Published online before print October 20, 2003, doi: 10.1161/01.HYP.0000097549.70134.D8
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(Hypertension. 2003;42:968.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats
From the Departments of Internal Medicine and Pharmacology, Department of Veterans Affairs Medical Center, and the Roy J. and Lucille Carver College of Medicine, University of Iowa, Iowa City.
Correspondence to Ulla C. Kopp, PhD, Department of Internal Medicine, VA Medical Center, Bldg 3, Room 226, Highway 6W, Iowa City, IA 52246. E-mail ulla-kopp{at}uiowa.edu
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Abstract |
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In rats fed high sodium diet, increasing renal pelvic pressure
3 mm Hg activates renal mechanosensory nerves, resulting in a renorenal reflex–induced increase in urinary sodium excretion. The low activation threshold of the renal mechanosensory nerves suggests a role for natriuretic renorenal reflexes in the regulation of arterial pressure and sodium balance. If so, interruption of the afferent renal innervation by dorsal rhizotomy (DRX) at T9-L1 would impair urinary sodium excretion and/or increase arterial pressure during high dietary sodium intake. DRX and sham-DRX rats were fed either a high or a normal sodium diet for 3 weeks. Mean arterial pressure measured in conscious rats was higher in DRX than in sham-DRX rats fed a high sodium diet, 130±2 vs 100±3 mm Hg (P<0.01). However, mean arterial pressure was similar in DRX and sham-DRX rats fed a normal sodium diet, 115±1 and 113±1 mm Hg, respectively. Steady-state urinary sodium excretion was similar in DRX and sham-DRX rats on high (17.9±2.2 and 16.4±1.8 mmol/24 h, respectively) and normal (4.8±0.3 and 5.0±0.4 mmol/24 h, respectively) sodium diets. Studies in anesthetized rats showed a lack of an increase in afferent renal nerve activity in response to increased renal pelvic pressure and impaired prostaglandin E2–mediated release of substance P from the renal pelvic nerves in DRX rats fed either a high or a normal sodium diet, suggesting that DRX resulted in decreased responsiveness of peripheral renal sensory nerves. In conclusion, when the afferent limb of the renorenal reflex is interrupted, a high sodium diet results in increased arterial pressure to facilitate the natriuresis and maintenance of sodium balance.
Key Words: renal nerves • hypertension, sodium dependent • sodium, dietary • urine • natriuresis
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Introduction |
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In the kidney, the majority of renal sensory nerves containing substance P are located in the renal pelvic wall.1,2 The afferent renal nerves project to the ipsilateral dorsal root ganglia at the T6-L2 level, with the majority of cell bodies of the afferent renal nerves being at the T9-L1 level.3,4 The renal sensory nerves are activated by increases in renal pelvic pressure within the physiologic range.5 The increase in afferent renal nerve activity (ARNA) produced by the increased renal pelvic pressure leads to a reflex decrease in efferent renal sympathetic nerve activity (ERSNA) and diuresis and natriuresis, ie, a renorenal reflex response.6
Increasing renal pelvic pressure elicits a series of events eventually leading to increases in ARNA. Among the various mechanisms activated by increased renal pelvic pressure is stimulation of bradykinin-2 receptors that activate protein kinase C, which leads to activation of cyclooxygenase-2 and increased prostaglandin E2 (PGE2) synthesis.7–9 PGE2 activates cAMP, which leads to a calcium-dependent release of substance P from the renal sensory nerves.10,11 Substance P increases ARNA by stimulating neurokinin-1 receptors.12
The responsiveness of renal sensory nerves is modulated by dietary sodium, being suppressed by a low and enhanced by a high sodium (HNa) diet.5 The altered responsiveness of renal sensory nerves is mediated by changes in angiotensin II (Ang II) levels in the renal pelvic wall. Ang II inhibits the PGE2-mediated release of substance P from the renal sensory nerves.
The threshold for activation of renal mechanosensory nerves is <3 mm Hg under conditions of an HNa intake.5 The low activation threshold of renal mechanosensory nerves together with the natriuretic nature of the renorenal reflexes suggest that activation of these reflexes is an important component of the spectrum of renal mechanisms involved in the renal control of water and sodium homeostasis.
We reasoned that if activation of afferent renal nerves contributes to the homeostatic regulation of arterial pressure and sodium balance, then selective afferent renal denervation would alter the hemodynamic responses to a dietary sodium load. We tested this hypothesis by measuring arterial pressure in conscious rats with bilateral dorsal rhizotomy (DRX) at T9-L1 or sham operation. The rats were fed either an HNa or a normal sodium (NNa) diet for 25 days.
