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J Physiol (2003), 548.3, pp. 875-880
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.038075
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ABSTRACT |
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Angiotensin II (Ang II) fails to constrict renal medullary vasculature, possibly due to the counteraction of local vasodilators, such as prostaglandins or nitric oxide (NO). The effects of exogenous Ang II on intrarenal circulation were determined in anaesthetised rats that were untreated or pretreated with indomethacin (Indo) or L-NAME. The total renal blood flow (RBF), representing cortical perfusion, and outer and inner medullary blood flow (OMBF and IMBF) were measured. In untreated rats, Ang II decreased RBF in a dose dependent manner. Intravenous administration of 30 ng kg-1 min-1 Ang II decreased RBF by 38 % and OMBF by 9 % (both significant); IMBF was unaffected. Indo (5 mg kg-1 I.V.) significantly and similarly decreased OMBF and IMBF without affecting RBF. Ang II decreased IMBF by 27 % in Indo-pretreated rats, but caused no change in rats without pretreatment. The decreases in OMBF and RBF were comparable with or without Indo pretreatment. Inhibition of NO synthesis with L-NAME (0.6 mg kg-1 I.V.) significantly decreased RBF, OMBF and IMBF. Ang II infusion into L-NAME-pretreated rats induced a further significant decrease in RBF and OMBF without changing IMBF. We conclude that within the inner medulla, but not the outer medulla or cortex, prostaglandins effectively counteract the vasopressor effect of circulating Ang II.
(Received 19 December 2002; accepted after revision 19 February 2003; first published online 14 March 2003)
Corresponding author J. Sadowski: Laboratory of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, PL02-106 Warsaw, Poland. Email: sadowski{at}cmdik.pan.pl
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INTRODUCTION |
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Since the renal inner medulla is notorious for its low rate of blood flow and minimal reserve of oxygen (Heyman et al. 1997), the maintenance of adequate perfusion of this zone is critically important for its survival, for the functional integrity of the kidney and for appropriate renal regulation of body fluid balance and arterial pressure. The perfusion of the medulla could be jeopardised by increasing the vasopressor activity of a number of hormones, especially angiotensin II (Ang II). However, we recently presented our own results and reviewed the data published by others, indicating that during elevation of blood Ang II activity the perfusion of the renal cortex was reduced but that of the inner medulla or papilla was preserved (Badzynska et al. 2002). A possible explanation of this phenomenon is that in this region Ang II-dependent reduction of perfusion was prevented by the action of local vasodilator agents, such as prostaglandins or nitric oxide (NO).
The potential role of each of these agents in protecting medullary circulation against the vasoconstrictor effect of Ang II was suggested on the basis of a wide variety of studies in vivo and in vitro, as outlined in a number of recent reviews (Navar et al. 1996; Arendshorst et al. 1999; Edwards et al. 2000; Bergström & Evans, 2000). Nevertheless, it is extremely difficult to form an opinion on the real rather than potential buffering role of vasodilators, and their relative power, from studies using different methodology and experimental protocols applied in animals of different species, sex and/or age, and studied under different conditions of anaesthesia, salt balance, plasma volume, etc. In order to limit the degree of uncertainty in interpretation, we have undertaken to examine in one study the relative roles of intrarenal prostaglandins and NO in buffering Ang II action in the kidney. This was accomplished by infusing moderately pressor doses of the hormone to anaesthetised rats under control conditions and after pretreatment with indomethacin (Indo) or L-NAME.
Because of the complex architecture of medullary microcirculation, the mechanism of changes in perfusion of the inner medulla (papilla) may be difficult to define (Edwards et al. 2000; Bergström & Evans, 2000). For instance, decreased perfusion may be the result of local vasoconstriction or reduced supply of blood to the region due to increased vascular resistance upstream at the initial segments of the descending vasa recta or in the efferent and/or afferent arterioles of juxtamedullary glomeruli, or at more than one of these sites. In order to obtain a rough insight into the location of resistance changes related to the action of Ang II and its interplay with local vasodilator agents, we measured perfusion of both the outer and inner medulla (by laser-Doppler flowmetry). The renal artery flow (measured by Transonic probe) was used as a close approximation of cortical perfusion (Badzynska et al. 2002).
