NO dependency of RBF and autoregulation in the spontaneously hypertensive rat - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:40 |只看该作者 |倒序浏览 |打印

作者：Simona Racasan, Jaap A. Joles, Peter Boer, Hein A. Koomans, and Branko Braam作者单位：Department of Nephrology and Hypertension, University Medical Center, 3508 GA Utrecht, The Netherlands
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      【摘要】. t% V5 x  L6 B8 E2 ~
   In the spontaneously hypertensive rat (SHR), renal blood flow (RBF) has been reported to be very dependent on nitric oxide (NO); however, autoregulation is normal, albeit shifted to higher perfusion pressures. To test the hypothesis that in the SHR NO dependency of RBF autoregulation is diminished, we investigated RBF autoregulation in anesthetized young male SHR and normotensive Wistar-Kyoto (WKY) rats before and during acute intravenous NO synthase (NOS) inhibition with N -nitro- L -arginine ( L -NNA) and urinary excretion of nitrate plus nitrite (U NOx V) at different renal perfusion pressures (RPP). Under baseline conditions, SHR had higher mean arterial pressure (147 ± 4 mmHg) and renal vascular resistance (16 ± 1 U) than WKY (105 ± 4 mmHg and 10 ± 0.5 U, respectively, P < 0.05). RBF was similar (9.4 ± 0.5 vs. 10.3 ± 0.1 ml · min -1 · g kidney wt -1 ). Acute NOS blockade increased mean arterial pressure similarly, but there was significantly more reduction in RBF and hence an enhanced increase in renal vascular resistance in SHR (to 36 ± 3 vs. 17 ± 1 U in WKY, P < 0.001). The renal vasculature of SHR is thus strongly dependent on NO in maintaining basal RBF. The lower limit of autoregulation was higher in SHR than WKY in the baseline situation (85 ± 3 vs. 71 ± 2 mmHg, P < 0.05). Acute L -NNA administration did not decrease the lower limit in the SHR (to 81 ± 3 mmHg, not significant) and decreased the lower limit to 63 ± 2 mmHg ( P < 0.05) in the WKY. The degree of compensation as a measure of autoregulatory efficiency attained at spontaneous perfusion pressures was comparable in SHR vs. WKY but with a shift of the curve toward higher perfusion pressures in SHR. Acute NOS blockade only increased the degree of compensation in WKY. Remarkably, U NOx V was significantly lower at spontaneous RPP in SHR. After reduction of RPP, the observed decrease in U NOx V was significantly more pronounced in WKY than in SHR. In conclusion, the renal circulation in SHR is dependent on high levels of NO; however, the capacity to modulate NO in response to RPP-induced changes in shear stress seems to be limited.
      【关键词】 urinary excretion renal perfusion pressures
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THE KIDNEY ' S INTRINSIC property to regulate vascular tone so that renal blood flow (RBF) and glomerular filtration rate (GFR) remain relatively constant during perturbations of renal perfusion pressure (RPP) protects the tubular system from rapid changes in filtered load ( 7, 24 ). On the basis of several observations, it seems likely that nitric oxide (NO) release, depending on perfusion pressure-dependent variations in shear stress, can also dynamically modulate renal vascular tone. Endothelial NO synthase (NOS) is present in the preglomerular vasculature, and the afferent arteriole has been demonstrated to constrict on inhibition of NO synthesis ( 15 ). Thus one would anticipate that with a gradual increase in perfusion pressure, there is increasing release of NO due to increased shear stress, which at a particular perfusion pressure is overcome by the autoregulatory response (i.e., the lower limit of autoregulation).