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Methods |
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Animals and Experimental Design
The experimental protocols were approved by the Institutional Animal Care and Use Committee. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium (0.2 mmol/kg IP, Abbott Laboratories). Bilateral DRX (n=28)13 or sham-DRX (n=30) was performed in littermates at T9-L1. The sham-DRX procedure was identical to DRX except that the dorsal roots were not sectioned. Rats were placed on NNa pellets (Na+=163 meq/kg, Teklad) with 0.9% NaCl drinking fluid (HNa diet, n=38) or tap water drinking fluid (NNa diet, n=20).5 Nine days later, the rats were placed in metabolic cages for 10 days for measurements of daily urinary sodium excretion.
Recording of Pulsatile Arterial Pressure in Conscious Rats
Three weeks after DRX and sham-DRX surgery, rats were anesthetized with methohexital sodium (0.14 mmol/kg IP, Jones Pharma Inc). A polyurethane catheter was placed into the femoral artery, tunneled subcutaneously to the back of the neck, and exteriorized. Starting 24 hours after surgery, arterial pressure was recorded simultaneously in conscious DRX and sham-DRX rats for 2 hours for 4 consecutive days.
After arterial pressure recordings, the rats were anesthetized (pentobarbital sodium, 0.2 mmol/kg IP plus 0.04 mmol · kg-1 · h-1 IV) for studies of the responsiveness of afferent renal nerves.
The left kidney was approached by flank incision. A PE-10 catheter was placed in the right ureter for urine collection. A PE-50 catheter placed in the left ureter was used to increase renal pelvic pressure by elevating its free end above the kidney.1,5,11 ARNA was recorded from the peripheral portion of the cut end of 1 renal nerve. ARNA integrated over 1-second intervals was expressed as a percentage of that at baseline.1,5–9,11,12
Effects of Increasing Renal Pelvic Pressure on ARNA
DRX rats (n=9) and sham-DRX rats (n=10) fed the HNa diet were studied. Renal pelvic pressure was increased by 5 and 15 mm Hg, in random order, for two 5-minute experimental periods bracketed by 10-minute control and recovery periods.
Substance P Release From an Isolated, Renal Pelvic Wall Preparation
Renal pelvises were placed in HEPES buffer containing 0.14 mmol/L indomethacin. The experiments were started after a 130-minute equilibration period.5,10,11
Effects of PGE2 on Substance P Release
The renal pelvises from DRX (n=8) and sham-DRX (n=10) rats fed the NNa diet were studied in parallel. All pelvises were exposed to 0.14 µmol/L PGE2 during the 5-minute experimental period, which was bracketed by four 5-minute control and recovery periods. The incubation medium, aspirated every 5 minutes, was stored at -80°C for later analysis of substance P.
Drugs
Substance P antibody was acquired from Peninsula Laboratories and PGE2 from Cayman Chemicals. All other agents were from Sigma Chemicals unless otherwise stated.
Analytical Procedures
Urinary sodium concentrations were determined with a flame photometer. Substance P in the incubation medium was measured by ELISA.1,5,8,10,11
Statistical Analysis
The Mann-Whitney U test, Friedman 2-way ANOVA, and a shortcut ANOVA were used to evaluate the effects of DRX on mean arterial pressure (MAP), ARNA responses to increased renal pelvic pressure, and PGE2-mediated substance P release. A significance level of 5% was chosen. Data in text and figures are expressed as mean±SE.14,15
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Results |
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Arterial Pressure in Conscious Rats Fed the HNa Diet
Measurement of daily urinary sodium excretion for 10 consecutive days showed that urinary sodium excretion reached a steady state after 2 days. Daily intakes of food and water, averaged over the last 8 days, were similar in DRX and sham-DRX rats, 31±1 and 31±1 gm/24 h and 58±3 and 57±4 mL/24 h, respectively. Likewise, urinary sodium excretion (Figure 1) and body weight were similar in the 2 groups, 281±8 and 281±8 g, respectively. However, the similar daily urinary sodium excretion in the 2 groups was achieved at markedly different arterial pressures. Conscious, pulsatile arterial pressure, averaged over 2 hours, was higher in every DRX rat compared with its sham-operated littermate on each of the 4 consecutive days (Figure 2). MAP averaged 130±2 and 100±3 mm Hg in DRX and sham-DRX rats, respectively (P<0.01). The coefficient of variation averaged 8.3±0.8% and 8.6±1.3% in DRX and sham-DRX rats, respectively.
