(Hypertension. 1996;28:825-832.)
© 1996 American Heart Association, Inc.
Articles |
Nerve-Mediated Antidiuresis and Antinatriuresis After Air-Jet Stress Is Modulated by Angiotensin II
the Department of Medicine–Nephrology, University of Erlangen–Nurnberg, and Department of Medicine–Nephrology, Schwabing City Hospital, Munich (J.F.E.M.), FRG.
Correspondence to Roland Veelken, MD, Department of Medicine IV, University of Erlangen–Nurnberg, Loschgestraße 8½, 91054 Erlangen, FRG.
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Abstract |
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A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98±4% (n=6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31±3 to 8±4 µL/min per gram kidney weight, P<.05, n=12) and sodium excretion (from 4.3±0.9 to 1.2±0.3 µmol/min per gram kidney weight, P<.05, n=12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 µg ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve–mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats.
Key Words: angiotensin II • sympathetic nervous system • stress • hemodynamics • rats
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Introduction |
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The octapeptide Ang II interacts with the SNS in different ways. It modulates the SNS response to stimulation of cardiovascular reflexes by central mechanisms1 and facilitates noradrenergic transmission in several organs.2 3 4 5 For example, Ang II enhances the response to sympathetic nerve stimulation in resistance vessels2 5 and in the heart.6 However, pharmacological concentrations of exogenous Ang II often have been used to demonstrate the effects of the peptide on sympathetic transmission. The question of whether endogenous Ang II exerts comparable effects on noradrenergic neurotransmission remains controversial.2 7 8
The renal sympathetic nerves are important in the regulation of sodium excretion and therefore of volume and BP homeostasis.9 Inadequate control of RSNA may directly contribute to the development of high BP, at least in some experimental models of hypertension.10 11 Thus, an interaction between Ang II and the SNS in the kidney could play an important role in the control of volume homeostasis. Several authors have shown that Ang II facilitates sympathetic nerve transmission in the kidney.12 13 14 However, most of these experiments were performed in isolated organs, in anesthetized animals with a stimulated renin-angiotensin system, or with the use of pharmacological doses of exogenous Ang II; furthermore, the renal sympathetic nerves were stimulated electrically.13 14 It is not always easy to decide what relevance these findings have for intact, conscious animals or for men with a normal or moderately stimulated renin-angiotensin system and a renal sympathetic nerve tone controlled by the central nervous system.
In fact, few authors have examined the renal interaction between Ang II and the SNS under conditions of normal Ang II concentrations and of an intact central control of RSNA. Szabo et al4 used baroreflex-mediated changes of RSNA in anesthetized rabbits and measured renal norepinephrine spillover. These authors demonstrated facilitation of transmitter release only by pharmacological amounts of exogenous Ang II but not by endogenous Ang II.4 Persson et al15 and Nelson and Osborn16 studied reflex-evoked antinatriuresis in conscious dogs. Inhibition of Ang II formation and AT1 receptor blockade did not affect the reflex-mediated antinatriuresis.15 16 Hence, the question of whether endogenous Ang II in conscious animals is able to influence the renal response to centrally evoked changes in RSNA is still a matter of debate.
Our aim in this study was to test the hypothesis that endogenous Ang II modulates the antinatriuretic and antidiuretic effects of the renal nerves in intact, conscious rats. Ang II could either directly affect the neurotransmission between sympathetic fibers and tubular cells or enhance the effects of sympathetic activity on tubular cells by other mechanisms, eg, by affecting intracellular signal transduction.
We used air-jet stress to induce an endogenous increase of RSNA without a change in BP, HR, or renal hemodynamics17 18 and to increase RSNA without electrical stimulation.13 14 Air-jet stress modulates primarily tubular sodium reabsorption via the renal nerves.17 18 Since both the presumed presynaptic and tubular Ang II receptors are AT1 receptors,19 20 we used the AT1 receptor blocker ZD 7155 [(5,7-diethyl-1-2-[2'-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-ylmethyl)-1,2,3,4-tetrahydro-1,6,-naphthyridin-2-one hydrochloride)]21 as a tool to block endogenous Ang II.
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Methods |
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Animal Preparation
Male Sprague-Dawley rats (250 to 300 g body weight; Charles River Wiga, Sulzfeld, FRG) were kept in a room at 24±2°C, 60% to 80% humidity, and a 12-hour light/dark cycle. Rats were fed a normal diet containing 0.2% sodium (C-1000, Altromin) and were allowed free access to tap water. All procedures were performed in accordance with the guidelines of the American Physiological Society.