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METHODS |
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Male Wistar rats weighing 280-330 g, maintained on dry pellet diet and given free access to water, were anaesthetised with 100 mg (kg body weight)-1 intraperitoneal thiopentabarbital (Thiopental, Biochemie GmbH, Vienna, Austria). The experimental procedures were approved by the external Regional Ethical Committee (Warsaw). Throughout the surgical preparation and experimental procedures body temperature was maintained at about 37 °C by means of a heated pad. In order to compensate for fluid losses during surgical preparation, 3 % bovine albumin in Ringer solution was infused at 0.22 ml kg-1 min-1.
Surgical preparations
A cannula was placed in the trachea to ensure a free airway; the jugular vein was cannulated for infusion of fluids and drugs. For measurement of mean arterial blood pressure a Teflon catheter, 0.4 mm in outer diameter, was introduced into the right femoral artery. The left kidney was exposed from a subcostal flank incision and placed in a plastic holder similar to that used for micropuncture experiments; the inside of the holder was padded in such a way that the kidney's dorsal curvature (and not the side surface) was facing upwards. The ureter was cannulated to ensure drainage of the left renal pelvis. In order to keep renal perfusion pressure (RPP) stable, a screw-controlled snare was placed on the aorta above the left renal artery. The snare was slightly tightened to lower blood pressure distal to the constriction site by 10 mmHg. Later during experiments the snare could be loosened or tightened as needed, so that the mean blood pressure below the snare, equivalent to RPP, was maintained constant. Thereafter a flow probe, 1 mm in diameter, was placed on the renal artery and connected to a Transonic flowmeter (type T106, Transonic Systems Inc., Ithaca, NY, USA) for measurement of total renal blood flow (RBF). Subsequently, two laser-Doppler (lD) needle probes, were inserted into the kidney from its dorsal surface along the cortico-papillary axis, for estimation of outer and inner medullary blood flow (OMBF and IMBF).
The lD probes (type PF 402) were connected to a lD flowmeter (Periflux 4001, Perimed, Jarfalla, Sweden); the system measures the lD flux (the product of the number of blood cells moving and their mean velocity) within an area of less than 1 mm3 beneath the tip of the probes; results are expressed in arbitrary perfusion units (PU). Thus, only relative changes are measured but a calibration procedure enabled comparison of the results between animals. In agreement with the accepted usage, throughout this paper the cortical, outer medullary and inner medullary fluxes are termed 'flows' (RBF, OMBF and IMBF, respectively).
After experiments the rats were killed with an overdose of the anaesthetic. The positions of the lD probe tips (in the outer medulla (about 3 mm from kidney surface, close to the outer stripe-inner stripe border) and in the inner medulla (5 mm from surface, close to outer-inner medullary border)) were verified by cross-sectioning the kidney.
Experimental procedures and protocols
At the end of surgical preparations, bovine serum albumin infusion was replaced by infusion of isotonic saline solution at 0.22 ml kg-1 min-1. After placement of blood flow probes for measurement of OMBF, IMBF and RBF, about 1 h was allowed for stabilisation, and RPP was adjusted to 100-105 mmHg and kept constant throughout the experiment. We have repeatedly shown that in this experimental preparation and at constant RPP the three variables measured (RBF, OMBF and IMBF) are stable over at least 2 h.
The baseline values were first recorded for 30 min during isotonic saline infusion. Thereafter records were obtained during infusion of drugs and, whenever possible, after cessation of drug infusion.
Effects of different doses of Ang II on RBF, OMBF and IMBF. Infusion of Ang II (Hypertensin, Ciba-Geigy, Switzerland) at 10, 30 and 60 ng kg-1 min-1 I.V. was performed in rats receiving baseline isotonic saline solution. The hormone was infused until stabilisation of OMBF, IMBP and RBF, for about 20 min. At least 30 min intervals were left between infusions of individual Ang II doses. The number of tests varied between individual dose groups (see Fig. 1).
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Figure 1. Effects of three doses of angiotensin II (ANG II) on total renal blood flow (RBF) and outer and inner medullary blood flow (OMBF and IMBF) Means ± S.E.M. are shown as percentages of the initial control value (100 %). Absolute mean values in ml min-1 (RBF) and perfusion units (OMBF and IMBF) are shown on the bars. Numbers (n) are given in parentheses. * Significantly different from 100 % control value at P < 0.05. | ||
Effects of Ang II in rats pretreated with Indo. Indo (5 mg kg-1 in 1.5 ml alkalinised saline) (Metindol; Polfa, /Lód'z, Poland), a prostaglandin synthesis inhibitor, was infused for 5 min. After stabilisation of RBF, OMBF and IMBF at a new level, Ang II was infused I.V. at 30 ng kg-1min-1 and effects on the three variables were determined.