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The responsiveness of renal mechanosensory nerves was studied in a separate group of DRX and sham-DRX rats similarly treated as the rats described earlier. Body weight, 307±7 and 314±7 g, and daily urinary sodium excretion, 17.1±3.0 and 17.0±2.5 mmol/24 h, in DRX and sham-DRX rats were similar to those in the previous groups. Likewise, conscious MAP was similar to that in the previous group, being 134±5 and 106±2 mm Hg in the DRX and sham-DRX rats, respectively (Figure 2). After anesthesia, MAP was 118±4 vs 100±1 mm Hg (P<0.01) in the DRX and sham-DRX rats, respectively. In sham-DRX rats, increasing renal pelvic pressure (5.9±0.2 and 16.0±0.2 mm Hg) resulted in marked increases in ipsilateral ARNA (Figure 3) and contralateral urinary sodium excretion, from 1.1±0.2 to 1.3±0.3 µmol · min-1 · g-1 (P<0.05) and from 1.1±0.2 to 1.4±0.2 µmol · min-1 · g-1 (P<0.01), respectively. In DRX rats, increasing renal pelvic pressure to a similar extent failed to increase ipsilateral ARNA (Figure 3) and urinary sodium excretion, from 0.6±0.1 to 0.8±0.2 µmol · min-1 · g-1 (NS) and from 0.8±0.1 to 0.9±0.2 µmol · min-1 · g-1 (NS).
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P<0.01, ARNA response to increasing renal pelvic pressure, 16.0±0.2 vs 5.9±0.2 mm Hg.
Arterial Pressure in Conscious Rats Fed the NNa Diet
Daily intakes of food, 30±1 and 31±1 g/24 h, and of water, 42±2 and 44±2 mL/24 h, were similar in DRX and sham-DRX rats. Likewise, urinary sodium excretion (Figure 1) and body weight (233±7 and 254±11 g) were similar in the 2 groups of rats. Conscious MAP was similar in DRX and sham-DRX rats, averaging 115±1 and 113±1 mm Hg in the DRX and sham-DRX rats, respectively (Figure 4). The coefficient of variation averaged 7.6±0.8% and 8.8±0.7% in DRX and sham-DRX rats, respectively.
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Our studies in DRX and sham-DRX rats fed the HNa diet suggested that T9-L1 DRX reduces the responsiveness of peripheral renal sensory nerves. Therefore, the responsiveness of the renal sensory nerves was tested in DRX and sham-DRX rats fed the NNa diet to exclude the possibility that the similar MAP in the 2 groups was related to incomplete DRX. PGE2 elicited a marked reversible release of substance P from the sham-DRX pelvises that was significantly greater than that from DRX pelvises (Figure 5). Baseline substance P release was also higher from sham-DRX pelvises than from DRX pelvises (P<0.05).
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Discussion |
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The results of these experiments show that steady-state daily urinary sodium excretion is similar in rats with and without intact afferent renal innervation fed an HNa or NNa diet. However, the similar urinary sodium excretion was achieved at different levels of arterial pressure in rats fed the HNa diet. In DRX rats, MAP was markedly elevated compared with that in their sham-operated littermates. In contrast, MAP was similar in DRX and sham-DRX rats fed the NNa diet. These findings suggest that interruption of the afferent limb of renorenal reflexes results in the development of increased arterial pressure to facilitate natriuresis and maintenance of sodium balance during HNa intake.
Arterial Pressure Versus Urinary Sodium Excretion in DRX and Sham-DRX Rats
The renorenal reflexes are activated by increases in renal pelvic pressure commonly seen during high urine flow rate,5 suggesting that the afferent renal nerves are tonically active. Supporting this argument are studies in anesthetized rats showing that total, ie, efferent plus afferent, unilateral renal denervation produces an increase in contralateral ERSNA and a decrease in contralateral urinary sodium excretion.16 Because the functional response to activation of the renal sensory nerves includes increased sodium excretion at unchanged renal and systemic hemodynamics,6 renorenal reflexes might be an essential component of the mechanisms activated to maintain body sodium balance during excess sodium intake. Measurements of steady-state daily urinary sodium excretion showed that the DRX and sham-DRX rats excreted similar amounts of sodium when fed the HNa or NNa diet. However, in rats fed the HNa diet, the similar amounts of sodium excreted were achieved at markedly different arterial pressures in the 2 groups of rats. The differences in MAP between DRX and sham-DRX rats were reproducible, as demonstrated by the similar MAP differences in DRX and sham-DRX rats fed the HNa diet in 2 separate studies.