One week before the experiments, rats were anesthetized with intraperitoneal methohexital sodium (Brevimytal, Eli Lilly & Co). A group of six rats was bilaterally denervated; the others underwent sham operation. In short, bilateral flank incisions were made and renal denervation was performed by surgically stripping the renal arteries and veins of adventitia, cutting all visible renal nerve bundles under a dissection microscope (x25), and coating the vessels with a solution of 10% phenol in 95% ethanol as previously described.22 23 This renal denervation procedure prevents the renal vasoconstrictor response to suprarenal lumbar sympathetic nerve stimulation, prevents the antinatriuretic response to environmental stress, reduces renal catecholamine histofluorescence to nondetectable levels, and reduces renal tissue norepinephrine concentration to less than 5% of control.18 22
On the day of the experiments, rats were again anesthetized with intraperitoneal methohexital sodium. Polyethylene catheters were inserted into a femoral vein and femoral artery, and anesthesia was continued with intravenous methohexital sodium. The catheters were led out at the neck of the rat. Polyethylene tubing was inserted into the bladder and led out through the abdominal wall. A bipolar electrode (0.2 mm stainless steel wire, Science Products) was placed on the left renal sympathetic nerve by a flank incision for direct recording of RSNA as described previously.24 RSNA was amplified (x10 000 to 50 000) and filtered (high pass, 30 Hz; low pass, 1000 to 3000 Hz) with a band-pass amplifier (P511, Grass Instrument Co) and high-impedance probe (Grass HIP511). The amplified and filtered signal was channeled to an oscilloscope (Hameg) and polygraph (Grass model 7DA) for visual evaluation, to an audio amplifier-loudspeaker (Grass model AM8 audio monitor) for auditory evaluation, and to a rectifying voltage integrator (Grass model 7P10). The integrated voltage signals were displayed on the polygraph. The quality of the RSNA signal was assessed by its pulse synchronous rhythmicity and by examination of the magnitude of the decrease in recorded RSNA during sinoaortic baroreceptor loading with an intravenous injection of methoxamine. When an optimal RSNA signal was observed, the recording electrode was fixed to the nerve bundle with silicone adhesive (Wacker Sil-Gel 604, Wacker-Chemie). The electrode cable was then secured in position by suturing it to the abdominal trunk muscles. Finally, the electrode cable was tunneled to the back of the neck and exteriorized, and the flank incision was closed in layers. Integrated RSNA was expressed as microvolts per second per 1-second interval. Because of the limitations of comparing values of multifiber RSNA among rats, the data are expressed as percent change from control values.
After surgical preparation, rats were placed in rat holders for steady-state urine collection. Urine was collected in 10-minute fractions. Physiological saline was infused at a rate of 60 µL/min from the end of anesthesia until the end of all experimental maneuvers. The physiological saline contained sufficient quantities of inulin and PAH for determination of inulin and PAH clearances. Other researchers have used a background infusion of 60 µL/min for comparable experiments and have reported no adverse effects of such a flow rate for steady-state conditions.18 22 Theoretically, the relations of GFR to RPF might shift slightly.
Rats were allowed an equilibration period of at least 6 hours after the end of anesthesia. Experimental protocols were started after urine output equaled saline input for at least four 10-minute periods. UV and UNaV values of the last of these sampling periods were used as the data point at 0 minutes at the beginning of the first control period of the experimental protocol.
Experimental Protocols
Assessment of Doses of the AT1 Receptor Antagonist ZD 7155
We administered three doses of the Ang II receptor antagonist ZD 7155 (6, 30, and 60 µg IV) to inhibit the effects of Ang II. To test for blockade of systemic AT1 receptors with the Ang II receptor antagonist, we injected 20 ng Ang II IV 10 minutes before and 10 minutes after ZD 7155 administration. In four additional experiments, we injected 20 ng Ang II 4 hours after pretreatment with 30 and 60 µg ZD 7155 IV. In all experimental protocols described below, 20 ng Ang II IV was injected at the end of the protocols if proper blockade of AT1 receptors had to be demonstrated.
The lowest dose (6 µg) of ZD 7155 did not block the pressor response to Ang II. To test whether 6 µg ZD 7155 blocked the excretory effects of Ang II within the kidney, we used the following protocol: 6 µg ZD 7155 or vehicle (0.9% NaCl) was injected intravenously at the beginning of a series of experiments after a steady state (saline input=urine output) had been achieved. After two 10-minute control periods, a nonpressor infusion of Ang II (13 ng/min) was begun for an additional 10 minutes. Two 10-minute recovery periods followed.