Effects of Ang II in rats pretreated with L-NAME. After baseline recordings, L-NAME (N
-nitro-L-arginine methyl ester, Sigma Chemical Co., St Louis, MO, USA), a non-selective inhibitor of NO synthesis, was given as an I.V. bolus at 0.6 mg kg-1. After stabilisation of RBF, OMBF and IMBF at a new level, Ang II was infused at 30 ng kg-1min-1.
Statistics
Single comparisons of mean values between the control and the experimental period were made using Student's t test for dependent variables. Differences in mean values between groups were first evaluated by the classic one-way ANOVA. When the result indicated significant differences and only when more precise evaluation was needed (Ludbrook, 1994), a single comparison was made using the modified Student's t test for independent variables. There was no need for multiple comparisons. S.E.M. was used throughout as a measure of data dispersion and P < 0.05 was accepted as the level of statistical significance.
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RESULTS |
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Figure 1 shows that Ang II significantly decreased RBF; the response was dose dependent, as indicated by ANOVA of the three dose groups (F = 27; P < 0.01). In the case of OMBF the responses to the three Ang II doses were also significant but less pronounced; the dependence on the dose was of borderline significance (F = 3.15; P = 0.057). In strong contrast to the above, IMBF did not change in response to Ang II at doses of 10, 30 or 60 ng kg-1 min-1.
The responses of RBF, OMBF and IMBF to Indo and then to Ang II (30 ng kg-1 min-1) administered to Indo-pretreated rats are shown in Fig. 2. Indo did not significantly alter RBF but decreased both OMBF and IMBF to 77 and 74 % of the respective control values. Subsequently, under prostaglandin cyclooxygenase blockade obtained with Indo, Ang II significantly decreased each of the three parameters measured. The response to Ang II was pronounced for RBF (reduced by 31 % compared to the pre-Ang II level) and much smaller and similar for OMBF and IMBF (reduced by 12 and 10 %, respectively, compared to the pre-Ang II level). Interestingly, the sum of Indo and Ang II effects turned out to be quite similar for RBF, OMBF and IMBF (a reduction of about 35 % of the initial saline control).
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Figure 2. Effects of Indo and of infusion of Ang II given after Indo on total RBF, OMBF and IMBF
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Non-selective inhibition of NO synthesis with L-NAME significantly decreased RBF, OMBF and IMBF (Fig. 3). Since ANOVA indicated significant variability among the three groups (F = 3.98; P < 0.03) and mean values for RBF and OMBF were equal, it can be concluded that the decrease in IMBF was smaller than that in the two other groups. In the cases of RBF and OMBF, subsequent administration of Ang II caused a further significant decrease, which was more pronounced for RBF. In contrast, there was no further decrease in IMBF, as observed after Ang II infusion in untreated animals (Fig. 1).
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Figure 3. Effects of L-NAME and of infusion of Ang II given after L-NAME on total RBF, OMBF and IMBF
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Figure 4 compares the responses to Ang II (30 ng kg-1 min-1) measured in untreated rats and those pretreated with Indo or L-NAME. In the case of RBF, no difference was observed between decreases after Ang II in control, Indo-pretreated or L-NAME-pretreated rats, as examined by one-way ANOVA (F = 1.27; P = 0.29). In the three groups, post-Ang II decreases in OMBF were much smaller than those in RBF (though still significant) and the differences between groups were not significant (F = 0.94; P = 0.4). In the case of IMBF a significant decrease in response to Ang II was seen only in rats pretreated with Indo; no change was observed in the two other groups.