Indeed, blockade of NO synthesis has been demonstrated to decrease the lower limit of autoregulation and improve the efficiency of autoregulation in several studies. Kramp et al. ( 18 ) showed that the lower limit decreased 15 mmHg in anesthetized male Wistar rats following N G -nitro- L -arginine methyl ester ( L -NAME), although autoregulatory efficiency was not specifically calculated. In our laboratory, we demonstrated that impaired RBF autoregulation in the contralateral kidney of two-kidney, one-clip (2K1C ) Goldblatt hypertensive rats was improved by NO synthesis inhibition ( 27 ). In line with these observations is enhancement of tubuloglomerular feedback during NO synthesis inhibition ( 8, 28 ), enhancement of myogenic contractions with increases in perfusion pressure in the juxtamedullary nephron preparation ( 14 ), and enhancement of the myogenic component of dynamic autoregulation in dogs ( 17 ). Nevertheless, there is ongoing debate as to whether autoregulation is modulated by NO. Autoregulation studies in dogs by Majid and Navar ( 20 ) and Baumann et al. ( 2 ) and in rats by Beierwaltes et al. ( 3 ) and Kvam et al. ( 19 ) failed to demonstrate a role for NO in the autoregulation of RBF. The reasons for these discrepancies are not clear.. l- _3 S+ f# S. G
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In the spontaneously hypertensive rat (SHR), an ambiguous situation seems to exist. On the one hand, renal NO dependency has been reported to be increased ( 29 ), which could lead to a diminished autoregulatory efficiency. On the other hand, RBF autoregulation is preserved relatively well in the SHR, albeit at a higher range of perfusion pressures ( 1, 16, 21 ). The influence of NO on autoregulation in this model has been investigated in one study ( 19 ). However, the study used a dose of the nonspecific NOS inhibitor N G -monomethyl- L -arginine ( L -NMMA) that did not decrease RBF in normotensive Wistar-Kyoto rats (WKY), so that effective probing of the NO dependency of autoregulation may have been hindered ( 19 ).
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In view of the enhanced NO dependency of RBF, together with the relatively well-preserved autoregulation, the hypothesis of the present study was that in the SHR there is an inability to modulate NO release with changes in RPP. In view of this hypothesis, questions in the present study were 1 ) is the renal vasculature under enhanced influence of NO under baseline conditions in the SHR and 2 ) is RBF autoregulation in the SHR less influenced by NO release due to pressure-dependent changes in shear stress? To test this hypothesis, RBF autoregulation was studied in anesthetized male SHR and normotensive WKY before and during acute NOS blockade with a high dose of the potent inhibitor N G -nitro- L -arginine ( L -NNA). Then, a second group of rats was used to measure urinary nitrate and nitrite excretion (U NOx V) during gradual reduction of RPP in similar experimental conditions.* p, B8 D6 i! l; I$ ~  a6 l& n
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METHODS3 @. X0 Z) {$ ~' O

Animals. Male WKY and SHR (Iffa-Credo), weighing 200-250 g, were housed at an ambient temperature of 22°C, humidity 60%, and exposed to a 12:12-h light-dark cycle. Rats were fed normal rat chow (Special Diets Services, Witham, Essex, UK) and had free access to tap water. Sentinel animals were housed under the same conditions and regularly monitored for infection by nematodes and pathogenic bacteria and antibodies for rodent viral pathogens (International Council for Laboratory Animal Science, Nijmegen, The Netherlands). The protocol was approved by the Utrecht University Board for studies in experimental animals.# A9 t5 K8 C' a( b: i

Surgical procedure and infusions. On the day of the experiment, the rats were anesthetized with 60 mg/kg body wt ip pentobarbital sodium and then placed on a servo-controlled surgical table that maintained body temperature at 37°C. The trachea was intubated with a PE-200 catheter. A PE-50 catheter was placed in the left jugular vein for infusion of the solutions and a second PE-10 catheter was introduced for supplemental anesthetic. The left femoral artery was cannulated with a PE-50 tubing for measurement of the mean arterial pressure (MAP). A flared PE-50 catheter was placed in the bladder for collection of the urine from the right kidney. The left kidney was exposed by a flank incision, isolated from the surrounding fat, and placed into a plastic holder. A PE-10 catheter was introduced in the left ureter to allow urine collection and a 1RB ultrasonic flow probe was placed around the left renal artery and connected to a transit time blood flowmeter (model T206, Transonics, Ithaca, NY) for measurement of RBF. The RPP in the left kidney was varied by means of a sling placed around the aorta between the renal arteries. During surgery, animals received an intravenous infusion of 150 mM NaCl containing 6% bovine serum albumin (Sigma, St. Louis, MO) at a rate of 10 µl · min -1 · 100 g body wt -1, which was changed to a 150 mM NaCl solution with 1% bovine serum albumin infused at the same rate for the rest of the experiment. The solutions also contained 15% polyfructosan (Inutest, Fresenius Pharma Austria) for measurement of renal clearance.0 x8 D2 @2 o6 s- @