Air-Jet Stress Experiments With Low-Dose ZD 7155
After a steady state (saline input=urine output) had been achieved following the experimental procedures, the AT1 receptor antagonist ZD 7155 or vehicle (0.9% NaCl) was given as a bolus injection (30 µL volume IV) in a first series of air-jet stress experiments. Half an hour later, the experiments were begun.
After two 10-minute control periods, all rats were exposed to 10 minutes of air-jet stress by a continuous stream of air into the rat's face. Two more 10-minute sampling periods were allowed for recovery. Blood samples of 150 µL were taken at the midpoint of each 10-minute collection period for assessment of GFR and PAH (see below). The amount of blood withdrawn was replaced by a maintenance infusion within 2.5 minutes and had no effect on steady-state or systemic hemodynamics. After the recovery periods, we injected 20 ng Ang II (Bachem, dissolved in 0.9% NaCl) intravenously (20 µL) to test to what extent the antagonist blocked the BP response to the peptide. At the end of the experiments, 10 mg/kg body wt of the ganglionic blocking agent trimethaphan camsylate (F Hoffmann–LaRoche) was injected to shut off postsynaptic RSNA. The background activity remaining thereafter was subtracted from the activity recorded throughout the experiment. Finally, the rats were killed and both kidneys excised and weighed. The experimental protocol was repeated with bilaterally denervated rats.
Dose-Response Experiments: Effects on Renal Excretory Function During Air-Jet Stress
The experimental protocol for the dose-response experiments (n=6) was identical to the one described above except that we did not measure RSNA or assess GFR and RPF. In each rat, only one dose of ZD 7155 was injected (6, 30, or 60 µg ZD 7155 and vehicle IV). When we used a dose of 6 µg ZD 7155, BP, HR, UV, and UNaV responses were not different from the group in which we measured RSNA. Hence we pooled the data.
A last series of experiments (n=6) consisted of two control periods and three recovery periods after the injection of either 6, 30, or 60 µg ZD 7155 IV for evaluation of the immediate influence of these concentrations on renal excretory function.
Urine Analysis
UV was determined gravimetrically. Urinary and plasma sodium as well as potassium concentrations were measured by flame photometry. UV values were expressed per gram kidney weight. Urinary and plasma inulin and PAH concentrations were determined by the anthrone and ethylenediamine methods, respectively.25 26 GFR was measured as inulin clearance: CIn=(V·UIN)/PIN, where UIN and PIN are urinary and plasma inulin concentrations, respectively, and V is urine flow rate. RPF was determined by PAH clearance: CPAH=(V·UPAH)/PPAH, where UPAH and PPAH are urinary and plasma PAH concentrations, respectively.
Statistics
Repeated measures ANOVA was used for assessment of the significance of differences within groups (control period versus treatment versus air-jet stress). Two-way ANOVA was used for comparisons between groups. The Newman-Keuls test was used for post hoc testing. Only a priori defined hypotheses were tested. A value of P<.05 was considered significant. Statistical analysis was carried out with the CSS Statistica software package (StatSoft). Results are expressed as mean±SE.
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Results |
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Assessment of Doses of the AT1 Receptor Antagonist ZD 7155
To test for the blockade of systemic AT1 receptors with the Ang II receptor antagonist ZD 7155, we injected 20 ng Ang II IV 10 minutes before and 10 minutes after ZD 7155 administration. The results are shown in Fig 1
. The higher doses of 30 and 60 µg blocked the pressor response to exogenous Ang II significantly by 79±3% and 83±2%, respectively (Fig 1). The lowest dose did not significantly affect the pressor response to exogenous Ang II (Fig 1). After 4 hours, the higher doses of ZD 7155 still blocked responses to exogenous Ang II to the same extent (30 µg: 78±4%; 60 µg: 80±3%). In all experimental protocols described below, 20 ng Ang II was injected intravenously at the beginning and end of the protocols (time interval of 45 minutes) if proper blockade of AT1 receptors had to be demonstrated. The results were not different from the results shown in Fig 1.
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A nonpressor dose of Ang II (13 ng/min) induced water and sodium retention. Pretreatment with 6 µg ZD 7155 significantly reduced the antidiuretic and antinatriuretic responses to this nonpressor dose of Ang II in conscious rats. Hence, 6 µg ZD 7155 must have affected renal AT1 receptors (Fig 2).