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Figure 4. A comparison of Ang II effects on total RBF, OMBF and IMBF in control rats and animals pretreated with Indo or L-NAME. Ang II was infused at 30 ng kg-1 min-1. Means ± S.E.M. are percentage changes from pre-Ang II control. * Significantly different from pre-Ang II control at P < 0.05; † significantly different from the change measured after Ang II alone (Saline, | ||
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DISCUSSION |
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The present results confirm the data recently reported by ourselves and by others, indicating no reduction of perfusion or even increased perfusion of the inner medulla or papilla in response to exogenous Ang II, in contrast to overt hypoperfusion of the cortex (Walker et al. 1999; Badzynska et al. 2002). We have now extended the studies and shown that within the outer medulla Ang II did induce a decrease in perfusion. However, in response to a slightly pressor dose of Ang II (30 ng kg-1 min-1) OMBF decreased by only a modest 9 %, compared to a 35 % reduction observed for RBF. We showed previously that Ang II-dependent changes in renal artery flow (RBF) and in cortical blood flow (lD) were highly correlated (r = 0.96), indicating that the former variable is a reliable measure of average whole-cortex perfusion (Badzynska et al. 2002).
Receptor studies and experiments with isolated intrarenal vessels, blood-perfused juxtamedullary nephron preparations and split hydronephrotic kidneys, indicate that resistance vessels determining perfusion of the medulla (afferent and efferent arterioles of juxtamedullary glomeruli as well as descending vasa recta) express type 1 Ang II (AT1) receptors and are able to constrict in response to Ang II. However, the vasoconstriction may not occur in the presence of, or may be abrogated by application of, vasodilator agents known to antagonise the Ang II pressor effect in the kidney (Navar et al. 1996; Arendshorst et al. 1999; Edwards et al. 2000; Pallone & Silldorff, 2001). This suggests very strongly that the maintenance of inner medullary or papillary perfusion or even increased perfusion after Ang II is due to a local action of vasodilator agents, possibly stimulated by the hormone. The present observation that perfusion was reduced at the level of the outer medulla, albeit only slightly compared with the cortex, suggests that buffering of vasoconstrictor influence must have occurred already in the initial segments of the descending vasa recta or even further upstream, in the arterioles of the juxtamedullary glomeruli. The absence of IMBF reduction after each of the three Ang II doses, beginning with the borderline pressor dose of 10 ng kg-1 min-1, argues against the suggestion that the response of the renal inner medulla/papilla to the hormone is dose dependent, vasoconstriction occurring with low doses, but no change or vasodilatation occurring with high dosage (Arendshorst et al. 1999). In agreement with our data, Huang et al. (1991) found no effect of Ang II on papillary blood flow within the dose range 10-150 ng kg-1 min-1. Walker et al. (1999) recently showed a greater increase in papillary perfusion in young rats after 300 ng kg-1 min-1 than after 150 ng kg-1 min-1 Ang II.
The major candidates for vasodilators that could offset or prevail over Ang II-dependent vasoconstriction are intrarenal prostaglandins and/or NO; a role in this for intrarenal kinins is also a possibility. There is ample evidence supporting or questioning the role of each of these agents. Our results, showing a significant reduction in the perfusion of the medulla but not in the total (cortical) blood flow after Indo administration, confirm the long-standing evidence on the tonic vasodilator influence of prostaglandins on the medullary microcirculation, at least in anaesthetised and surgically prepared animals. In the present study, this influence was also specifically demonstrated in the outer medulla, which has not been widely documented previously. However, in female rats Parekh & Zou (1996) also showed a post-Indo decrease in blood perfusion of the inner stripe of the outer medulla, derived from measurement of the rate of elimination of locally generated hydrogen (Parekh et al. 1991). In our experiments, after elimination of prostaglandin synthesis with Indo, Ang II did induce a pronounced decrease in both OMBF and IMBF, whereas in untreated rats there was a minor response in OMBF and no change in IMBF (Fig. 1). This accords with the conclusion from many reports that prostaglandins antagonise the vasoconstrictor effect of Ang II in the kidney, especially within the medulla (Navar et al. 1996; Edwards et al. 2000). In agreement with our finding of a decrease in OMBF, in the study quoted above Indo pretreatment was a necessary condition for Ang II to reduce perfusion of the inner stripe of the outer medulla (Parekh & Zou, 1996). Our observation that OMBF and IMBF decreased to a similar degree after Indo pretreatment suggests that the action of prostaglandins occurred in the initial segment of the descending vasa recta (in the outer stripe of the outer medulla) or in the arterioles of juxtamedullary glomeruli. Corresponding to our findings in normal male rats, in the split hydronephrotic kidney preparation (female rats) Steinhausen et al. (1990) showed that in juxtamedullary nephrons intravenous Ang II caused only a minor reduction in afferent arteriolar diameter (smaller than in the respective vessels of midcortical glomeruli by a factor of four) and did not affect the diameter of efferent arterioles. Remarkably, post-angiotensin vasoconstriction was restored to the magnitude seen in midcortical glomeruli by local application of Indo. An opposed action of Ang II and prostaglandin E2 (PGE2) on the diameter of isolated vasa recta was elegantly shown by Pallone (1994) who also reviewed earlier reports suggesting such an antagonism.
