 170 mm Hg during the study. Taken together, these findings indicate that the renal kallikrein–kinin system is involved in long-term blood pressure regulation, not only in states with a high sodium load, but probably also under normal conditions.
In contrast to the well established involvement of kinins in renal sodium and water handling, very little is known about the underlying mechanisms. The renal preservation of sodium is dependent on the existence of an osmotic gradient within the renal medulla. An increase in medullary blood flow leads to a more or less pronounced wash out and, thereby, attenuates the ability of the kidney to form a concentrated urine. Thus, the latter is dependent upon a well controlled blood flow through the vasa recta. An attenuated autoregulatory ability of medullary blood flow would increase perfusion in parallel to a rise in blood pressure and hence may explain pressure natriuresis. We propose, that the local kallikrein–kinin system in addition or even independently of blood pressure can modulate medullary blood flow. An enhancement in plasma sodium may indirectly increase the pressure dependence of medullary blood flow via the kallikrein–kinin system. This would facilitate a wash out of the osmotic gradient in the renal medulla, possibly increase the interstitial hydrostatic pressure in this region of the kidney and, therefore, support the elimination of the surplus sodium.
In the present study we pursued this question by determining the ability of the kidney to autoregulate medullary blood flow under normal conditions, during a high-salt diet, and during a high-salt diet combined with an acute blockade of bradykinin B2 receptors.
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2 Methods |
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All experiments were performed on 39 male, adult Sprague–Dawley rats weighing 350–400 g, which received a standard rat diet (Altromin 1314). One day prior to the measurements the animals were deprived of food but allowed free access either to normal water (NaCl content <0.1 g/l, control group) or to water with a NaCl content of 20 g/l (intervention groups). The investigation conforms with the Guide for the Care and the Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
2.1 Implantation surgery
All operations were done under aseptic conditions. On the day of the study, general anaesthesia was introduced and maintained by 1 g/kg bwt urethane i.p. (Sigma). The animals were then placed on a thermostated table to maintain normal body temperature. After an incision in the left groin, a polyethylene catheter (I.D.: 0.54 mm, O.D.: 0.96 mm with narrowed tip) was implanted into the left femoral artery in such a way that the tip was placed distally to both renal arteries. A schematic of the implantations is depicted in Fig. 1. Another catheter of the same dimensions was inserted into the femoral vein. The latter line was used to continuously infuse a warmed (37°C) solution of 0.9% NaCl (10 ml/h/kg bwt) throughout the surgery and the following experiment. The abdominal cavity was then opened via a midventral incision and the left renal artery and vein were prepared. After stripping all visible nerve fibres, denervation of the kidney was completed by painting the renal artery with a phenol solution (5% phenol in ethanol). An ultrasound transit time flow probe (Type 1RB, Transonic Systems) was positioned around the left renal artery. In addition, a 500-µm optical fibre (PF500, Fiberware), with a patch attached near one end, was inserted into the renal cortex and another one into the renal medulla using a technique similar to that described by Mattson et al. [11]. The patch of both fibres was then fixed directly on the renal capsule using enbucrilate (Braun Melsungen). Finally, an inflatable cuff was placed around the aorta, above the origin of the renal arteries. The cuff and the arterial catheter were connected to an extracorporal electro-pneumatic pressure control system which allowed us to reduce and to maintain renal perfusion pressure (RPP) on a preset level with high precision [12].
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2.2 Measurements
Blood pressure (BP) was measured in the abdominal aorta by means of a Statham pressure transducer (Type P23Db) and a Gould pressure processor. Heart rate (HR) was recorded instantaneously with a rate meter (4600 Gould pressure processor). Whole kidney blood flow (RBF) was measured continuously via the ultrasound transit time flowprobe, placed around the renal artery (I.D.=1 mm). The optical fibres were connected via a specifically designed probe and a modified clip (PM10, Moore Instruments) to a two-channel laser-Doppler flux monitor (MBF3D, Moore Instruments). To minimize the loss of light along the line, a matching gel (Moore Instruments) was introduced into the connection. Briefly, this device uses the Doppler effect to determine the velocity of red blood cells in an illuminated section of tissue. In addition, the controller of the laser-Doppler monitor analyses differences in intensity between the emitted and the received light to determine the number of moving cells. These interim results are used by the instrument to calculate an index (for further details see [13]), which has been shown to qualitatively reflect local blood flow in different regions of the kidney [11].
During the experiments, BP, HR, RBF, laser-Doppler flux (LDF) of the renal medulla (LFM), and LDF of the renal cortex (LFC) were recorded continuously. After analog-to-digital conversion, all data were stored on-line by a computer system (IBM compatible PC, Labtech Notebook). HR was sampled every fifth second. Direct signals of the BP, RBF, LFM, and LFC were concomitantly stored with a sampling rate of 100 Hz.