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Air-Jet Stress Experiments With Low-Dose Ang II Receptor Blockade
Ten minutes of air-jet stress induced marked antinatriuresis and anitidiuresis in intact and conscious rats, whereas mean arterial BP and HR did not change significantly (Fig 3). UV dropped from 31±3 to 8±4 µL/min per gram kidney weight during the stress period (P<.05), and UNaV decreased from 4.3±0.9 to 1.2±0.3 µmol/min per gram kidney weight (P<.05). The excretory response to air-jet stress depended considerably on the effects of RSNA: Our renal nerve recordings demonstrate that RSNA increased in response to air-jet stress (Fig 4), and denervation of both kidneys 7 days before the experiments abolished the antinatriuresis and antidiuresis induced by air-jet stress (Fig 3). The changes in urine and sodium output in response to air-jet stress were independent of changes in GFR and RPF, as these parameters did not change during the experiment in rats with either innervated or denervated kidneys (Fig 5).
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After intravenous pretreatment with 6 µg ZD 7155, air-jet stress induced no significant change in UNaV (Fig 3
). A decrease in UV was still detectable (from 26±3 to 18±2 µL/min per gram kidney weight, P<.05), although this decrease was significantly blunted compared with that in control rats (Fig 3). Six micrograms of ZD 7155 did not influence the duration or magnitude of the renal nerve response to air-jet stress (Fig 4) and did not affect either GFR or RPF (Fig 5). (Given the settings of our Grass recording equipment, the basal absolute RSNA levels for controls and the groups treated with ZD 7155 were 340±34 and 351±39 µV, respectively.)
Dose-Response Experiments: Effects on Renal Excretory Function During Air-Jet Stress
Two higher doses of ZD 7155 (30 and 60 µg IV) abolished the renal excretory responses (UNaV and UV) to air-jet stress (Fig 6). UNaV and UV after air-jet stress in rats pretreated with 30 µg ZD 7155 did not change (Fig 7). In rats pretreated with 60 µg ZD 7155, UV and UNaV tended to increase in response to air-jet stress (Fig 6), an effect similar to that observed after renal denervation (Fig 2).
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The three doses of the AT1 receptor blocker showed different effects on baseline values before air-jet stress after intravenous administration.
Six micrograms of ZD 7155 did not affect BP (118±4 mm Hg before versus 114±5 mm Hg 10 minutes after the drug, P=NS) or HR. Thirty micrograms ZD 7155 lowered BP after intravenous injection (116±5 mm Hg before versus 103±6 mm Hg 10 minutes after the drug, P<.05) without affecting HR. However, the effect on BP of 30 µg ZD 7155 was not sustained. Twenty minutes before the air-jet stress, BP had returned to levels (114±6 mm Hg) not significantly different from those in saline-treated rats.
Sixty micrograms of ZD 7155 induced a marked decrease of BP. Mean arterial pressure dropped from 120±5 to 93±5 mm Hg (P<.05) 10 minutes after drug injection. At the beginning of the air-jet stress period, BP was 105±3 mm Hg in rats treated with 60 µg ZD 7155 versus 118±5 mm Hg in saline-treated rats (P<.05); HR was not significantly different between these groups (Fig 6).
Fig 7 shows the effects of ZD 7155 on baseline UV, UNaV, and urinary potassium excretion in the absence of air-jet stress. The lowest dose (6 µg) had no effect on either parameter. Thirty micrograms of ZD 7155 significantly increased both UV (from 33±4 to 46±5 µL/min per gram kidney weight, P<.05) and UNaV (from 3.6±0.7 to 4.8±0.3 µmol/min per gram kidney weight, P<.05). Sixty micrograms of ZD 7155 did not significantly increase UV or UNaV. Urinary potassium excretion was not affected by any dose of ZD 7155 (Fig 7).
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Discussion |
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Our data demonstrate that blockade of AT1 receptors by ZD 7155 blunted or abolished the renal response to air-jet stress. Our renal nerve recordings and renal denervation experiments confirmed that the antidiuresis and antinatriuresis evoked by air-jet stress depended considerably on increases in RSNA. By using air-jet stress to increase RSNA, we could avoid the problems related to electrical stimulation of nerve fibers. This is important because it is difficult to determine what relationship exists between exogenous electrical stimulation and endogenously generated sympathetic nerve activity. The impairment of the air-jet stress response by ZD 7155 occurred at a dose (6 µg) of the drug that did not affect BP, HR, renal hemodynamics, RSNA, or the BP response to 20 ng Ang II. However, 6 µg ZD 7155 blunted the antinatriuresis induced by nonpressor doses of Ang II (13 ng/min). We conclude that endogenous Ang II modulates the renal effects of physiological variations in RSNA in conscious rats.
