Published online before print December 19, 2005, doi: 10.1161/01.HYP.0000197390.10412.c4
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(Hypertension. 2006;47:609.)
© 2006 American Heart Association, Inc.
Part 2 Original Articles |
A Novel Mechanism Contributing to Development of Dahl Salt–Sensitive Hypertension
Role of the Transient Receptor Potential Vanilloid Type 1
From the Department of Medicine, Michigan State University, East Lansing.
Correspondence to Donna H. Wang, Department of Medicine, B316 Clinical Center, Michigan State University, East Lansing, MI 48824. E-mail donna.wang{at}ht.msu.edu
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Abstract |
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To determine the role of the transient receptor potential vanilloid type 1 (TRPV1) channels in development of hypertension in Dahl salt–sensitive (DS) rats fed a high-salt diet (HS), male DS and Dahl salt–resistant (DR) rats were maintained on a low-salt diet (LS) or HS for 3 weeks. HS significantly increased systolic blood pressure in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Intravenous bolus injection of capsazepine (3 mg/kg), a selective TRPV1 antagonist, significantly increased mean arterial pressure in conscious DR+HS rats compared with DR+LS, DS±HS, and DS±LS rats. In contrast, capsaicin (10 or 30 µg/kg), a selective TRPV1 agonist, dose-dependently decreased mean arterial pressure in all of the groups with the most profound magnitude in DR+HS rats compared with the other 3 groups. TRPV1 expression in mesenteric resistance arteries and the renal cortex and medulla, calcitonin gene–related peptide levels in dorsal root ganglia, and calcitonin gene–related peptide–positive sensory nerve density in mesenteric resistance arteries were significantly decreased in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Taken together, our data indicate that the TRPV1 receptor is activated and its expression upregulated during HS intake in DR rats, which acts to prevent salt-induced increases in blood pressure. In contrast, TRPV1 expression and function are impaired in DS rats, which renders DS rats sensitive to salt load in terms of blood pressure regulation.
Key Words: peptides • rats, Dahl • hypertension, sodium-dependent • blood pressure
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Introduction |
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Both clinical and experimental studies have shown a correlation of dietary salt intake and the prevalence and progression of hypertension.1 Salt-sensitive hypertension is more prevalent in blacks and the elderly, who are accompanied by a decrease in sensory nerve function.2 Studies in animals provide compelling evidence showing that sensory nerves play a key role in preventing salt-induced elevation in blood pressure,3 suggesting that a defect in sensory nerve function may contribute to increased salt sensitivity in humans. Dahl salt–sensitive (DS) rats have been used as a model of human salt–sensitive hypertension given that salt load exaggerates the development of hypertension in this strain that is genetically predisposed to hypertension4,5 and that these rats exhibit elevated insulin resistance, which mimics the black hypertensive population.6 Thus, studies of DS rats may provide valuable clues to the pathogenesis of salt-sensitive hypertension and related traits in black patients.
The transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated nonselective ion channel expressed primarily in sensory nerves of unmyelinated C-fibers or thinly myelinated A
-fibers innervating cardiovascular tissues including the heart, kidney, and blood vessels.2,7,8 The TRPV1 functions as a molecular integrator of multiple chemical and physical stimuli including capsaicin, lipid metabolites, proton, and noxious heat.9–12 Activation of the TRPV1 expressed in sensory nerves causes release of a number of sensory neurotransmitters, commonly substance P and calcitonin gene–related peptide (CGRP), which are potent vasodilators in many vascular beds.2
Although our previous studies show that the TRPV1 plays a counterregulatory role in preventing salt-induced increases in blood pressure in a normal rat,13 it is unknown whether the TRPV1 and TRPV1-positive sensory nerves participate in blood pressure regulation in a salt-sensitive hypertensive model that is genetically predisposed. In other words, it is unknown whether there is impairment in the TRPV1 function in DS rats before and after high-salt (HS) intake and, if so, whether the impairment constitutes 
1 defects leading to increased salt sensitivity in this strain. This study was, therefore, designed to define the function and regulation of the TRPV1 in DS and resistant rats.