2.3 Experimental protocols
All experiments were started in the early morning to avoid interferences with circadian rhythms, e.g., renin liberation. The air conditioned laboratory was strictly isolated from disturbances and the animals were connected to the recording instruments via extension cables. At the beginning of the experiments proper function of the LDF measurement was tested by a short reduction in RPP to nearly 0 mm Hg (Fig. 2). As depicted, the sudden fall and the following rise in RPP were accompanied by similar time courses of RBF, LFC and LFM. If the step decrement in RPP did not lead to a concomitant reduction in LFC and LFM, the animals were excluded from the study. In addition, proper location of the optical fibres within the kidney was verified at the end of the experiment by inspecting the location of the fibre tips.
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2.4 Validation of the LDF measurement
Fig. 2 shows an original recording of a single experiment. It is apparent that an occlusion of the inflatable cuff elicited a brusque fall in RPP down to roughly 0 mm Hg (panel A). This sudden fall in RPP was rapidly followed by a reduction in RBF, which reached almost 0 ml/min during the occlusion (panel B). Since this test was performed to test for proper function of the implanted optical fibres special attention was paid to the decline and the minimum level of the LFC and LFM signals, which are depicted on panel C and panel D, respectively. All three blood flow signals responded to the single step deflation of the aortic cuff by a more or less pronounced overshoot. This hyperaemia was followed by a slow downward trend of the whole kidney blood flow (panel B) as well as the LFC signal (panel C). In contrast, the hyperaemic reaction of the renal medulla was somewhat shorter and LFM was restored to baseline levels within only a few seconds (panel D). If the LDF signals of the optical fibres did not follow the brusque fall in RPP within a few seconds, the animals were excluded from the study.
Only a minor fraction of the blood which passes through the renal artery reaches the renal medulla. Thus, the blood flow of the renal cortex nearly represents whole kidney blood flow. It was, therefore, possible to validate the output of the cortical fibre by performing a regression analysis between the LFC signal and RBF, measured via the transit time flowprobe. A stepwise reduction in RPP from 90 to 30 mm Hg was used to elicit concomitant changes in RBF as well as in LFC. The statistical analysis of these data revealed a tight coupling between the blood flow signals of the control group (
, r=0.97, n=15) as well as of group 2 (
, r=0.99, n=12) and of group 3 (
, r=0.99, n=12). Remarkably, the regression line intersected the y-axis around a value of 20% in all groups instead of reaching the origin (Fig. 3). The ‘offset’ of the RBF and the laser Doppler measurements were determined via a single-step reduction in RPP to 0 mm Hg (Table 1). The mean values±S.E. which were obtained during each protocol are shown in Fig. 4.
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2.5 Local autoregulation
2.5.1 Control conditions
After a stabilization period of 30 min the animals received 0.5 ml 0.9% NaCl s.c. This vehicle administration served to avoid different volume loading between the experimental groups. Resting blood pressure RBF, LFC, and LFM of the 15 rats in this group, were then continuously recorded for a period of 10 min with a sampling rate of 100 Hz (HR with a sampling rate of 0.2 Hz). Afterwards the extracorporal control system was adjusted to reduce mean RPP stepwise to the following pressures 90, 80, 70, 60, 50, 40 and 30 mm Hg. RPP was stabilized at every pressure level for a period of 10 min. The pneumatic cuff was then deflated completely and about 10–20 min were allowed for recovery.
2.5.2 Sodium intake and local autoregulation
The 12 animals of this group served to investigate the influence of an enhanced sodium intake on the autoregulation of cortical and medullary blood flow. To this end, the rats received drinking water with a NaCl content of 2% (20 g/l) instead of water with a NaCl content <0.01% over 5 days before experimentation. All other treatment and the measurements were conducted as in the control group.
2.5.3 Influence of kinins on local autoregulation
The 12 rats of this group were provided drinking water with a NaCl content of 2% over the last 5 days prior to the experiment. At the end of the stabilization period the animals received a subcutaneous bolus injection of the bradykinin B2 receptor antagonist Hoe 140 (300 µg/kg bwt dissolved in 0.5 ml isotonic saline). This dose has been shown earlier to significantly reduce the blood pressure lowering effect of an intraarterial bradykinin administration for more than 3 h [5]. Thereafter, RPP, RBF, LFC and LFM were determined with the same protocol as used in the control group.
