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(Hypertension. 1998;32:649-653.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Rapid Communication: Salt-Sensitive Hypertension Induced by Sensory Denervation

Introduction of a New Model

Donna H. Wang; Jianping Li; ; Jingxin Qiu

From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.

Correspondence to Donna H. Wang, MD, Department of Internal Medicine, 8.104 Medical Research Bldg, University of Texas Medical Branch, Galveston, TX 77555-1065. E-mail dwang{at}utmb.edu

	Abstract

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Abstract—To test the novel hypothesis that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure, newborn Wistar rats were given 50 mg/kg capsaicin subcutaneously on the 1st and 2nd day of life. Control rats were treated with vehicle. Immediately after the weanling period, male rats were divided into 4 groups and fed different sodium diets for 2 weeks: capsaicin pretreatment plus high sodium diet (4%, CAP-HS), capsaicin plus normal sodium diet (0.5%, CAP-NS), control plus high sodium diet (CON-HS), and control plus normal sodium diet (CON-NS). Both tail-cuff systolic blood pressure and mean arterial pressure with anesthesia were significantly higher in CAP-HS than in CAP-NS, CON-HS, and CON-NS (P<0.05), but they were not different among the latter 3 groups. Radioimmunoassay revealed that levels of calcitonin gene–related peptide in dorsal root ganglia were markedly decreased by capsaicin treatment (P<0.05). Twenty-four-hour urine volume and urine sodium excretion were significantly lower in CAP-HS than in CON-HS but were higher in CAP-HS and CON-HS compared with CAP-NS and CON-NS (P<0.05). Urine potassium excretion was not different among the 4 groups. Thus, this study provides the first evidence that neonatal degeneration of capsaicin-sensitive sensory nerves renders the rat salt-sensitive in terms of blood pressure regulation. Furthermore, our data suggest that neonatal capsaicin treatment may impair renal sodium and water excretion responses to high sodium intake. This model will provide a novel experimental paradigm for exploring underlying molecular mechanisms linked with salt-sensitive hypertension and sensory nerve function.

Key Words: capsaicin • sodium, dietary • nervous system • hypertension • renal circulation

	Introduction

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In addition to well-known sympathetic and parasympathetic innervation of the autonomic nervous system, the cardiovascular system receives dense innervation from the sensory nervous system.¹ Sensory afferent nerves have cell bodies located in the dorsal root ganglia and send efferent processes to a variety of cardiovascular tissues.^{2 3 4} It has been established that sensory afferent fibers release a variety of vasodilator neuropeptides, eg, calcitonin gene–related peptide (CGRP) and substance P, in response to local stimuli.⁵ These vasodilator neuropeptides chronically released from sensory nerves may play a role in blood pressure regulation because it has been demonstrated that altered synthesis or release of these vasodilator neuropeptides occurs in genetic and experimental hypertensive animal models.^{6 7 8 9 10 11}

Capsaicin is widely used as a toxin for sensory neurons, and the loss of CGRP and substance P after capsaicin treatment has been used to map the distribution of peripheral sensory nerve fibers.¹² Treatment of newborn rats with an appropriate dose of capsaicin results in a selective and permanent destruction of up to 90% of peripheral unmyelinated afferent fibers¹³ and leads to enhanced development of deoxycorticosterone-induced hypertension.¹⁴ Moreover, intrathecal administration of capsaicin in adult rats also selectively depletes spinal substance P and CGRP within small primary afferent nerve fibers^{15 16 17 18} and leads to enhanced development of 1-kidney renal wrap hypertension in the rat.¹⁸ Despite the fact that the sensory nervous system has been implicated in blood pressure regulation, it is unknown whether impairment of the sensory nervous system is sufficient to induce hypertension. The present study was therefore designed to test the novel hypothesis that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure.