Protocols. In the first set of experiments, RBF autoregulation was assessed in male WKY and SHR, n = 8/group. The rats were allowed to equilibrate for 60 min before the measurements were started. Then, RPP was reduced in a random fashion in steps of 5 mmHg by adjusting the sling around the aorta. After each reduction in RPP, RBF was recorded for 30-40 s, and then the sling was released and RPP and RBF were allowed to return at baseline values. After the baseline autoregulation curve was obtained, a bolus injection of 1.5 mg/kg body wt L -NNA was administered intravenously, followed by an infusion of 10 µg · kg -1 · min -1 L -NNA. The steady-state function and autoregulation were measured after equilibration at a new level of MAP and RBF.4 h& w0 b9 u; e7 ?6 ^. D* B9 y
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In the second set of experiments ( n = 6/group), the equilibration period was followed by a 30-min urine collection at spontaneous RPP. Then, the RPP in the left kidney was reduced by adjusting the sling placed on the aorta between the renal arteries to 90 mmHg in WKY and to 130 and then 90 mmHg in SHR; at each level of RPP, a 10-min equilibration period was followed by a 30-min urine collection. In SHR, after urine was collected at the RPP of 130 mmHg, the sling was released and a 15-min recovery period was observed. An arterial blood sample (300 µl) was collected from the femoral catheter at the midpoint of each urine collection period. At the end of each experiment, the left kidney and heart were harvested, blotted dry, and weighed.6 F5 p$ c8 @5 k& o2 A8 l% n7 s
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Analyses. Inulin was photometrically determined with indolacetic acid after hydrolyzation to fructose ( 12 ). Sodium and potassium concentrations were measured with an IL 543 flame photometer (Instrumentation Laboratory, Lexington, MA). Urinary NO x concentration was determined by quantification of the nitrite content with a commercially available fluorimetric kit (Cayman Chemicals) ( 23 ).

Calculations and statistics. Values are expressed as means ± SE. GFR, urinary sodium and potassium excretion, and fractional excretions were calculated using standard formulas. The RBF autoregulation curve was generated by extrapolating the values of RBF at different levels of RPP by linear regression to exact values of RPP. Renal vascular resistance (RVR) was calculated as RPP divided by RBF corrected for kidney weight. The lower limit of autoregulation and the degree of compensation were calculated by the method previously described ( 27 ).
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Briefly, the raw data of the autoregulation curves were subjected to nonlinear regression analysis using the logistic equation. The lower limit of autoregulation was defined as the perfusion pressure where the third derivative of the fitted curve is zero, which defines the shoulder in a sigmoidal curve. The method is described in detail elsewhere ( 27 ). The advantage of this mathematical method is that it avoids the inter-individual variations introduced by manual determination of the lower limit, the use of an arbitrary value for the decrease in RBF in the estimation of the lower limit, and also corrects for the error introduced by the limited number of perfusion pressures at which RBF is actually measured. It should be emphasized that by this mathematical method, the lower limit of autoregulation is defined as the shoulder of the curve, which reflects the RPP at which autoregulation becomes manifest and not the value at which the autoregulation reaches maximal efficiency. This is different and consistently lower than the more often defined inflection point. More specifically, this calculation defines the lower limit of autoregulation as the point between no adaptation of flow (to changing RPP) and any measurable adaptation. This calculated lower limit contrasts with the more commonly used theoretical (or mathematical) intercept of the lower curve and the autoregulated curve, or the middle of the inflection between lines, however, has the advantages mentioned above.
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The degree of compensation is a measure of autoregulatory efficacy. With the use of the first derivative of the logistic equation and the obtained parameters, the slope of each individual curve was estimated at various RPP, and the degree of compensation was calculated for each of these RPP values. The interpretation of the degree of compensation is as follows: when there is no change in RBF on a decrease in RPP, the value is 100%, whereas when the change in RBF equals the change expected if the vascular bed does not autoregulate, the value is 0. Data were compared with unpaired t -test and one- or two-way ANOVA for repeated measurements where appropriate. The Student-Newman-Keuls test was used as a post hoc test ( P 5 _  o# [  F/ k+ k: z
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RESULTS% B" g9 w! a% D7 P8 q* W5 z3 |$ r8 m

