Departments of Internal Medicine and Physiology, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242
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ABSTRACT |
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Central nervous system (CNS) renin-angiotensin activity
influences the basal level of renal sympathetic nerve activity (RSNA) and its reflex regulation. The effect of type 1 angiotensin II (ANG
II)-receptor antagonist treatment (losartan) on cardiac baroreflex regulation of RSNA and renal sodium handling was examined in rats with
cirrhosis due to common bile duct ligation (CBDL). Basal levels of
heart rate, mean arterial pressure (MAP), RSNA, and urinary sodium
excretion were not affected by intracerebroventricular administration
of either losartan or vehicle to CBDL rats. After acute intravenous
isotonic saline loading (10% body wt) in vehicle-treated CBDL rats,
MAP was unchanged and the decrease in RSNA seen in normal rats did not
occur. However, in losartan-treated CBDL rats, there were significant
concurrent but transient decreases in MAP (20 ± 2 mmHg) and
RSNA (
25 ± 3%). The natriuretic response to acute volume
loading in losartan-treated CBDL rats was significantly less than that
in vehicle-treated CBDL rats only at those time points where there were
significant decreases in MAP. Antagonism of CNS ANG II type 1 receptors
augments the renal sympathoinhibitory response to acute volume loading
in CBDL. However, the natriuretic response to the acute volume loading
is not improved, likely due to the strong antinatriuretic influence of
the concomitant marked decrease in MAP (renal perfusion pressure)
mediated by widespread sympathetic withdrawal from the systemic vasculature.
common bile duct ligation; renal sympathetic nerve activity; renal sodium handling
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INTRODUCTION |
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IN HEPATIC CIRRHOSIS, the initiation and maintenance of a positive sodium balance are major derangements of the disease. One of the mechanisms that contributes significantly to the increased renal sodium retention is increased renal sympathetic nerve activity (RSNA) (4, 9, 12, 15, 23, 29). In the rat model of cirrhosis due to common bile duct ligation (CBDL), RSNA is significantly increased at 1 wk and increases progressively thereafter (4, 12). Renal denervation improves the ability of CBDL rats to excrete both acute (4) and chronic sodium loads (9).
The mechanisms responsible for this heightened level of RSNA in cirrhosis have been studied in the CBDL model (12, 23). Normally, RSNA is substantially regulated by both high-pressure arterial (sinoaortic; 16) and low-pressure cardiac (cardiopulmonary; 13) baroreceptors. Both arterial and cardiac baroreflex regulation of RSNA are abnormal in CBDL (23). The defect in arterial baroreflex regulation is located in the central nervous system (CNS) defect at the site where central processing of afferent input (afferent aortic depressor nerve activity) is converted into the appropriate efferent output (RSNA). The defect in cardiac baroreflex regulation of RSNA is located in the peripheral cardiac baroreceptor as reflected by both an increased pressure threshold and a decreased sensitivity or gain of the afferent limb compared with normal rats.
CNS alterations that may be involved in these baroreflex defects have not been defined. Several lines of evidence suggest that angiotensin II (ANG II) is involved in the regulation of sympathetic nerve activity (1, 3, 22, 26). ANG II receptors are located in CNS areas that influence RSNA (rostral ventrolateral medulla, nucleus tractus solitarius), either directly via connections to the intermediolateral column of the spinal cord or indirectly through modulation of arterial and cardiac baroreflex function (1, 25).
The activity of the renin-angiotensin system, as reflected by circulating concentrations of renin and ANG II, is increased in CBDL (21). This raises the possibility that CNS effects of ANG II may contribute to both the increased basal level of RSNA and the abnormal arterial and cardiac baroreflex regulation of RSNA in CBDL.
