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(Hypertension. 1995;25:878-882.)
© 1995 American Heart Association, Inc.

Articles

Renal Afferent Denervation Prevents Hypertension in Rats With Chronic Renal Failure

Vito M. Campese; Ella Kogosov

From the Division of Nephrology, Department of Medicine, University of Southern California, Los Angeles.

Correspondence to Vito M. Campese, MD, Division of Nephrology, LAC/USC Medical Center, 2025 Zonal Ave, Los Angeles, CA 90033.

	Abstract

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Abstract Increased activity of the sympathetic nervous system has been described in chronic renal failure, but its role in the genesis and maintenance of hypertension associated with this condition has not been established. The kidney has an intense network of chemoreceptors and baroreceptors that send impulses to the brain. To what extent activation of these receptors by the scarred kidney or the uremic milieu may contribute to this model of hypertension is unknown. In the present study, we evaluated the effect of bilateral dorsal rhizotomy on the development of hypertension and neuroadrenergic activity in the anterior, lateral, and posterior hypothalamic nuclei, in the locus ceruleus, and in the nucleus tractus solitarius of Sprague-Dawley rats that underwent 5/6 nephrectomy or were sham operated. Neuroadrenergic activity was determined by calculating norepinephrine turnover rate after inhibition of norepinephrine synthesis with -methyl-DL-p-tyrosine methyl ester hydrochloride. The endogenous norepinephrine concentration was significantly greater in the posterior and lateral hypothalamic nuclei and the locus ceruleus, but not in the nucleus tractus solitarius, and the anterior hypothalamic nuclei of uremic rats compared with control rats. In rats with chronic renal failure and sham rhizotomy, the turnover rate of norepinephrine in the posterior (15.3±1.61 nmol · g^-1 · h^-1) and lateral hypothalamic nuclei (11.7±2.12 nmol · g^-1 · h^-1) and in the locus ceruleus (26.6±2.42 nmol · g^-1 · h^-1) was significantly faster (P<.01) than in rats with renal failure and dorsal rhizotomy (4.1±0.51, 4.7±0.77, and 5.1±1.13 nmol · g^-1 · h^-1, respectively) or control animals with or without rhizotomy. The turnover rate of norepinephrine in the anterior hypothalamic nuclei and the nucleus tractus solitarius was not different among the three groups of rats. These studies demonstrated that in rats with chronic renal failure, bilateral dorsal rhizotomy in the dorsolateral aspect of the vertebral bodies (T10 to L2) prevents in large part the development of hypertension and the increase in norepinephrine turnover rate in the posterior and lateral hypothalamic nuclei and the locus ceruleus. The data provide evidence that renal afferent impulses from the kidneys of rats with chronic renal failure may activate areas of the brain involved in the neuroadrenergic regulation of blood pressure. This mechanism may contribute to the genesis of hypertension in uremic rats.

Key Words: afferent pathways • hypertension, renal • kidney failure • denervation

	Introduction

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A large body of evidence indicates the presence of functional abnormalities of the sympathetic nervous system in uremic animals and humans.^{1 2} To what extent these abnormalities contribute to the genesis and maintenance of hypertension associated with chronic renal failure has not been established.

In patients with chronic renal failure, blood levels of norepinephrine (NE), an indirect marker of sympathetic nervous system activity, are usually increased.^{3 4 5 6 7} A direct and significant correlation between plasma concentrations of catecholamines and levels of blood pressure has been described by some researchers³ but not by others.^{1 4} Converse et al⁸ observed a greater rate of sympathetic nerve discharge in peroneal postganglionic sympathetic fibers of patients on chronic hemodialysis compared with that in control subjects. In patients with bilateral nephrectomy, the rate of sympathetic discharge was lower than in patients with their native kidneys, and this increased rate was accompanied by lower mean arterial pressure and regional vascular resistance.

Studies in rats with experimentally induced chronic renal failure have provided conflicting results. On one hand, the content of NE has been shown to be reduced in the entire brain, in brain synaptosomes isolated from the cerebral cortex, and in peripheral tissues of uremic rats.^{9 10 11} On the other hand, we observed an increase in the turnover of NE in the posterior hypothalamic nuclei and locus ceruleus (two regions involved in the neurogenic control of blood pressure) of rats that had undergone 5/6 nephrectomy. Microinjection of 6-hydroxydopamine in the posterior hypothalamic nuclei normalized blood pressure in these rats,¹² supporting the notion that increased activity of the sympathetic nervous system plays a role in the pathogenesis of hypertension in uremic rats.