MAP, RBF, and RVR. There were no differences between the two groups in body and left kidney weight, but the heart/body weight ratio was significantly higher in the hypertensive group (0.35 ± 0.01%) than in WKY (0.32 ± 0.01%, P
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Fig. 1. A : mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) before (open bars) and during (filled bars) acute N G -nitro- L -arginine ( L -NNA) infusion in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. B : changes (delta) in MAP, RBF, and RVR after acute L -NNA infusion in WKY (open bars) and SHR (filled bars). kw, Kidney weight. * P
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Autoregulation curves. The RBF autoregulation curves before and after acute NOS blockade are shown in Fig. 2. Both groups demonstrate autoregulation before the infusion of L -NNA. In the baseline situation, the hypertensive group had a significantly higher value of the lower limit of autoregulation (85 ± 3 mmHg) compared with WKY (71 ± 2 mmHg). Acute NOS blockade reduced the lower limit of autoregulation in the normotensive group to 63 ± 2 mmHg ( P 5 ~8 X- ]  e8 E% A& j" }

Fig. 2. RBF autoregulation in WKY ( A ) and SHR ( B ) under baseline ( ) and during acute infusion of L -NNA ( ). RPP, renal perfusion pressure; NOS, nitric oxide synthase.) j3 h9 R+ p! C
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Fig. 3. Autoregulation curves generated from the curve fitting to a sigmoidal curve. The bold line indicates the average curve. The dots indicate the calculated lower limit for each autoregulation curve. A : WKY before L -NNA; B : WKY after L -NNA; C : SHR before L -NNA; and D : SHR after L -NNA. BW, body weight.* U% P9 O6 y) ]3 W" O

Fig. 4. Efficiency of autoregulation expressed as degree of compensation in WKY ( A ) and SHR ( B ) under baseline ( ) and during acute L -NNA infusion ( ). * P : D' X! d5 Q! e( O* n/ i

Renal excretory function. Urine flow, GFR, and urinary excretions of sodium and potassium were not different between WKY and SHR at baseline MAP, despite the fact that MAP was significantly higher in the SHR than WKY rats (155 ± 2 vs. 111 ± 1 mmHg, P
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Table 1. Kidney function in anesthetized male WKY and SHR at different RPPs  U( n" i* A6 G0 e+ h
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Fig. 5. Urinary excretion rates of nitrate and nitrite (U NOx V) at different RPPs in normotensive WKY ( A ) and SHR ( B ). * P