	Methods

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Animals
Pregnant Wistar female rats (Charles River Laboratories Inc, Wilmington, Mass) were housed in the animal care unit for at least 1 week before parturition. On the 1st and 2nd day of life, neonatal rats received 50 mg/kg capsaicin SC as described.^{19 20} Control rats were treated with equal volumes of vehicle solution (5% ethanol, 5% Tween 80 in saline). All treatments were performed with rats under ether anesthesia. After 3 weeks, male and female rats were divided, and only male rats were used in the present study. Male rats were divided into 4 groups and pair-fed different sodium diets for 2 weeks: capsaicin pretreatment plus high sodium diet (4%, CAP-HS, n=13), capsaicin plus normal sodium diet (0.5%, CAP-NS, n=14), control plus high sodium diet (CON-HS, n=15), and control plus normal sodium diet (CON-NS, n=15). The rat food was purchased from Harlan Teklad Diets. At the end of the 2-week treatment period, half of the rats in each group were anesthetized with a single intraperitoneal injection of 80 mg/kg ketamine and 1 mg/kg xylazine, and the carotid artery was catheterized for the measurement of mean arterial pressure (MAP) with a Statham 231D pressure transducer (Gould) coupled to a Gould 2400s recorder. After 20 minutes of stabilization, MAP was recorded for 20 minutes, and the MAP value for each rat was calculated as the average of measurements during this period. The other half of the rats in each group were decapitated for the collection of the dorsal root ganglia for CGRP measurement.

Systolic Blood Pressure
Indirect tail-cuff systolic blood pressures were routinely obtained in all rats by use of a Narco Bio-Systems Electro-Sphygmomanometer. The pressures were measured in conscious rats every 4 days for 12 days, beginning 1 day before dietary treatment. The blood pressure value for each rat was calculated as the average of 3 separate measurements at each session.

Water Intake, Urine Volume, and Urinary Na⁺ and K⁺ Concentrations
Water intake and urine excretion were routinely determined in each of the 4 groups by use of metabolic cages. These parameters were measured in rats every 4 to 6 days for 13 days, beginning 1 day before dietary treatment. Urinary Na⁺ and K⁺ concentrations were determined using a flame atomic absorption spectrophotometer (Perkin-Elmer).

Radioimmunoassay
At the end of the experiment, the rats were killed by decapitation, and the cervical, thoracic, and lumbar dorsal root ganglia from each animal were immediately dissected and frozen in liquid nitrogen. To determine immunoactive CGRP content in the dorsal root ganglia from each of the 4 experimental groups, a commercially available rabbit–anti-rat CGRP radioimmunoassay kit (Phoenix Pharmaceuticals) was used. This antibody has 100% cross-reactivity with rat -CGRP and 79% with rat ß-CGRP. There is no cross-reactivity with rat amylin, calcitonin, somatostatin, or substance P. The assay was performed as recommended by the supplier, and the total protein content in each sample was determined by the Bradford method (Bio-Rad).

Statistical Analysis
Values are mean±SE. Differences between groups were determined by ANOVA followed by the Tukey-Kramer multiple comparison test. Differences were considered statistically significant at P<0.05.

	Results

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Body weight was not significantly different among the 4 groups before the dietary treatment (Table). Body weight increased significantly over the experimental period and was not significantly different among the 4 groups at the end of the experiment (Table). Thus, neonatal treatment with capsaicin does not alter somatic development of rats fed either a normal or a high sodium diet.

View this table: [in this window] [in a new window]   Table 1. Body Weight (g) of Rats Before and After Dietary Treatment

Beginning at the 5th day after dietary treatment and for the rest of the study period, tail-cuff systolic blood pressure was significantly higher in the CAP-HS rats than in CAP-NS and CON-NS rats (Figure 1). Over the same period except for the 9th day after treatment, systolic blood pressure was also significantly higher in the CAP-HS than in CON-HS rats (Figure 1). Direct measurement of MAP at the end of the experiment confirmed the results obtained from tail-cuff measurement, ie, MAP (mm Hg) was significantly higher in CAP-HS (133±9, n=8) than in CON-NS (105±3, n=11), CON-HS (106±6, n=8), and CAP-NS (106±5, n=9) rats. Thus, neonatal treatment with capsaicin does not increase blood pressure in rats fed a normal sodium diet but leads to the elevation of blood pressure in rats fed a high sodium diet.

View larger version (20K): [in this window] [in a new window]   Figure 1. Systolic blood pressure in rats fed a normal sodium diet and subjected to vehicle (CON-NS, n=15) or capsaicin (CAP-NS, n=14) pretreatment or fed a high sodium diet and subjected to vehicle (CON-HS, n=15) or capsaicin (CAP-HS, n=13) pretreatment. Values are mean±SE; *P<0.05 vs CON-NS and CAP-NS, +P<0.05 vs CON-HS.