As expected, inhibition of NO synthesis reduced perfusion within all three areas examined: the cortex, outer medulla and, with relatively least effect, the inner medulla. These results support the suggestion of tonic vasodilator influence of NO throughout the kidney. The response to subsequent administration of Ang II varied depending on the zone, from no change in the inner medulla to modest or pronounced decreases in the outer medulla and averaged whole cortex, respectively, which corresponds with the response pattern observed in rats with intact NO synthesis. Since IMBF was equally unaffected by Ang II in L-NAME-treated and in untreated rats where the hormone could stimulate the synthesis of NO, a major role for NO buffering of Ang II action in the inner medulla seems unlikely. However, a number of studies seem to be at variance with such a conclusion. Thus, from the determination of NO trapping by haemoglobin infused into kidney tissue, Zou et al. (1997) concluded that a subpressor dose of Ang II (5 ng kg-1 min-1) increased NO concentration in kidney tissue, more efficiently in the medulla than in the cortex. Furthermore, inhibition of NO synthesis blocked an Ang II-dependent increase in inner medullary or papillary blood flow (Zou et al. 1997; Ortiz et al. 1998). Differences in rat strains, hydration status, Ang II dosage and other details of the experimental protocol could account for the discordance between these results and ours. Experience with different methods for measurement of NO concentration in tissue is still limited. Indeed, in our polarographic measurements of NO using selective electrodes, Ang II (10 ng kg-1 min-1) was actually found to decrease rather than increase NO concentration in kidney tissue (M. Grzelec-Mojzesowicz & J. Sadowski, unpublished observations), in contrast to an increase measured with the subpressor dose (Zou et al. 1997).
Earlier indirect evidence indicating involvement of intrarenal kinins, possibly interacting with prostaglandins and NO, in the control of renal circulation and function (Navar et al. 1996) was more recently strengthened by an observation that an inhibition of bradykinin B2 receptors reduced renal interstitial fluid PGE2 and cGMP, a mediator of NO action (Siragy et al. 1997); furthermore, additional inhibition of prostaglandin or NO synthesis did not modify changes in renal haemodynamics and function compared with the effect of B2 blockade alone. It appears that both PGE2 and NO could mediate bradykinin action and the potential role of kinins requires further investigation.
In summary, these studies have confirmed that a slightly pressor dose of Ang II failed to reduce perfusion of the inner medulla with blood, in contrast to a distinct reduction in the cortex. In addition, a modest Ang II-dependent decrease in blood flow was documented for the outer medulla. We compared in a single study the role of intrarenal prostaglandins and NO as potential agents to buffer the vasodepressor effects of circulating Ang II. The data indicate that in the inner medulla the buffering agent was a prostaglandin, probably PGE2, but there was no indication of an involvement of NO.
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| Arendshorst WJ, Brännström K & Ruan X (1999). Action of angiotensin II on the renal microvasculature. J Am Soc Nephrol 10, S149-S161 | [Medline] |
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| Bergström G & Evans RG (2000). Integrative aspects of the renal medullary circulation. In The Renal Circulation, ed. Anderson WP, Evans RG & Stevenson KM, pp. 235-253. JAI Press Inc., Stanford, CT, USA | |
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, Indo (5 mg kg-1 I.V.); 
, infusion of Ang II (30 ng kg-1 min-1 I.V.) after Indo. Means ± S.E.M. are shown as a percentages of pre-Indo control (
, 100 %). Absolute mean values in ml min-1 (RBF) and perfusion units (OMBF, and IMBF) are shown on the bars. Numbers (n) are given in parentheses. * Significantly different from pre-Indo control at P < 0.05; † significantly different from the value measured after Indo at P < 0.05.