DISCUSSION

The first question was whether the renal vasculature is under enhanced influence of NO at baseline conditions in the SHR. At baseline conditions, SHR displayed a slightly but not significantly lower RBF and an increased RVR compared with WKY controls. This indicates a net vasoconstrictor force in the kidney of the SHR. Indeed, inhibition of NO formation leads to more pronounced decrease of RBF in SHR than in WKY. Our finding is in accordance with previous studies that found a more important reduction of RBF on NOS inhibition in SHR ( 4 ). In particular, Kvam et al. ( 19 ) documented a stronger increase in RVR following L -NMMA in SHR compared with WKY; however, RBF in WKY rats did not decrease. The absence of a decrease in RBF in normotensive rats upon acute NOS inhibition in the study by Kvam et al. is different from previous studies using L -NAME and L -NNA ( 2 - 4, 17, 18, 20, 26, 27 ). This might point toward incomplete NO blockade, which makes an understanding of the mentioned study difficult. Access of L -NMMA to the different NOSs that participate in the regulation of blood flow may have been incomplete in both strains. NO dependency of the renal circulation has been assessed and found to be present in other models such as 2K1C Goldblatt hypertension ( 26, 27 ), Brown-Norway, Wistar and Long-Evans rats (32). Thus, under baseline conditions, a more pronounced vasoconstrictor force in the SHR is counterbalanced by increased NO so that the RBF is salvaged, which is similar to several other models of hypertension.+ G! m7 q7 {$ _# r! @
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Remarkable in this regard is our finding that under baseline RPP, NOx excretion is significantly less in SHR than in WKY. Data in the literature on this subject are conflicting. Some authors find increased NOx excretion in SHR compared with WKY ( 21, 29 ). Two other groups have found lower values of NOx excretion in SHR than in WKY at this age ( 5, 11 ). There are two methodological aspects that may explain the present finding. In most studies, urine was collected in conscious animals, whereas the rats in our study were anesthetized. Furthermore, a loss of the circadian rhythm of NOx excretion has been found in the SHR compared with WKY ( 5 ); we collected urine for 30 min during the day instead of a 24-h collection. Another possibility is that in the vascular system NO is quenched by increased levels of reactive oxygen species (ROS) ( 23, 25 ) and that the resulting compounds are possibly not metabolized to NO 2 and NO 3. Finally, an option is that indeed less NO is available, however, that the sensitivity of the vascular wall is higher in SHR than in WKY.: g" R* ]/ J: I! f( B
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The second question is whether in SHR the RBF autoregulation is less influenced by variations in perfusion pressure. Previously, we demonstrated in the 2K1C model that autoregulatory capacity was diminished and that NOS inhibition restored efficacy and decreased the lower limit of autoregulation ( 27 ). Furthermore, Hayashi et al. ( 10 ) demonstrated that NOS inhibition leads to a decrease in the perfusion pressure at which a myogenic response is observed in afferent arterioles of the hydronephrotic kidney model in SHR. Hoffend et al. ( 13 ) reported a similar observation in normotensive Munich-Wistar rats. Taken together, these studies indicate that under particular conditions, dynamic NO release can indeed shift the lower limit of autoregulation to a higher pressure and decrease the efficiency of the autoregulatory response.
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Autoregulation in SHR showed characteristics that have been reported before: the lower limit is shifted to a higher value of RPP in the SHR compared with WKY. In other words, there is a shift in the autoregulatory plateau, so that the autoregulation curve is aligned with the ambient increased perfusion pressures in the SHR. Autoregulatory efficiency, as assessed by the calculation of the degree of compensation, was imperfect in both SHR and WKY. Changes in perfusion pressure were corrected for by 85-90% under baseline conditions. This finding is in contrast to reports showing almost perfect autoregulatory efficiency in the SHR ( 16 ). The present data set was subjected to the same calculation method described previously ( 27 ), which avoids interobserved error, as has been recently emphasized by others ( 9 ). Acute NOS inhibition increased efficiency of autoregulation at perfusion pressures below 100 mmHg and decreased the lower limit of autoregulation in the WKY. This is somewhat in variation with the absence of a statistical decrease in the lower limit in Sprague-Dawley rats with NO inhibition in a previous study, although the numerical decrease was similar ( 27 ). Autoregulation characteristics in SHR were not affected by NOS inhibition. Kvam et al. ( 19 ) failed to show any effect of L -NMMA on RBF autoregulation in the 10-wk-old SHR. However, they also failed to show an effect of NOS inhibition in WKY ( 19 ). As mentioned, this might reflect incomplete inhibition of NO synthesis. Wang and Cupples ( 30 ) investigated the transfer functions in normotensive Brown-Norway and Long-Evans rats and in SHR before and during NOS inhibition with L -NAME. RBF dynamics were improved by NO blockade in the normotensive strains, but this was not the case in SHR. At this point, we would like to emphasize that the main observation of the study is the absence of an increase in efficacy of autoregulation on NO inhibition in the SHR.