The ratio of 24-hour urine volume to water intake is shown in Figure 2. On the 6th day after dietary treatment and for the rest of the study period, this ratio was significantly higher in CON-HS and CAP-HS than in CON-NS and CAP-NS rats. Furthermore, this ratio was not different between CON-NS and CAP-NS but was significantly lower in CAP-HS than in CON-HS rats. These results indicate that neonatal treatment with capsaicin does not alter proportional urine excretion in rats fed a normal sodium diet but may impair proportional urine excretion when rats are loaded with salt.

View larger version (18K): [in this window] [in a new window]   Figure 2. Ratio of 24-hour urine volume to water intake in rats fed a normal sodium diet and subjected to vehicle (CON-NS, n=6) or capsaicin (CAP-NS, n=6) pretreatment or fed a high sodium diet and subjected to vehicle (CON-HS, n=6) or capsaicin (CAP-HS, n=6) pretreatment. Values are mean±SE; *P<0.05 vs CON-NS and CAP-NS, +P<0.05 vs CAP-HS.

At the end of the experiment, urine sodium excretion was significantly higher in CON-HS and CAP-HS than in CON-NS and CAP-NS rats (Figure 3). Moreover, urine sodium excretion was not different between CON-NS and CAP-NS but was significantly lower in CAP-HS than in CON-HS, indicating that neonatal treatment with capsaicin does not influence urine sodium excretion in rats fed a normal sodium diet but may impair urine sodium excretion when rats are loaded with salt. In contrast, urine potassium excretion was not significantly different among the 4 groups, indicating that capsaicin pretreatment does not alter urine potassium excretion in rats fed either a normal or a high sodium diet.

View larger version (12K): [in this window] [in a new window]   Figure 3. Twenty-four-hour urine volume and urinary sodium and potassium excretion in rats fed a normal sodium diet and subjected to vehicle (CON-NS, n=5) or capsaicin (CAP-NS, n=5) pretreatment or fed a high sodium diet and subjected to vehicle (CON-HS, n=5) or capsaicin (CAP-HS, n=5) pretreatment. Values are mean±SE; +P<0.05 vs CON-NS, *P<0.05 vs CON-HS, #P<0.05 vs CAP-NS.

To confirm the effectiveness of neonatal capsaicin treatment, immunoactive CGRP content in the dorsal root ganglia from each of the 4 experimental groups was determined with the use of radioimmunoassay (Figure 4). The results showed that CGRP content in the dorsal root ganglia was decreased (P<0.05) about 6- to 7-fold in CAP-NS and CAP-HS rats when compared with CON-NS. Moreover, CGRP content in the dorsal root ganglia was significantly lower in CON-HS than in CON-NS rats. Thus, neonatal treatment with capsaicin results in depletion of CGRP in the dorsal root ganglia of rats fed either a normal or a high sodium diet.

View larger version (29K): [in this window] [in a new window]   Figure 4. Immunoactive CGRP content in the dorsal root ganglia of rats fed a normal sodium diet and subjected to vehicle (CON-NS, n=8) or capsaicin (CAP-NS, n=8) pretreatment or fed a high sodium diet and subjected to vehicle (CON-HS, n=7) or capsaicin (CAP-HS, n=7) pretreatment. Values are mean±SE; +P<0.05 vs CON-NS, *P<0.05 vs CON-HS.

	Discussion

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The present study demonstrated for the first time that neonatal degeneration of capsaicin-sensitive sensory nerves in rats leads to a significant increase in blood pressure when a high sodium diet is given. This observation is important because it has been shown that (1) substantial decreases in CGRP-containing sensory nerves in the mesenteric arterial bed occur in spontaneously hypertensive rats (SHR),^{6 7} indicating that there are inherited abnormalities in either generation or maintenance of sensory nerves in SHR; (2) the plasma CGRP concentration is lower in adult SHR than in age-matched normotensive control rats, indicating that release of CGRP from sensory nerves is decreased in SHR²¹ ; and (3) vasodilator responses to exogenous CGRP increase with age in SHR, suggesting that sensitivity of receptors to CGRP is increased due to the decreased release of CGRP from sensory nerves.^{6 7} The defect in sensory vasodilator function may produce an imbalance that could contribute to the development and maintenance of hypertension in SHR.