Importantly, MAP was similar in DRX and sham-DRX rats fed the NNa diet. Thus, in contrast to sham-DRX rats, which were able to excrete a 4-fold difference in sodium intake at similar MAP, DRX rats were able to excrete a similar increased sodium intake only at the expense of a marked increase in MAP. The slope of the relation between the change in daily urinary sodium excretion and the change in MAP was +0.75 in DRX rats and -1.17 mmol · 24 h-1 · mm Hg-1 in sham-DRX rats. Thus, DRX rats were characterized by impaired pressure natriuresis (Figure 6).17
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MAP was lower in sham-DRX rats fed HNa than in sham-DRX fed the NNa diet. However, it is questionable whether the lower MAP in the sham-DRX rats fed the HNa diet was related to the HNa diet’s causing a depressor effect. Because of time restrictions related to (1) afferent reinnervation five weeks after DRX (shown in pilot studies) and (2) the time required to achieve sodium balance after the DRX/sham-DRX surgical procedures, DRX and sham-DRX were performed in littermates subsequently placed on the HNa or NNa diet. Whereas body weight was similar in DRX and sham-DRX littermates on each diet, body weight in the NNa-diet rats was lower than in the HNa-diet rats at the time arterial pressure was recorded. This was related to the fact that body weight was lower in NNa- than in HNa-diet rats, 177±7 versus 228±6 g, at the time of DRX/sham-DRX surgery. The weight gain was similar in the 2 groups of rats over the 3-weeks period on each diet. The body weight differences emphasize the risk in comparing rats that are not littermates and in which experiments not run in parallel. Also, previous studies that examined the effects of HNa and NNa diets on arterial pressure in the same rat provided no evidence for the HNa diet to have a depressor effect.18,19
Whereas the current studies suggest a role for renorenal reflexes in the long-term regulation of sodium balance during an HNa diet, a role for the renorenal reflexes has also been demonstrated in the short-term regulation of sodium balance during sodium restriction.20 Measurements of urinary sodium excretion for 24 hours showed a transient sodium loss from the DRX kidneys when sodium delivery was restricted. The transient sodium loss most likely reflected the DRX kidneys’ inability to increase ERSNA via renorenal reflex mechanisms.
Mechanisms Involved in Increased Arterial Pressure
Numerous studies have shown that severing the dorsal roots, ie, the afferent nerves proximal to the dorsal root ganglia, reduces the number of substance P– and calcitonin gene–related peptide–containing nerves in the dorsal horn.21 There are few studies examining the effects of DRX on peripheral afferent innervation. However, there are reports showing that DRX at T6-L2 and L6/S1 reduced the number of substance P– and calcitonin gene–related peptide–containing nerves around the hepatic artery and portal vein22 and in urinary bladder,23 respectively. Therefore, we examined whether the responsiveness of afferent renal nerves was altered by DRX. Three weeks after DRX, increasing renal pelvic pressure failed to increase ARNA. The lack of ARNA responses in DRX rats was even more conspicuous considering that the rats were fed the HNa diet. In agreement with our previous studies,5 increasing renal pelvic pressure resulted in marked increases in ARNA in the sham-DRX rats fed an HNa diet. Further studies in isolated renal pelvises derived from normotensive DRX rats showed that baseline substance P release and PGE2-mediated substance P release were reduced compared with those in sham-DRX. Altogether, these studies suggest that severing the central processes of the afferent nerves at T9-L1 results in desensitization of the afferent renal nerves. Whether T9-L1 DRX reduced the number of afferent renal nerves and/or impaired the mechanisms involved in activation of the afferent renal nerves is currently not known. Nevertheless, our findings suggest that impaired function of the afferent renal nerves contributes to the elevated MAP in DRX rats fed an HNa diet.
It is possible that T9-L1 DRX interrupted the afferent innervation not only of the kidneys but also of other visceral organs. However, previous studies on the role of the afferent innervation of 2 major vascular beds, the liver and mesentery, in cardiovascular control would not support the notion that an intact afferent innervation of these visceral vascular beds plays a major role in the maintenance of arterial pressure under conditions of HNa intake. Studies that examined the role of afferent hepatic nerves in the cardiovascular response to an HNa diet showed a similar modest increase in conscious arterial pressure in hepatic innervated and denervated rats.24 Although there is little information on the effects of dietary sodium on arterial pressure after afferent and/or afferent plus efferent denervation of other visceral organs, available evidence in NNa-diet animals shows that activation of afferent mesenteric nerves elicits excitatory rather than inhibitory cardiovascular reflexes.25
Wang and coworkers26 have presented evidence for salt-sensitive hypertension in rats neonatally treated with capsaicin to destroy the sensory innervation of all organs. Our current findings would suggest that lack of intact afferent renal innervation in capsaicin-treated rats might contribute to the increased arterial pressure in these rats when fed an HNa diet.