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METHODS |
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Animals
Adult male Sprague-Dawley rats, 200-250 g, were allowed free access to normal sodium-containing rat pellet diet (Teklad, Na+ 172 meq/kg) and tap-water drinking fluid. All experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the guidelines of the University of Iowa Animal Care and Use Committee.Anesthesia
Rats were anesthetized intraperitoneally with methohexital (short duration) or pentobarbital sodium (long duration) at 50 mg/kg ip.Model Preparation
In methohexital anesthetized rats, a midline abdominal incision was made and the common bile duct was cut between ligatures (4, 9, 12, 15, 23, 29). After closure of the abdominal wound and recovery from anesthesia, the CBDL rats were returned to their cages with free access to normal sodium rat pellet diet and tap water. Subsequent studies were performed 3 wk after CBDL when ongoing renal sodium retention and edema formation are present. At 3 wk after CBDL, intracerebroventricular cannulas were placed. Three to four days after intracerebroventricular cannulation, the RSNA electrode and the vascular and bladder catheters were placed.Procedures
Catheterization. Catheters were inserted into a jugular vein for drug and solution infusion and into a carotid artery for measurement of mean arterial pressure (MAP) and heart rate (HR).
Intracerebroventricular cannulation. Three to four days before the acute experiment, the rats were anesthetized and placed in a cranial stereotaxic apparatus. A stainless steel cannula was inserted into the lateral cerebral ventricle by methods previously described (24). Coordinates were 0.3 mm posterior to the bregma, 1.4 mm lateral to the midline, and 4.0 mm below the cortical surface (19). The cannula was held in place with stainless steel jeweler's screws and cranioplastic cement. At the end of the acute experiment, 2 µl of isotonic saline colored with methylene blue were injected intracerebroventricularly, and placement of the cannula was confirmed at autopsy.
RSNA recording electrode. The left kidney was exposed through a left flank incision via a retroperitoneal approach. With the use of a dissecting microscope, a renal nerve branch from the aorticorenal ganglion was isolated and carefully dissected free. The renal nerve branch was placed on a recording electrode. RSNA was amplified (×20,000-30,000) and filtered (low 30 Hz, high 3,000 Hz) via a Grass HIP511 High Impedance Probe, leading to a Grass P511 Bandpass Amplifier. The amplified and filtered neurogram was then channeled to a Tektronix 5113 Oscilloscope and Grass model 7D polygraph for visual evaluation, to a audio amplifier-loudspeaker (Grass model AM8) for auditory evaluation, and to a rectifying resistance-capacitance voltage integrator with a 20-ms time constant (integrated RSNA, Grass model 7P3). The quality of the RSNA signal was assessed by its pulse synchronous rhythmicity and by examining the magnitude of decrease in recorded RSNA during sinoaortic baroreceptor loading with an intravenous bolus injection of norepinephrine (1-3 µg). When an optimal RSNA signal was observed, the recording electrode was fixed to the nerve preparation with a silicone cement (Wacker Sil-Gel). The electrode cable was then sutured to the back muscles, tunneled to the back of the neck, and exteriorized. Finally, the flank incision was closed in layers.
Bladder catheter. Through a suprapubic incision, a modified polyethylene catheter was sutured into the urinary bladder, exteriorized, and secured by suturing to adjacent muscle, subcutaneous tissue, and skin.
Experimental Protocol
Three weeks after CBDL, rats possessing intracerebroventricular cannulas were anesthetized, catheterized, and instrumented with a RSNA electrode as previously described. At the onset of surgery, an intravenous infusion of isotonic saline at 0.05 ml/min was begun. After surgery, the rats were allowed to recover in individual metabolism cages for a 3- to 4-h postsurgical equilibration period. To reliably collect urine samples, the rats were placed in Plexiglas cylinders, which permitted forward and backward movement but did not allow the rats to turn around. One hour thereafter, control measurements of MAP, RSNA, and HR were made for a 10-min control urine collection period (C1). Losartan, an ANG II AT1 receptor antagonist, was administered intracerebroventricularly at a dose of 10 nmol (4.6 µg in 0.1 µl isotonic saline) to the experimental group (CBDL-losartan), whereas the control group (CBDL-vehicle) received intracerebroventricular isotonic saline vehicle. After another 10-min control urine collection period (C2), isotonic saline was infused in a volume equal to 10% body weight at a rate of 2 ml/min with continuous measurement of MAP, RSNA, and HR. Urine was collected over consecutive 10-min experimental urine collection periods for 100 min (E1-E10).We have previously demonstrated that 10 nmol icv losartan (dose used herein) completely prevented the pressor response (20 mmHg) to 1 nmol icv ANG II in normal rats (20).