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Methods |
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Preparation of Animals and Samples
All of the experiments were approved by the Institutional Animals Care and Use Committee. Male Dahl salt–resistant (DR) and DS rats (4 to 5 weeks old, Charles River Laboratory, Wilmington, MA) were housed in a temperature-controlled room with a 12:12-hour light/dark cycle. DR and DS rats were selected randomly to receive either a low-sodium diet (LS; 0.3% NaCl) or a high-sodium diet (HS; 8% NaCl) for 3 weeks and were grouped as DR+LS, DR+HS, DS+LS, and DS+HS. Rats drank water ad libitum throughout the experiment.
Systolic blood pressure was measured 1 day before dietary treatment (day 0) and at the end of each week after dietary treatment with the use of a NarcoBio-Systems Electro-Sphygmomanometer. At the end of the third week, subgroups (n=4 to 7) from each of the 4 groups were euthanized by decapitation without subjecting to acute experiments. The cervical, thoracic, and lumbar dorsal root ganglia (DRG) were collected and stored at –80°C for CGRP assay. Mesenteric resistance arteries and the renal cortex and medulla were dissected and collected for Western blot analysis of the TRPV1 and for immunohistochemical staining of CGRP.
Blood Pressure Response to TRPV1 Receptor Antagonist
At the end of the experiment, subgroups from each of the 4 groups (n=6 to 7) were anesthetized with ketamine and xylazine (80 and 4 mg/kg IP, respectively), and the left carotid artery and jugular vein were cannulated for measurement of mean arterial pressure (MAP) and heart rate (HR) and for intravenous administration of capsazepine (CAPZ, a selective TRPV1 antagonist, 3 mg/kg), respectively. Three hours after surgery, baseline MAP and its response to CAPZ were obtained with the rats fully awake and unrestrained.14
Blood Pressure Response to TRPV1 Receptor Agonist
To determine function of the TRPV1 in DR and DS rats fed an LS or HS diet, capsaicin (a selective TRPV1 agonist, 10 or 30 µg/kg, bolus) or vehicle was intravenously injected into subgroups of each of the 4 groups (n=5 to 6) of rats anesthetized with urethane (1.5 g/kg IP) given that capsaicin is an irritant and causes severe pain in conscious rats. Catheters were implanted as described above. Each dose of injection was separated by a 30-minute interval. To determine the specificity of capsaicin, CAPZ (3 mg/kg) was injected 10 minutes before capsaicin administration in separate subgroups (n=5 to 6).
Radioimmunoassay
A rabbit anti-rat CGRP radioimmunoassay kit (Phoenix Pharmaceuticals) was used to determine CGRP contents in DRG as described previously.14 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 total protein content in DRG, determined by using a protein assay kit (Bio-Rad Laboratories), was used for normalization of CGRP contents in DRG samples.
Western Blot Analysis
Western blot analysis was performed as described previously,13 with the use of primary antibody targeted to TRPV1 (1:800, Santa Cruz Biotechnology) and secondary antibody conjugated with horseradish peroxidase. The membranes were developed using an ECL kit (Amersham Pharmacia Biotech) and exposed to film (Hyperfilm-ECL, Amersham Pharmacia Biotech). The films were scanned and analyzed with the use of the Image Quantity Program (Scion) to obtain integrated densitometric values. ß-Actin was used to normalize protein loading on membranes.
Immunohistochemistry
Immunofluorescence staining of CGRP (1:400, Sigma) in mesenteric resistance arteries was performed as described previously14 with the use of secondary antibody conjugated to Cy3 (1:500, Jackson ImmunoResearch). The slides were viewed under Zeiss Pascal confocal laser scanning microscope using a 543-nm laser. Negative control was performed by omission of primary antibodies, which showed no specific immunoreactivity.
Statistical Analysis
All of the values are expressed as mean±SE. A 2-way ANOVA followed by a Bonferroni test (Figures 1 and 2
), a 1-way ANOVA followed by a Bonferroni test (Figure 3), and an unpaired Student t test (Figures 4, 5, and 6) were used for comparisons between groups. Differences were considered statistically significant at P<0.05.