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Collectively, the behavior of RBF regulation in SHR suggests that the maintenance of RBF in SHR is more dependent on ambient NO availability than in WKY, but that the capacity of the SHR kidney to vary NO production in adaptation to changes in RPP is limited. In view of the increased vasoconstrictor force in the SHR, one could propose that a vasoconstrictor that is concomitantly released on gradual increases in RPP supports autoregulation and nullifies a potential opposing effect of NO. Another option is that no more NO is produced on a further increase in perfusion pressure in the SHR. In this regard, NO may be scavenged by ROS ( 23, 24 ). It remains remarkable that in the 2K1C model, in which ROS also seem to be increased ( 6 ), NO blockade can affect autoregulation. In view of the interaction between the renal nerves and NO in the SHR concerning tubular reabsorption ( 31 ) and renal hemodynamics ( 19 ), renal nerves could be involved in the autoregulation behavior in SHR. In the present study, we cannot exclude that the renal nerves offset a potential action of NO on autoregulation.
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The present observation suggests that in SHR the dynamic release of NO with changes in RPP is impaired. This is intriguing because we could also demonstrate that the renal vasculature is under a more pronounced tonic influence of NO in the SHR compared with WKY. To illustrate this point, we calculated NO dependency of RBF in two ways. First, we calculated the change in RBF from the baseline to the L -NNA infusion periods ( Fig. 6 A ) and, second, we calculated the percentage of baseline value that this change represents in each strain for different perfusion pressures ( Fig. 6 B ). The RBF difference steadily increases with increasing RPPs for both strains, the percentage that the decrease in blood flow represents from the baseline value decreases in the WKY at low perfusion pressures and then increases at higher pressures. In contrast, in the SHR, the percentage of RBF influenced by NO does not change on increasing RPP. This observation underlines the fact that NO release is modulated in the WKY kidney, whereas it seems to be fixed to a certain level in the SHR renal circulation.
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Fig. 6. Change in RBF after acute infusion of L -NNA in WKY ( ) and SHR ( ) at different perfusion pressures in absolute values ( A ) and expressed as percentage of the baseline value at different perfusion pressures ( B ). # P 1 a# U/ k. s. e6 n
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The second set of experiments was conducted to test the effects of RPP changes on NOx excretion. We found that a decrease in RPP is accompanied by a significant decrease in U NOx V, which confirms our assumption that NO production in the kidney is modulated by RPP, presumably due to changes in shear stress that affect RBF autoregulation. The effect of RPP change on U NOx V in SHR is significantly less pronounced than in WKY, which supports the hypothesis from the RBF autoregulation data that the capacity of SHR kidney to modulate NO production in response to changes in shear stress is limited.
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In conclusion, autoregulation of the RBF in SHR is preserved compared with WKY but shifted toward higher perfusion pressures and is not significantly influenced by acute NOS blockade. This is in contrast to our previous findings in the 2K1C model. Although increased NO in the renal circulation maintains the baseline RBF, the dynamic capacity of the kidney vasculature to adapt NO production to changes in RPP is limited. This is supported by the attenuated decrease in U NOx V observed in SHR during changes in RPP.

ACKNOWLEDGMENTS: w. ?$ P$ s. v/ @
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We thank P. Martens, R. de Winter, A. Dijk, N. Willekes, and H. Ijzerman for providing technical assistance.
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This study was supported by the Netherlands Kidney Foundation (C99.1823) and an International Fellowship Training Award of the International Society of Nephrology.
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