At the completion of the experiment, rats were euthanized with an overdose of pentobarbital. The postmortem background RSNA signal was measured for 30 min; this value averaged 15-20% of the total signal (i.e., signal + noise) and was subtracted from all experimental values of RSNA. At autopsy, both pleural spaces and peritoneal cavity were inspected for evidence of fluid collection. The kidneys and livers were removed, blotted, and weighed.
Analysis
MAP, HR, and integrated RSNA data were acquired digitally at a 1-Hz sampling rate using a Data Translation DT-2801 A-D Board, Labtech Notebook v. 4.2 software (Laboratory Technology, Wilmington, MA) and a PC. Data from each 10-min urine collection period were averaged to give a single value for that period. Because of potential differences in the numbers of nerve fibers and the degree of nerve fiber-electrode contact, absolute values of integrated voltage from multifiber sympathetic nerve recordings cannot be reliably compared between rats or groups of rats. Therefore, data were analyzed as percent change from the baseline control period (C2, after intravenous or intracerebroventricular vehicle or losartan). Urine volume was determined gravimetrically, and urinary sodium concentration (UNa, meq/l) was measured by flame photometry. Urinary sodium excretion (UNaV) equals UNa · V, where V equals urinary flow rate; UNaV is presented per gram kidney weight.Statistical analysis was performed with two-factor (group, response) analysis of variance with repeated measures on one-factor and Duncan's post hoc test (27). Data are presented as means ± SE.
Other Groups
Normal rats.
Using similar methods and experimental design, we have previously
administered acute intracerebroventricular losartan to normal rats on a
regulated normal sodium diet (8) and chronic intraperitoneal losartan
to normal rats on an unregulated sodium diet (7). In normal rats given
vehicle (4, 7, 8), acute volume loading increases cardiac filling
pressure, increases afferent vagal nerve activity, and decreases RSNA
in association with a diuresis and natriuresis. In comparison, normal
rats given acute intracerebroventricular losartan showed small (but
significant) decreases in basal RSNA (23%) and greater
decreases in RSNA (i.e., enhanced cardiac baroreceptor reflex gain,
+14%) (8), whereas such changes were not significant in the case of
normal rats given chronic intraperitoneal losartan (7). In normal rats
given chronic intraperitoneal losartan, there was no significant effect on either the urinary sodium excretory response to the acute volume load or the chronic renal adaptation to an increase in dietary sodium
intake (7).
CBDL rats. In preliminary studies in CBDL rats (n = 8), we attempted to evaluate the effect of chronic systemic administration (intraperitoneal) of losartan, a strategy we had used successfully in congestive heart failure rats to demonstrate an improvement in both cardiac baroreflex regulation of RSNA (improved peripheral cardiac baroreceptor sensitivity) and the ability to excrete both acute and chronic sodium loads (7). However, in contrast to congestive heart failure rats, wherein chronic systemic losartan administration was associated with modest decreases in MAP (7), attempts at chronic systemic losartan administration in CBDL rats was associated with profound reductions in MAP (mean of 51 ± 6 mmHg) and a high mortality rate (5 of 8, 63%).
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RESULTS |
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Table 1 shows the baseline data on body,
liver, and kidney weights and liver- and kidney-to-body weight ratios
for the CBDL-vehicle and CBDL-losartan groups. The values for liver
weight and liver weight-to-body weight ratio agree well with multiple
previous studies in our laboratory (4, 9, 12, 15, 23), as seen in the
legend to Table 1. Table 2 shows the MAP,
HR, RSNA, and UNaV data for the
CBDL-vehicle and CBDL-losartan groups before (C1) and after (C2)
intracerebroventricular administration of isotonic saline vehicle or
losartan. There were no significant differences between groups before
intracerebroventricular administration of isotonic saline vehicle or
losartan (i.e., C1). When C2 was compared with C1, there were no
significant immediate effects of acute intracerebroventricular
administration of either isotonic saline vehicle or losartan.