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P<0.05 compared with corresponding DR or DS rats treated with CAP at the dose of 10 µg/kg. #P<0.05 compared with corresponding DR or DS rats treated with CAP at the dose of 30 µg/kg.
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Results |
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Figure 1 shows systolic blood pressure in DR and DS rats fed an LS or HS diet. Systolic blood pressure levels were the same in 4 experimental groups at the beginning of the protocol (108±4 mm Hg in DR+LS; 104±5 mm Hg in DR+HS; 112±4 mm Hg in DS+LS; and 108±4 mm Hg in DS+HS). After 3 weeks of dietary treatment, systolic blood pressure was significantly elevated in DS+HS rats (181±8 mm Hg; P<0.05) compared with the DS+LS (123±5 mm Hg), DR+LS (120±6 mm Hg), and DR+HS (126±7 mm Hg) rats, confirming that DS rats are sensitive to HS intake in terms of blood pressure regulation.
To determine whether blockade of the TRPV1 affects blood pressure in DR and DS rats fed an HS diet, MAP and HR responses to bolus injection of CAPZ (3 mg/kg), a selective TRPV1 antagonist, were examined under the fully awake and unrestrained state of rats. Baseline MAP was significantly higher in DS+HS rats (166±8 mm Hg; P<0.05) compared with DS+LS (118±5 mm Hg), DR+LS (113±8 mm Hg), and DR+HS (116±6 mm Hg) rats. However, there were no significant differences in HR among DR+LS rats (391±10 bpm), DR+HS (387±7 bpm), DS+LS (383±9 bpm), and DS+HS (398±12 bpm) rats. As shown in Figure 2A, the MAP elevation began immediately after administration of CAPZ and reached the peak in 1 to 2 minutes after administration in DR rats fed an HS diet. The pressor action of CAPZ lasted for &6 to 7 minutes. The peak MAP responses to CAPZ infusion were significantly elevated in DR+HS rats (20±4 mm Hg; P<0.05) compared with the DR+LS (4±2 mm Hg), DS+LS (3±1 mm Hg), and DS+HS (7±2 mm Hg) rats. Therefore, blockade of the TRPV1 leads to an increase in blood pressure in DR rats fed an HS diet but not in DS rats fed an HS diet, indicating that TRPV1 activation plays a compensatory role in preventing salt-induced increases in blood pressure in DR rats and that the protective effect of the TRPV1 in DS rats may be impaired. As shown in Figure 2B, no significant change in HR was observed during this experimental period in any of the 4 groups. To rule out the possibility that different baseline blood pressure levels in these rats may affect the MAP responses to CAPZ, MAP responses to phenylephrine (PE) were examined in conscious DR or DS rats fed an LS or HS diet. PE (4 µg/kg, IV) increased MAP transiently and decreased HR in all 4 of the groups. In contrast to MAP responses to CAPZ, PE elevated MAP indistinguishably in 4 groups (27±4 mm Hg in DR+LS; 25±5 mm Hg in DR+HS; 28±4 mm Hg in DS+LS; and 26±3 mm Hg in DS+HS; P>0.05), indicating that the MAP response pattern induced by CAPZ is specific and that the inability of CAPZ in increasing MAP in DS+HS rats to the same extent as that in DR+HS rats is not because of a difference in baseline blood pressure.
To determine whether activation of the TRPV1 affects blood pressure in DR and DS rats fed an LS or HS diet, a selective TRPV1 agonist, capsaicin, was given to each of the 4 group rats. In a urethane-anesthetized state, baseline MAP was significantly higher in DS+HS rats (162±6 mm Hg; P<0.05) compared with DS+LS (112±4 mm Hg), DR+LS (109±5 mm Hg), and DR+HS (115±4 mm Hg) rats. As expected, capsaicin caused a triphasic MAP response and a decrease in HR in both DR and DS rats. The initial transient hypotension was followed by a brief pressor and a prolonged depressor phase. The prolonged depressor phase 3 reached the peak in 1 to 3 minutes after injection of capsaicin. Capsaicin produced a dose-dependent depressor phase in DR and DS rats fed an LS and HS diet. As shown in Figure 3, the magnitude of decreases induced by capsaicin (10 and 30 µg/kg) was significantly greater in DR+HS rats (14±3 and 27±5 mm Hg; P<0.05) compared with DR+LS rats (6±1 and 11±2 mm Hg), DS+LS rats (5±1 and 13±2 mm Hg), and DS+HS rats (8±1 and 16±3 mm Hg), indicating that TRPV1 function or expression is enhanced in DR rats fed an HS diet but not in DS rats fed an HS diet. Moreover, the decreases in MAP induced by capsaicin were blocked by CAPZ in all of the rats, indicating the specificity of capsaicin action.