2.6 Data analysis
The first 10 min after the stabilization period were used to calculate mean baseline values of RPP, HR, RBF, LFC and LFM, respectively. Data were expressed as percent of the baseline level unless stated otherwise. The relationship between changes in LFC and RBF was evaluated by a linear regression analysis. Statistical comparisons were made by advanced analysis of variance (ANOVA) and the Student–Newman–Keuls test was used for post hoc testing. A probability level of P<0.05 was taken to indicate significance. All data are depicted as means±S.E. unless stated otherwise.
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3 Results |
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The fluid intake of the animals on a normal sodium diet was significantly lower than the fluid intake of the animals with a high sodium intake (control group: 38±1 ml/24 h; group 2: 62±5 ml/24 h, P<0.01 vs. control; group 3: 65±4 ml/24 h, P<0.01 vs. control). No significant differences in basal BP, HR, blood flow or haematocrit were observed (Table 1).
3.1 Influence of sodium intake on local autoregulation
As presented in panel A of Fig. 4, a stepwise reduction in RPP under control conditions elicited a concomitant fall in RBF below 90 mm Hg (, n=15). A regression analysis of the data revealed a mean slope of about 8–9% change in RBF/10 mm Hg in this range. No significant differences were observed between the control group and the sodium loaded animals (, n=12). Panel B shows the signals of LFC, which were obtained concomitantly with the signals of whole kidney blood flow. Although, the course of these curves differed slightly between the control group and the sodium loaded animals none of the deviations reached statistical significance. In contrast, the medullary LDF signals of the control group autoregulated to a larger degree (panel C, ). The high sodium diet blunted LFM autoregulation (panel C, ). Thus, LFM fell to nearly 50% during the stepwise pressure reduction.
3.2 Influence of kinins on local autoregulation
The results from the animals (n=12) treated with the bradykinin receptor B2 antagonist are shown in Fig. 4. As observed under control conditions, RBF as well as LFC were similarly affected by the reduction in RPP (panel A and B). The comparison between the RBF values of this group, group 2, and the control group revealed no significant differences with respect to RBF or LFC. In contrast, Hoe 140 reestablished LFM autoregulation in the animals of this group. Thus, at a pressure of 70 mm Hg and at all lower RPP levels, LFM differed significantly from the values of group 2 (closed circles).
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4 Discussion |
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Our data provide evidence that enhanced sodium uptake attenuates the capability of the kidney to autoregulate LFM at a reduced RPP. Acute B2 receptor blockade reestablishes LFM autoregulation under these conditions.
The animals used in this study drank significantly higher volumes of water during the sodium rich diet than under control conditions. This data is in accordance with results of previous experiments and probably reflects an increased water and electrolyte turn-over during sodium load [14]. The interdependence between such an increased intake of sodium and the development of hypertension has been subject to a number of studies in the recent years [15–22]. These studies show that a long-term sodium load can, to a certain extent, elevate systemic blood pressure in healthy animals. This observation seems to imply a direct coupling between blood pressure and sodium load, even under conditions of an intact excretory function of the kidney. In several experiments, however, very high sodium concentrations (around 8%) were used to induce hypertension in rats. Meneely et al. [23]reported that such high dietary sodium challenge can lead to histologically visible damage of the kidney. Thus, it seems likely that a rise in blood pressure observed after such high sodium intake [23, 24]is due to renal damage rather than to a physiological modulation in renal excretory function. The findings of Majima et al. [10]speak in favour of this interpretation. The authors observed that kininogen deficient Brown Norway Katholiek (BNK) rats developed hypertension between the 8th and the 11th week of age in response to a 2% NaCl diet. The healthy control rats, in contrast, showed no significant increase in systolic blood pressure during this treatment. Increasing the sodium content of the diet to 6% or 8% not only affected the blood pressure of the BNK rats, but also caused a significant increase in blood pressure of healthy animals.
In our study, the animals received 2% NaCl with the drinking water over a period of 5 days. Since, under this regime renal damage is not to be expected, we assume that the observed changes in medullary blood flow autoregulation are due to sodium-dependent modulations in physiological mechanisms, e.g., the renal kallikrein–kinin system.