ZD 7155 is a novel compound that antagonizes the actions of Ang II at AT1 receptors. It proved to be a specific antagonist of Ang II receptors in vitro.27 One experimental series in Sprague-Dawley rats suggested that ZD 7155 might be slightly more potent and longer lasting than losartan in comparable doses.28 In two-kidney, one clip hypertensive rats, a dose of 3 mg/kg PO lowered BP within 1 hour, and this effect was accompanied by sustained inhibition of tissue Ang II binding up to 24 hours.29 Plasma levels of ZD 7155 were no longer detectable after 24 hours despite continued Ang II receptor occupancy in the kidney and adrenal cortex.30 No displacement from AT2 receptors occurred. In our hands, intravenous bolus injections of 60 and 30 µg ZD 7155 inhibited the BP response to the same extent after exogenous Ang II bolus injections 45 minutes and 4 hours after administration. Six micrograms of ZD 7155 inhibited the antidiuresis and antinatriuresis induced by a nonpressor infusion of Ang II, indicating blockade of renal AT1 receptors. However, we cannot exclude the possibility that this low dose of the AT1 receptor antagonist also affected Ang II receptors in other regional vascular beds involved in the control of regional hemodynamics.
Our data extend previous studies in anesthetized animals that demonstrated an interaction between pharmacological Ang II concentrations and the renal nerves, which were stimulated electrically in some of these studies.12 13 14 In contrast to our results, other researchers were unable to demonstrate an interaction between reflex-mediated antidiuresis/antinatriuresis and endogenous Ang II in conscious animals.15 16 We cannot fully explain this discrepancy but wish to point out some differences between these previous reports15 16 and our results. Species differences between rats and dogs used by others15 16 may play a role. Persson et al15 used common carotid occlusion, and Nelson and Osborn16 used hemorrhage to activate cardiovascular reflexes, whereas we used air-jet stress to increase RSNA selectively.17 18 Furthermore, these authors did not perform nerve recordings or renal denervation to verify that the observed renal responses were really due to increased RSNA.15 16 Nelson and Osborn used dogs after unilateral nephrectomy, which might affect glomerular and tubular functions. Finally, differences between the compounds used to block Ang II may play a role, because the ability of Ang II–blocking drugs to penetrate the renal tissue may determine the magnitude of the physiological response to these drugs.31
Koepke et al17 18 first used air-jet stress in salt-sensitive rats or rats on a high sodium diet to elicit reproducible increases in RSNA without sustained changes in systemic hemodynamics. Our data extend these previous reports, because we obtained the stress responses in "normal" Sprague-Dawley rats on a normal sodium diet. We could confirm the reports by Koepke et al in that we observed only transient, nonsignificant changes in BP but prolonged effects on RSNA, UV, and UNaV. We also confirmed that the renal effects of air-jet stress depended considerably on the renal nerves. Sodium retention in response to air-jet stress is due to a tubular rather than a hemodynamic effect of the renal nerve, ie, a stimulation of proximal tubular sodium reabsorption9 17 18 without any change in GFR or RPF.17 18 The role of stress-induced increases in RSNA in the regulation of body volume and BP is supported by the observation that air-jet stress or similar types of stress elicit hypertension in stress-sensitive rat strains11 32 and that renal denervation delays the development of this type of hypertension.32
Pretreatment with the AT1 receptor blocker ZD 7155 blunted or even abolished the antinatriuretic and antidiuretic effects of air-jet stress. Higher doses of ZD 7155 exhibited some diuretic, natriuretic, and BP-lowering effects (it is possible that the natriuretic effect of the highest dose of ZD 7155 was blunted by the fall in BP). However, the lowest dose (6 µg) of ZD 7155 did not change baseline conditions. In fact, 6 µg ZD 7155 did not even block the BP response to exogenous Ang II, indicating that AT1 receptors in the systemic circulation were not blocked. However, this dose of ZD 7155 still impaired the renal response to air-jet stress. Our data thus demonstrate that endogenous, intrarenal Ang II interacts specifically with sympathetic nerve–mediated antidiuresis and antinatriuresis. This interaction occurred in the absence of any measure to stimulate the endogenous renin-angiotensin system. We cannot exclude some degree of activation of the renin-angiotensin system by postoperative stress or the sequelae of anesthesia, but the normal response to exogenous Ang II and the euhydrated volume status of the rats argue against this possibility. The fact that potassium excretion was not affected by any dose of ZD 7155 suggests that aldosterone-dependent mechanisms are not significantly involved in the responses observed