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Figure 1 shows the MAP, HR, RSNA, and
UNaV data for the CBDL-vehicle and
CBDL-losartan groups in response to acute volume loading. HR was not
significantly affected by acute intravenous isotonic saline volume in
either CBDL-vehicle or CBDL-losartan groups, and there was no
difference between the groups. MAP in CBDL-vehicle continuously trended
downward throughout the experiment from 112 ± 8 mmHg in C2 to 96 ± 10 mmHg in E10. MAP in CBDL-losartan displayed a sharp but
transient decrease from 111 ± 5 mmHg in C2 to 91 ± 5 mmHg in
E2; this was significant both within (vs. C2) and between groups (only
at E2). MAP returned to the control level within 20 min (i.e., by E4).
RSNA was constant throughout in CBDL-vehicle, whereas in CBDL-losartan
the pattern of RSNA response mimicked that of MAP. There was a sharp
but transient decrease from 100% in C2 to 75.3 ± 9.0% in E2; this
was significant both within (vs. C2) and between groups (only at E2).
RSNA gradually returned toward its control level thereafter. The
natriuretic response to acute volume loading was attenuated in
CBDL-losartan compared with CBDL-vehicle with significant differences
between groups at E1 and E2. When calculated as area under the curve, the overall natriuretic response in the CBDL-losartan group was 23 ± 3% less than in the CBDL-vehicle group
(P < 0.05).
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DISCUSSION |
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These data indicate that intracerebroventricular losartan, while not affecting the increased basal level of RSNA in CBDL, facilitates cardiac baroreflex inhibition of RSNA during acute volume loading.
It may be argued that since that portion of the arterial baroreflex which decreases RSNA in response to increased arterial pressure is normal in CBDL (23), then little effect of intracerebroventricular losartan on the relation between basal MAP (unchanged by intracerebroventricular losartan) and basal RSNA (i.e., arterial baroreflex resetting) would be anticipated. However, studies in normal rats subjected to decreased dietary sodium intake to stimulate the activity of the renin-angiotensin system showed substantial arterial baroreflex resetting with intracerebroventricular losartan, i.e., basal RSNA decreased without a change in basal MAP (6). These results would suggest that despite evidence of increased activity of the renin-angiotensin system in CBDL rats (21) ANG II was either not having a detectable tonic central influence on arterial baroreflex regulation of RSNA or that its effect was being masked by some other influence.
The abnormal cardiac baroreflex regulation of RSNA in CBDL accounts for the attenuated renal sympathoinhibitory response to acute volume loading in cirrhosis (23). This failure of RSNA to normally diminish during acute volume loading contributes to the attenuated natriuresis as the natriuretic response is substantially improved by prior renal denervation (4). In contrast to normal rats wherein this acute volume-loading protocol decreases RSNA by 40-50% (4, 7, 8), CBDL-vehicle rats exhibited no decrease in RSNA during acute volume loading, reflecting abnormal cardiac baroreflex regulation of RSNA. However, intracerebroventricular losartan, although not immediately affecting HR, MAP, or RSNA (i.e., C2 vs. C1), altered the MAP and RSNA response to acute volume loading. CBDL-losartan rats exhibited a sharp but transient decrease in RSNA, which was associated in time with a similar sharp but transient decrease in MAP, suggesting that the decrease in MAP was, in the absence of a change in HR, a response to a more widespread sympathetic withdrawal from systemic resistance vasculature. It is possible that the more gradually progressive and lesser decrease in MAP in CBDL-vehicle rats was also related to a degree of systemic sympathetic withdrawal that was not reflected in RSNA. Ordinarily, the extent of reduction in RSNA would be limited by the decrease in MAP which, through arterial baroreflex function, would tend to increase RSNA (and HR). However, this is the aspect of arterial baroreflex regulation of RSNA (and HR) that is defective in CBDL (23); during decreased arterial pressure, despite normal decreases in afferent aortic nerve activity, there is an attenuated increase in RSNA (and HR). HR was unchanged in both groups despite the decreases in MAP. The natriuretic responses to acute volume loading were similar between CBDL-vehicle and CBDL-losartan in all periods except those where there were significant differences between groups in both MAP and RSNA (E2, and to a lesser extent E1). It would be anticipated that a greater degree of inhibition of RSNA during acute volume loading, as occurred transiently in the CBDL-losartan group, would be associated with an enhanced natriuretic response. However, the fact that the natriuretic response was less in the CBDL-losartan group is likely due to the overriding influence of the concurrent 20 mmHg decrease in MAP serving as a potent antinatriuretic stimulus. This need not involve a reduction in glomerular filtration rate and/or filtered sodium load as the pressure natriuresis mechanism can produce substantial changes in UNaV in the absence of such alterations.