In the last decades several potential mechanisms, which may cause an interdependence between sodium intake and blood pressure regulation, have been investigated in order to enhance the understanding of sodium-dependent changes in blood pressure regulation. Major attention was paid on humoral factors, e.g. the renin–angiotensin system, including aldosterone [25], and neural mechanisms, such as the sympathetic outflow from the central nervous system [26]. In spite of the insight provided by these studies, the underlying mechanisms of salt dependent changes in blood pressure are still not fully understood. One major limitation is the difficulty to assess the intrarenal structures, which are functionally modulated by a change in sodium intake. This was partly overcome by adapting laser-Doppler flux measurement in the early 1990s to qualitative measurements of medullary and cortical blood flow [11, 27, 28]. Although this method has limitations, it has several advantages compared to previous techniques, e.g. microsphere distribution, indicator dilution, and videomicroscopy (see [29, 30]for review). One difficulty is to assure proper location and proper function of the optical fibres during the measurements. As shown in Figs. 2 and 3
, we used two different approaches to assure proper function. In both cases, testing for the dynamical answer to a sudden fall in RPP (Fig. 2) and comparing the LFC with transit time measurements of RBF (Fig. 3), we observed close correlations to the established transit time method. These results were stable throughout all groups and, therefore, independent of the pretreatment of the animals. Interestingly, however, the regression analysis revealed an ‘offset’ of the LDF measurement especially at very low RPP (Fig. 3). An analysis of earlier studies revealed a similar ‘offset’ phenomenon: Majiid et al. lowered RPP to 10 mm Hg in the anaesthetized dog. Due to this intervention LFC was reduced to 
25%, in contrast to the reading of the electromagnetic flow probe, which was close to 0 ml/min [31]. Mattson et al. lowered RPP to 70 mm Hg in the anaesthetized rat and noted a similar offset by comparing the readings of an electromagnetic flowmeter with the readings of the LDF measurement [11]. The phenomenon may be caused by the temperature dependent motion of the erythrocytes within the blood vessels. In addition, the tendency of erythrocytes to aggregate at very low flow-rates may contribute to the flux values at low RPP. It seems, therefore, likely that in our experiments medullary blood flow, especially at low RPP, is lower than indicated by the laser Doppler signals. Currently, however, it is not clear if this high flux values are completely due to a limitation of LDF or if they may also reflect some physiological mechanism.
In our experiments we found an attenuated renal medullary blood flow autoregulation after feeding the animals a high-salt diet prior to the experiments (Fig. 4). With respect to the mentioned limitations, however, we cannot exclude that the observed lack of autoregulation may even be underestimated by our results. There have been previous studies which discuss renal medullary blood flow autoregulation controversially [11, 32, 33]. According to our data, LFM autoregulation is very sensitive to a sodium load. Thus, it seems likely, that studies carried out on hydropenic or volume loaded rats reveal other pressure–flow relationships than those achieved in animals on a normal fluid and/or sodium state. This hypothesis is supported by a recent study [34]in which it was observed that water restriction is profoundly intertwined with the autoregulation of LFM.
The role of the kallikrein–kinin system in the sodium-dependent development of hypertension, has been pointed out in rat strains devoid of kininogen [10], as well as during bradykinin B2 receptor blockade [10]. Mattson et al. [27]have shown that infusion of bradykinin into the renal medullary interstitium significantly increases local blood flow of this region. We tested the importance of bradykinin for renal autoregulation by administering the B2 receptor antagonist Hoe 140 to rats, which were fed a high-sodium diet over 5 days. As depicted in Fig. 4, the antagonist entirely abolished the effect of the sodium load on LFM. In spite of this clear response, we observed no major influences of the antagonist on whole kidney blood flow (RBF, panel A), or on LFC (panel B).
However, LFM autoregulation is influenced by several other factors, e.g., prostaglandins and endothelium derived nitric oxide [35], which may contribute to the influence of kinins on LFM. On the other hand, a sodium dependent modulation of counteregulatory systems (vasopressin, endothelin) may reduce or even overrule the impact of kinins on LFM autoregulation under normal conditions.
In conclusion, the data of the present study reveal a close relationship between autoregulation of medullary blood flow and sodium intake. Thus, enhanced sodium intake may lead to a wash out of the renal medulla and, therefore, enhance its own elimination. This sodium-dependent LFM autoregulation, is to a great extent dependent on renal kinins. This implies that the kallikrein–kinin system may be of particular importance in states with an increased sodium-dependence of BP regulation, e.g., in the development of sodium-dependent hypertension. In addition, kinins may contribute via a change in LFM autoregulation to the saluretic effect of ACE-inhibitors during enhanced sodium uptake.
Time for primary review 18 days.
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Acknowledgements |
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We are indebted to A. Gerhardt for expert technical assistance and skilful animal caretaking. We thank Dr. K. Wirth and Dr. B.A. Schölkens (Hoechst) for providing us with the bradykinin B2 receptor antagonist Hoe 140. This study was supported by the German Research foundation.
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 G. A. Eppel, G. Bergstrom, W. P. Anderson, and R. G. Evans Autoregulation of renal medullary blood flow in rabbits Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R233 - R244. [Abstract] [Full Text] [PDF]
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