In contrast to the genetic hypertensive model, both CGRP mRNA and protein content in the dorsal root ganglia are increased in deoxycorticosterone-salt hypertension.¹⁰ Moreover, bolus injection of CGRP_8–37, a specific CGRP receptor antagonist, dose-dependently increases MAP in deoxycorticosterone-salt hypertensive rats.⁹ These results suggest that increased neuronal synthesis and available stores of CGRP play a compensatory role to attenuate the elevated blood pressure in this experimental model of hypertension. In support of this notion, it has been shown that treatment of newborn rats with capsaicin results in a selective and permanent destruction of up to 90% of primary afferent fibers¹³ and leads to enhanced development of deoxycorticosterone-induced hypertension.¹⁴ In contrast to these studies that use either genetic or experimental hypertensive rats, ours was the first to study the response of blood pressure in normal rats pretreated with capsaicin and given a high sodium diet. The distinct observation from the present study shows that neonatal treatment with capsaicin results in a marked decrease (6- to 7-fold) in CGRP levels in the dorsal root ganglia and causes a normal rat to respond to a salt load with a significant and sustained rise in blood pressure. Considering the fact that capsaicin was injected subcutaneously, it is possible that capsaicin depleted the CGRP content similarly for each of the different dorsal root ganglia. Although we have not examined this possibility, our demonstration of decreased CGRP content in the dorsal root ganglia in capsaicin-treated rats provides unambiguous evidence for sensory denervation. These data provide the first evidence that neonatal degeneration of capsaicin-sensitive sensory nerves renders the rat salt-sensitive in terms of blood pressure regulation.

Increased salt intake results in increased renal salt and water excretion in a normal rat. This efficient adaptive process prevents progressive salt retention, volume expansion, and, one of its detrimental sequelae, hypertension. Our data show that the prohypertensive effects of capsaicin in rats given excess dietary sodium are accompanied by impaired increase in urine volume excretion and urinary sodium excretion. However, urinary potassium excretion is not modified by capsaicin treatment. It is known that capsaicin treatment alters the sensory and motor control of the bladder function,^{20 22} so that urine excretion occurs in frequent episodes and also with drippings. These conditions make precise measurement of urine parameters difficult because increased adherence of urine to the animal fur may occur. However, these artifacts are not assumed in the present experiments because urinary potassium excretion was not affected whereas urinary sodium excretion and urine volume were. Thus, our results suggest that capsaicin may selectively impair natriuretic response to a high salt intake and therefore blood pressure regulation, indicating that capsaicin-sensitive sensory nerves play a role in renal sodium and water handling and protect the rats against salt-induced hypertension.

The indication that capsaicin impairs the renal antihypertensive function mediated by sensory nerves is supported by the fact that (1) a dense network of capsaicin-sensitive CGRP-containing nerves is found in the kidney²³ (the innervation is greater in the medulla than in the cortex, and nerve fibers are detected also in renal tubules²³ ); (2) capsaicin-sensitive afferents of the kidney are activated by changes in interstitium ion concentration and by alterations in the excretory function of the kidney and renal blood flow^{24 25} ; (3) sensory neurotransmitters, such as CGRP and substance P, have direct and indirect effects on tubular ion transport and are very potent natriuretic and diuretic agents^{26 27 28 29} ; and (4) neonatal capsaicin treatment impairs natriuretic response to furosemide and diuretic response to an intragastric water load.^{20 30} Taken together, our results in conjunction with the data obtained from these previous studies suggest that the salt activation of the sensory nervous system may be one of the functionally significant components of the adaptive response of the kidney to an increased salt intake. We would like to add a cautionary note: because capsaicin impairs the micturition reflex, and bladders of capsaicin-treated rats can hold a volume of more than 5 cc without contracting while bladders of vehicle-treated rats have a capacity of about 1 cc,²⁰ increased retention of urine in the bladder may also contribute to decreased excretion of sodium and water in capsaicin-treated rats.

In conclusion, we have shown that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure. Our data also suggest that neonatal capsaicin treatment may impair natriuretic response to a high sodium intake. These results, combined with previous studies from other laboratories, provide decisive evidence that sensory nerves play significant functional roles in controlling tissue and body homeostasis and in impeding the development of salt-induced hypertension. This model will provide a novel experimental paradigm for exploring underlying molecular mechanisms linked with salt-sensitive hypertension and sensory nerve function.

	Acknowledgments

 
This study was supported by National Institutes of Health grant HL-52279 (Dr Wang).

Received March 9, 1998; first decision April 6, 1998; accepted July 16, 1998.

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