To determine the CGRP contents in DRG in each of the 4 groups, radioimmunoassay was used to quantify the levels of CGRP (Figure 4). HS intake for 3 weeks significantly increased CGRP contents in DGR in DR rats (DR+HS, 20.7±1.9 versus DR+LS, 15.9±1.5 pg/µg protein; P< 0.05). In contrast, HS intake decreased CGRP levels in DGR in DS rats (DS+HS, 13.0±1.1 versus DS+LS, 16.9±1.3 pg/µg protein; P<0.05), providing evidence of distinct effects of salt on sensory nerve function as measured by CGRP production.
To determine TRPV1 protein expression levels in the mesenteric resistance artery and the kidney, Western blot analysis was performed, and the results are shown in Figure 5 and 6
. In DR rats, HS treatment for 3 weeks increased TRPV1 levels in mesenteric resistance arteries and the renal cortex and medulla (DR+HS, 0.073±0.014 versus DR+LS, 0.056± 0.013% of ß-actin arbitrary in mesenteric arteries; DR+HS, 0.109±0.022 versus DR+LS, 0.084±0.017% of ß-actin arbitrary in the renal cortex; and DR+HS, 0.160±0.034 versus DR+LS, 0.118±0.026% of ß-actin arbitrary in renal medulla; P<0.05). In contrast, in DS rats, HS intake inhibited TRPV1 expression in mesenteric resistance arteries and the renal cortex and medulla (DS+HS, 0.035±0.010 versus DS+LS, 0.061±0.010% of ß-actin arbitrary in mesenteric arteries; DS+HS, 0.061±0.015 versus DS+LS, 0.088± 0.013% of ß-actin arbitrary in the renal cortex; and DS+HS, 0.063±0.021 versus DS+LS, 0.121±0.024% of ß-actin arbitrary in the renal medulla; P<0.05), indicating that salt modulates TRPV1 expression distinctively in DR and DS rats.
Immunofluorescence staining of the marker of primary afferent fibers, CGRP, revealed that CGRP-positive sensory fibers in mesenteric resistance arteries were remarkably less in DS rats fed an HS diet for 3 weeks when compared with DS rats fed an LS diet or DR rats fed an HS diet (Figure 7), providing anatomic evidence for salt-induced impairment in sensory nerves. To rule out the possibility that the damage in sensory nerves was caused by elevation in blood pressure in DS rats fed an HS diet, CGRP staining in mesenteric resistance arteries of sham Sprague-Dawley rats and deoxycorticosterone acetate (DOCA)–salt-hypertensive rats was also examined. In contrast to the finding in DS rats, no noticeable reduction in CGRP-positive sensory nerve fibers was observed in DOCA–salt-hypertensive rats that had similarly high systolic blood pressure of 192±8 mm Hg compared with sham Sprague-Dawley rats at 125±9 mm Hg, indicating that elevated blood pressure per se may not be the cause for decreased sensory innervation observed in DS rats fed an HS diet.
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Discussion |
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This study was designed to determine whether the TRPV1 plays a role in blood pressure regulation in DS and DR rats fed an LS or HS diet. We found the following: (1) blockade of the TRPV1 causes a remarkably elevated blood pressure in DR rats fed an HS diet but not in DS rats fed an HS diet; (2) stimulation of the TRPV1 induces a dose-dependent decrease in blood pressure in both strains, and the decrease is significantly bigger in DR rats fed an HS diet compared with DS rats fed an HS diet; (3) CGRP levels in DGR and TRPV1 contents in mesenteric resistance arteries and the kidney are increased in response to HS intake in DR rats but decreased in response to HS intake in DS rats; and (4) CGRP-positive sensory innervation is remarkably reduced in DS rats fed an HS diet but not in DR rats fed an HS diet. Taken together, our data show for the first time that TRPV1 activation occurs during HS intake in DR rats to prevent salt-induced increases in blood pressure and that the TRPV1 protective effect is impaired in DS rats that renders DS rats sensitive to salt intake in terms of blood pressure.