Because of the inhibitory nature of renorenal reflexes,6 the increased arterial pressure in DRX rats fed an HNa diet might be due ERSNA’s not being appropriately suppressed. Increased ERSNA leading to increased tubular sodium reabsorption27 might be partly responsible for the impaired pressure-natriuresis curve28 in DRX rats. Because DRX involves rather extensive surgery, daily urinary sodium excretion was not measured during the first 11 days of the HNa or NNa diet. Thus, our data do not exclude the possibility that the development of increased arterial pressure in the DRX rats fed the HNa diet was preceded by a greater positive sodium balance in DRX rats versus sham-DRX rats. In this respect, studies that have examined the effects of an HNa diet on arterial pressure in sinoaortic denervated (SAD) rats are of interest.29 These studies showed that in comparison with sham-SAD rats, an HNa diet increased arterial pressure in SAD rats in association with increased cumulative sodium balance during the first 5 days of an HNa diet.
If the mechanisms of increased arterial pressure in DRX rats are related to inappropriately high ERSNA in rats fed an HNa diet, then the question arises about the involvement of arterial and aortic baroreceptor reflexes in the control of ERSNA in DRX rats. Conversely, what is the role of renorenal reflexes in the control of ERSNA in the increased arterial pressure in SAD rats fed an HNa diet? Numerous anatomic and morphological studies would suggest that control of ERSNA is the result of a central interaction between the afferent renal and arterial/aortic baroreceptor neural input.30–34 In this context, it is interesting that the magnitude of the arterial pressure rise produced by the HNa diet in the DRX rats was similar to that in SAD rats fed an HNa diet.35
Are Differential Mechanisms Involved in Activation of Renal Sensory Nerves in Physiologic and Pathophysiologic Conditions?
Similar to the current studies, Janssen at al36 showed that conscious MAP was similar in DRX and sham-DRX rats fed an NNa diet. Furthermore, they showed that arterial pressure was lower in rats with total renal denervation than in sham-denervated rats. These studies suggested that the antihypertensive effect of afferent plus efferent renal denervation19,36 is related to interruption of the efferent renal nerve pathway in rats fed an NNa diet. The study by Jacob et al19 further showed lack of a significant increase in arterial pressure in renal-denervated rats fed an HNa diet. These findings would appear to contradict our current findings. However, it is important to note that rats with efferent plus afferent denervated kidneys have lost their ability to modulate ERSNA in response to changes in dietary sodium intake.
The depressor effects of T9-L1 DRX observed in rats with 1-kidney, 1-clip hypertension,37 5/6 nephrectomy,38 or exposed to intravenous infusion of cyclosporine39 would appear to contradict the present findings. However, it is likely that different mechanisms are involved in the activation of renal sensory nerves in normal and pathologic conditions. In this context, it is interesting that denervation of the ischemic kidney in the 2-kidney, 1-clip model of hypertension elicited an increase in contralateral urinary sodium excretion, whereas denervation of the nonclipped kidney elicited the expected decrease in contralateral urinary sodium excretion.40 Studies by Katholi and Woods37 would suggest that adenosine might be 1 of the mediators involved in the activation of renal sensory nerves in ischemic kidneys.
Perspectives
The present studies suggest that afferent renal nerves and renorenal reflexes are important mechanisms in the long-term regulation of arterial pressure under conditions of an HNa diet. These findings emphasize the importance of our previous studies in which it was shown that renorenal reflexes are impaired in spontaneously hypertensive rats41 and in rats with congestive heart failure.42 Impairment of renorenal reflexes would play a major role in the sodium-retention characteristics of these pathologic models.
Interfering with mediators involved in the activation of renal sensory nerves might lead to increased arterial pressure under conditions of HNa intake. For example, the bradykinin-2 receptor–deficient mouse, rats fed an essential fatty acid–deficient diet, and mice that lack EP2, 1 of the prostaglandin receptors, become hypertensive when fed an HNa diet.43–45 In view of the inhibitory effect of Ang II on renorenal reflexes,5 it is interesting that arterial pressure is increased in response to long-term administration of a low dose Ang II when rats are fed an HNa but not an NNa diet.46
The collective evidence suggests that under conditions of HNa intake, decreased activity of the afferent renal nerves results in development of increased arterial pressure to facilitate natriuresis as part of the overriding objective of maintaining sodium balance.
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Acknowledgments |
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This work was supported by grants from the Department of Veterans Affairs; National Institutes of Health—Heart, Lung and Blood Institute, grant RO1 HL66068, and Specialized Center of Research grant HL55006; and American Heart Association Grant-In-Aid 0150024N.
Received June 18, 2003; first decision July 8, 2003; accepted September 11, 2003.
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