The kidney is a sensory organ richly innervated with baroreceptors, chemoreceptors, and afferent nerves.^{13 14 15} Calaresu and Ciriello^{16 17} have demonstrated that renal afferent nerves project directly to a number of areas in the central nervous system, including the lateral tegmental fields, the paramedial reticular nucleus, the dorsal vagal complex of the medulla, the lateral hypothalamic area, and the paraventricular nuclei, and indirectly to the anterior and posterior hypothalamus, contributing to arterial pressure regulation. Stimulation of renal afferent nerves (caused by metabolites, such as adenosine, that are formed during ischemia, by uremic toxins, such as urea, or by electrical impulses) evokes reflex increases in sympathetic nerve activity and blood pressure.^{18 19 20} Renal afferent nerves appear to play an important role in the genesis of hypertension in the one-kidney, one clip and two-kidney, one clip Goldblatt models of hypertension in rats,²¹ but not in the deoxycorticosterone acetate–salt hypertension model, the one-kidney, one-wrap Grollman hypertension model, or in the spontaneously hypertensive rat.^{22 23 24 25}

The role of afferent signals from the kidney to the central nervous system in the pathogenesis of hypertension in rats with chronic renal failure has not been explored. In these studies we evaluated the effect of bilateral dorsal rhizotomy in the dorsolateral aspect of the vertebral bodies (from T10 to L2) on the development of hypertension and NE turnover in the hypothalamus (anterior, lateral, and posterior nuclei), locus ceruleus, and nucleus tractus solitarius in rats that had undergone 5/6 nephrectomy.

	Methods

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Male Sprague-Dawley rats weighing 200 to 300 g were fed normal rat chow (ICN Nutritional Biochemical) throughout the study. Four groups of rats were used for these studies. After anesthesia with sodium pentobarbital (50 mg/kg IP), the first group of rats underwent 2/3 nephrectomy of the right kidney; 1 week later they underwent total nephrectomy of the left kidney. At the time of the left nephrectomy, dorsal rhizotomy was performed. A dorsal incision was made and the thoracic and lumbar vertebral column exposed by gentle pulling of the musculature away from the vertebrae. An opening was made in the dorsolateral aspect of the vertebral bodies (T10 to L2) with a fine bone drill. The dura was opened, and the dorsal roots were visualized, pulled with a hook, and broken. A second group underwent 5/6 nephrectomy and sham dorsal rhizotomy. A third group underwent sham nephrectomy and sham rhizotomy. A fourth group of rats underwent sham nephrectomy and rhizotomy and was used as control. We elected to perform rhizotomy at the T10 to L2 levels because the greatest concentration of afferent fibers from the kidney to the brain stem occurs at these levels.²⁶ Blood pressure was measured weekly by the tail-cuff method, using an electrosphygmomanometer and physiograph recorder (MK-III, Narco Bio-Systems). Blood was drawn from the tails of the animals before and 1, 3, and 6 weeks after the 5/6 nephrectomy for measurement by autoanalyzer of serum creatinine.

Norepinephrine Turnover Rate
Four weeks after the total nephrectomy and rhizotomy or sham operation, NE turnover rate was calculated by assay of the endogenous NE concentration at time 0 and at 3 and 6 hours after the intraperitoneal injection of 80 mg/kg of -methyl-DL-p-tyrosine methyl ester (DL-2 methyl-3-[4-hydroxyphenyl]-alanine methyl ester) hydrochloride (Sigma Chemical Co) diluted in saline.^{27 28} The endogenous tissue levels of NE decline at a rate proportional to the initial NE concentrations.²⁹ Rats were killed by decapitation, and the brains were removed immediately, frozen under powdered dry ice, and stored at -70°C for no longer than 2 to 3 weeks. The brains were then placed on chucks and cut into consecutive 300-µm sections in a -10°C cryostat. In a 4°C cold room, micropunches 0.5 mm in diameter were obtained bilaterally from the anterior, lateral, and posterior hypothalamic nuclei, starting from 7.6 mm interaural, and from the locus ceruleus. Micropunches of the nucleus tractus solitarius were also obtained, starting from 2.8 mm interaural.^{30 31} Samples were sonicated in 0.03N perchloric acid and centrifuged, and the supernatant was assayed for catecholamines by the radioenzymatic method of Peuler and Johnson.³² This assay is based on the use of the enzyme catechol-O-methyltransferase, which transfers a radioactive methyl group from S-[methyl-³H]adenosyl-L-methionine to an endogenous catecholamine to form a radioactive O-methyl catecholamine derivative. The sensitivity of this method for NE is 1 to 2 pg.