Cardiac baroreflex regulation of RSNA is abnormal in CBDL, with the defect being located at the level of the peripheral cardiac baroreceptor, while central processing of afferent vagal nerve activity input is normal (23). The threshold for increases in cardiac filling pressure (left ventricular end-diastolic pressure) to increase afferent vagal nerve activity is increased and the gain (the increase in afferent vagal nerve activity/increase in cardiac filling pressure) is decreased. Thus, for a given increase in cardiac filling pressure, the afferent vagal nerve activity input to the CNS is decreased. Similar to the situation in congestive heart failure (10), this peripheral cardiac baroreceptor defect could be related to alterations in the mechanical properties of the cardiac chamber wall or their coupling to the nerve terminal or to the nerve terminal itself (13, 30). Increased ANG II levels are thought to contribute to structural cardiac remodeling (2). The cardiac structural remodeling may include alterations in distensibility and wall stress with desensitization of the cardiac baroreceptor. AT1-receptor antagonist treatment, like angiotensin-converting enzyme inhibitor therapy, is capable of favorably affecting the cardiac structural remodeling in congestive heart failure (2), which may lead to improvement in cardiac baroreceptor sensitivity. The current study, using acute intracerebroventricular losartan administration that would be unlikely to affect cardiac structural remodeling, was designed to assess the role of CNS sites in the defective arterial and cardiac baroreflex regulation of RSNA in CBDL. This similar strategy was effective in improving defective cardiac baroreflex regulation of RSNA in nephrotic syndrome which was associated with improved ability to excrete an acute sodium load (24). However, it is to be noted that the defect in cardiac baroreflex regulation of RSNA in nephrotic syndrome is located in the CNS with normal function of the peripheral cardiac baroreceptor (14, 18). The dose of intracerebroventricular losartan (10 nM), had it entirely leaked into the peripheral circulation and undergone its obligatory conversion to the active metabolite EXP3174, would have yielded a free plasma concentration of EXP3174 of 0.47 nmol/l, which is approximately 50% of the IC50 for antagonizing the ANG II pressor response in the rat (17, 28). Acute intracerebroventricular administration of losartan did not affect MAP in these studies. Thus it is unlikely that intracerebroventricular losartan leaked into the periphery in sufficient quantities to exert any significant effect on peripheral cardiac baroreceptor sensitivity in the CBDL rats.
In summary, intracerebroventricular losartan administration did not affect the basal level of RSNA in CBDL rats. Intracerebroventricular losartan produced a significant but transient facilitation of the renal sympathoinhibitory response to acute volume loading in CBDL rats. This did not result in an improved natriuretic response to the acute volume loading, likely due to the strong antinatriuretic influence of the concomitant marked decrease in MAP (renal perfusion pressure) mediated by widespread sympathetic withdrawal from the systemic vasculature.
Perspectives
Overall circulatory homeostasis and its sympathetic regulation are strongly dependent on the renin-angiotensin system in cirrhosis. Favorable effects on renal excretory function from antagonizing action of ANG II on reflex regulation of RSNA may be largely offset by adverse systemic hemodynamic responses, e.g., hypotension. These can occur because of interference with direct or indirect actions of ANG II (via reflex sympathetic regulatory mechanisms) on the systemic resistance vasculature. Such considerations underscore the well-known adverse renal effects of overly vigorous angiotensin-converting enzyme inhibitor therapy in cirrhotic patients. An attractive therapeutic concept is that of a kidney-specific prodrug whose action (e.g., antagonism of AT1 or ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by the National Institutes of Health Grants DK-15843, DK-52617, and HL-55006, and by the Department of Veterans Affairs.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. F. DiBona, Dept. of Internal Medicine, Univ. of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242 (E-mail: gerald-dibona{at}uiowa.edu).
Received 3 February 1999; accepted in final form 22 April 1999.
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