Blockade of Ang II receptors could possibly influence the magnitude of the RSNA increase evoked by air-jet stress via a central interaction because Ang II can modulate the central control of reflex increases in sympathetic nerve activity.1 However, our renal nerve recordings exclude this possibility and demonstrate that the interaction of endogenous Ang II and the SNS occurred within the kidneys. Our GFR and RPF measurements excluded an intrarenal hemodynamic (vascular or glomerular) effect of the low dose of ZD 7155. At higher doses of ZD 7155, a hemodynamic effect of the drug could possibly interfere with the tubular effects of the renal nerves.20 It should be mentioned that AT1 receptor antagonists can exert natriuresis in the absence of any change in GFR or renal blood flow.33 34 35 36 Since the two higher doses of ZD 7155 changed baseline BP, we did not investigate RSNA and renal hemodynamics during air-jet stress in the presence of these doses. Concentrations of AT1 blockers that affect BP could certainly elicit secondary changes in renal hemodynamics and nerve activity, which would hamper conclusions on the intrarenal effect of ZD 7155. However, our data clearly demonstrate that BP-lowering doses of the AT1 blocker still inhibit stress-induced antidiuresis and antinatriuresis.
Endogenous Ang II could modulate the nerve-mediated antinatriuresis and antidiuresis by either presynaptic or postsynaptic actions at the tubular level. Presynaptic facilitation of transmitter release from sympathetic varicosities by Ang II has been demonstrated.4 13 Ang II may also exhibit a postsynaptic synergism with released norepinephrine.14 37 The renal nerve–mediated response to air-jet stress could be mediated by 
1-adrenoceptor stimulating Na,K-ATPase in the proximal tubules.38 Under our experimental baseline conditions (saline diuresis), these mechanisms as well as the endogenous renin-angiotensin system were probably relatively inactive. During air-jet stress, we cannot precisely determine where along the tubules the reabsorption of salt and water occurred in our experimental setup. However, our data are consistent with the assumption that the main effect occurred at the proximal tubules.39 40 Ang II receptors are also present on proximal tubular cells and can stimulate Na,K-ATPase as well as the Na-H antiporter.35 Since Ang II blockade inhibited the response to air-jet stress almost completely, it is tempting to speculate that Ang II itself, via its tubular receptors, might mediate the nerve-induced antinatriuresis. However, this speculation is not consistent with many previous reports which have suggested that the renal nerve–induced sodium reabsorption requires -adrenoceptors.38 Moreover, it does not explain why the same dose of ZD 7155 that inhibits the stress response does not affect baseline sodium excretion. A more likely explanation is that intrarenal Ang II facilitates -adrenoceptor–mediated sodium reabsorption in response to stress via postsynaptic and presynaptic Ang II receptors.35 Increased intrarenal Ang II during air-jet stress could further enhance this effect. The renal nerve can stimulate renin release,41 and intrarenal ß-adrenoceptor stimulation has been shown to increase renal Ang II levels.42
Hence, our results could best be explained by two different actions of endogenous Ang II at the tubular level: a direct effect of AT1 receptors on sodium reabsorption, and an interaction of Ang II with the antinatriuretic properties of the renal sympathetic nerves. Both effects may contribute to the Ang II–dependent sodium retention in chronic renal failure.34
Our study demonstrates that endogenous Ang II modulates the antinatriuretic and antidiuretic effects of the sympathetic nervous innervation of the kidney via AT1 receptors. This modulation occurred in conscious rats with a normal renin-angiotensin system during physiological variations of RSNA. The interaction between Ang II and the SNS occurs most likely at the tubular level and may involve both presynaptic and postsynaptic actions of the peptide. The AT1 receptor blocker ZD 7155 may modulate volume and BP homeostasis by blunting the volume retention exerted by the SNS. Further studies will be necessary to elucidate the role of renal tubular interaction between Ang II and the SNS in models of hypertension or volume retention.
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Acknowledgments |
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This study was supported by ZENECA GmbH, Plankstadt, FRG. We thank Ellen S. Pentz, PhD, Charlottesville, Va, for reading the manuscript and making helpful suggestions.
Received July 5, 1995; first decision August 17, 1995; accepted May 20, 1996.
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