The turnover rate of NE was calculated according to the method of Brodie et al.¹⁵ The log of NE was plotted versus time, and the least-squares straight line provided the fractional turnover rate k. The NE turnover (pg · mg^-1 · h^-1) was calculated as the product of k times the endogenous concentration of NE. The half-life was calculated from the equation t_1/2=0.434÷slope. The 95% confidence intervals were determined for the turnover rates according to the method of Taubin et al.³³ A confidence interval of 1 standard error about the slope and endogenous concentration was established. The lower limit of the slope and the lower limits of the endogenous concentrations were multiplied to obtain the lower 95% confidence limits for the mean turnover rates. Similarly, 95% confidence limits were determined for the upper intervals. Each data point includes data from at least five rats.

The data were evaluated statistically by one-way ANOVA and the Scheffé's F test for comparisons among groups and by regression analysis with the computer programs STATVIEW and GRAPHICS 4.01. Values are given as mean±SEM.

	Results

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The data on body weight, blood pressure, and serum creatinine are summarized in Table 1. In rats with chronic renal failure (CRF) and sham rhizotomy, systolic blood pressure increased progressively with time after the nephrectomy (Fig 1). In CRF rats with bilateral rhizotomy, blood pressure increased only slightly 1 week after 5/6 nephrectomy, but thereafter remained unchanged. In CRF rats with sham rhizotomy, levels of creatinine were 31.8±5.3 µmol/L prior to nephrectomy, increased to 106±31 µmol/L after 1 week, and increased further to 141±27 µmol/L by 6 weeks after the 5/6 nephrectomy (Fig 1). In CRF rats with rhizotomy, serum creatinine increased from 35±8 to 91±17 µmol/L by 1 week after 5/6 nephrectomy and to 97±9 µmol/L by 6 weeks after 5/6 nephrectomy. After 6 weeks, serum creatinine in CRF rats with rhizotomy was significantly lower (P<.01) than in rats with CRF and sham rhizotomy. Blood pressure did not change with time in control rats or in control rats with sham rhizotomy.

View this table: [in this window] [in a new window]   Table 1. Blood Pressure, Body Weight, and Serum Creatinine

View larger version (22K): [in this window] [in a new window]   Figure 1. Line graph showing blood pressure in rats with 5/6 nephrectomy and sham rhizotomy (chronic renal failure, CRF), in CRF rats with dorsal rhizotomy (Rhiz) in the dorsolateral aspect of the vertebral bodies (T10 to L2), and in control rats with or without rhizotomy. *P<.01 compared with the other groups of rats; #P<.05 compared with control rats.

The endogenous concentration of NE in the posterior hypothalamic nuclei and locus ceruleus of CRF rats with sham rhizotomy was greater than in CRF rats with rhizotomy and in control animals with or without rhizotomy (Table 2). The baseline concentration of NE in the anterior and lateral hypothalamic nuclei of CRF rats with rhizotomy was lower (P<.05) than in CRF rats without rhizotomy or in control animals with or without rhizotomy. On the other hand, the baseline concentration of NE in the nucleus tractus solitarius was not different among the four groups of rats (Table 2). In CRF rats with sham rhizotomy, the turnover rate of NE in the posterior (15.3±1.6 nmol · g^-1 · h^-1) and lateral hypothalamic nuclei (11.7±2.1 nmol · g^-1 · h^-1) and in the locus ceruleus (26.6±2.4 nmol · g^-1 · h^-1) was significantly faster (P<.01) than in CRF rats with rhizotomy (4.1±0.5, 4.7±0.8, and 5.1±1.1 nmol · g^-1 · h^-1, respectively), control animals with rhizotomy (2.7±0.9, 3.8±1.9, and 3.3±1.1 nmol · g^-1 · h^-1, respectively), or control animals without rhizotomy (3.0±0.9, 5.0±1.0, and 3.7±1.2 nmol · g^-1 · h^-1, respectively) (Table 2 and Fig 2). The turnover rate of NE in the anterior hypothalamic nuclei and in the nucleus tractus solitarius was not different among the four groups of rats.

View this table: [in this window] [in a new window]   Table 2. Endogenous Norepinephrine Concentration and Turnover Rate

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graph showing norepinephrine turnover rate in the posterior (PH), anterior (AHA), and lateral (LH) hypothalamic nuclei and the locus ceruleus (LC) of control rats with or without rhizotomy (Rhiz); in rats with chronic renal failure and sham rhizotomy (CRF); and in rats with CRF and dorsal rhizotomy. *P<.01 compared with CRF rats with rhizotomy and with the two groups of control animals.

The turnover rate of NE in the locus ceruleus of rats with CRF and rhizotomy remained slightly higher than in control animals.

	Discussion

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This study has shown that bilateral dorsal rhizotomy prevents in large part the development of hypertension in rats with 5/6 nephrectomy. Moreover, bilateral dorsal rhizotomy normalized the alterations in NE turnover in the posterior and lateral hypothalamic nuclei and in the locus ceruleus of uremic rats. The finding that, in this model, hypertension is attenuated rather than abolished suggests that factors other than the renal nerves contribute to the development and maintenance of hypertension in these animals.

The pathogenesis of hypertension in chronic renal failure is probably multifactorial. For a long time, excessive renin secretion in relation to the state of sodium-volume balance has been recognized as the most important factor in the pathogenesis of this form of hypertension.^{34 35} Traditionally, the normalization of blood pressure that occurs after bilateral nephrectomy has been attributed to removal of the kidney, the major source of renin secretion.

Several lines of evidence support a role for increased activity of the sympathetic nervous system in the pathogenesis of hypertension associated with renal failure. Plasma norepinephrine levels are usually increased in uremic patients.^{2 3 4 5 6 7} Microelectrode recordings of postganglionic sympathetic action potentials in peroneal nerves have shown a greater rate of sympathetic nerve discharge in hemodialysis patients than in control subjects.⁶

The turnover rate of NE was significantly increased in the posterior hypothalamic nuclei and in the locus ceruleus of rats with 5/6 nephrectomy, and chemical destruction of the posterior hypothalamic nuclei by microinjection of a neurotoxin, 6-hydroxydopamine, reduced blood pressure in these animals.¹²

The mechanisms responsible for the activation of these nuclei in the central nervous system have not been elucidated. In this study, we tested the possibility that this activation may be the result of impulses generating from the affected kidney that are transmitted to the central nervous system.

The kidney is a sensory organ richly innervated with sensory and afferent nerves. There are two main functional types of renal sensory receptors and afferent nerves: renal baroreceptors, which increase their firing in response to changes in renal perfusion and intrarenal pressure, and renal chemoreceptors that are stimulated by ischemic metabolites or uremic toxins.^{13 14 15} The activation of these chemosensitive receptors may establish connections through renal afferent pathways with integrative nuclei of the sympathetic nervous system in the central nervous system.^{16 17 18 19 36} Stimulation of renal afferent nerves by ischemic metabolites, such as adenosine, or by uremic toxins, such as urea, evokes reflex increases in sympathetic nerve activity and blood pressure.^{18 19 20} Chronic stimulation of renal afferent nerves may lead to sympathetic overactivity and hypertension. The role of afferent inputs from the kidneys to the brain in the pathogenesis of some forms of experimental hypertension has been recognized for some time.²¹ Renal afferent nerves appear to be important in the maintenance of hypertension in one-kidney, one clip and two-kidney, one clip Goldblatt hypertensive rats,^{37 38} but not in the one-kidney, one-wrap Grollman hypertensive rats³⁹ or in spontaneously hypertensive rats.³⁷

Our data suggest that afferent signals arising from the kidneys may cause a reflex increase in sympathetic outflow from areas of the brain normally involved in the neurogenic control of blood pressure,^{40 41 42 43 44 45} ultimately resulting in hypertension. Converse et al⁸ have shown that in uremic patients on chronic dialysis, the decrease in arterial pressure after bilateral nephrectomy was associated with lower sympathetic nerve firing and regional vascular resistance. These findings also support the notion that increased afferent signals from the kidneys may cause reflex increases in efferent sympathetic nervous system activity and blood pressure.

In conclusion, our studies provide evidence that afferent signals from the scarred kidneys of rats with 5/6 nephrectomy may activate noradrenergic neurons in the posterior and lateral hypothalamic nuclei and in the locus ceruleus, and that this mechanism may be responsible, at least in part, for the rise in blood pressure in rats with chronic renal insufficiency. These conclusions are in keeping with the notion that in patients with chronic renal failure, the normalization of blood pressure that follows bilateral nephrectomy may be caused at least partly by elimination of afferent impulses from the scarred kidneys to the central nervous system.

	Acknowledgments

 
This study was supported by National Institutes of Health grants 1-RO1-HL-47881 and RO1-HL-35629 and by an extramural grant from Baxter Healthcare Corp.

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