The fact that blockade of the TRPV1 causes a significantly elevated blood pressure (20 mm Hg) in DR rats fed an HS diet indicates that the TRPV1 is activated during chronic HS intake, which serves to prevent salt-induced increases in blood pressure given that blood pressure in DR rats fed an HS diet is not elevated. These data suggest that HS intake or its associated neurohormonal or hemodynamic changes trigger(s) activation of the TRPV1 or TRPV1-induced events in DR rats that offset HS-induced harmful effects, including elevation in blood pressure.
Indeed, TRPV1 can be activated by a variety of physical and chemical stimuli, including capsaicin, lipid metabolites, decreased pH, and increased temperature leading to a release of sensory neuropeptides, such as CGRP and substance P.7,8 For example, several lines of evidence in vitro and in vivo have shown that the TRPV1 can be activated by an endocannabinoid compound, anandamide.10–12 Zygmunt et al10 show that in isolated rat hepatic, rat mesenteric, and guinea pig basilar arterial preparations, anandamide-induced relaxation is almost completely blocked either by the selective TRPV1 antagonist CAPZ, or by the selective CGRP receptor antagonist CGRP8–37. These results suggest that the TRPV1-mediated release of CGRP from sensory nerves is responsible for the anandamide-evoked vasorelaxation. We have shown recently that HS intake enhances anandamide-induced depressor effects12 and that anandamide contributes to the prevention of salt-induced increases in blood pressure via, at least in part, activating the TRPV1.12
In contrast to DR rats, CAPZ has no pressor effect in DS rats fed an HS diet. The lack of the pressor effect of CAPZ in DS rats fed an HS diet is unlikely because of the inability of additional increases beyond already high blood pressure given that PE causes a similar magnitude of increases in blood pressure in DR and DS rats fed an HS or LS diet. Rather, these results indicate that the TRPV1 has no protective effect in terms of counteracting salt-induced increases in blood pressure because of impaired function and regulation of this receptor in DS rats. This notion is supported by the fact that activation of the TRPV1 by its selective agonist capsaicin causes a dose-dependent decrease in blood pressure in DR rats fed an HS diet but not in DS rats fed an HS diet.
Direct examination of TRPV1 expression in the mesenteric resistance arteries, the renal cortex, and the renal medulla reveals that there are indeed distinctions between these 2 strains, that is, TRPV1 expression in these tissues is upregulated in response to HS intake in DR rats but downregulated by HS intake in DS rats. Given that TRPV1 contents in these tissues are not different in DR and DS rats fed an LS diet, these data indicate that DS rats may be predisposed to salt-induced impairment of the TRPV1. In addition to TRPV1 impairment, CGRP levels in DRG are similarly decreased, and CGRP-positive sensory nerves innervating mesenteric resistance arteries are remarkably reduced in DS rats fed an HS diet. This is in an agreement with a previous report from Katki et al,15 which indicates that CGRP expression is reduced in DRG in DS rats. Given that the same reduction in CGRP-positive sensory nerve fibers is not observed in deoxycorticosterone acetate–salt-hypertensive rats that have similarly high blood pressure, the finding suggests that elevation in blood pressure may not be the cause of sensory nerve impairment. Rather, these data indicate that salt-induced impairment in DS rats may not be limited to the TRPV1 but also sensory neurotransmitters or sensory nerve function/structure in general, leading to a lack of a powerful compensatory mechanism preventing salt-induced increases in blood pressure and rendering DS rats salt sensitive in terms of blood pressure regulation.
In addition to modulating vascular reactivity, sensory nerves and its neurotransmitters play a role in facilitating sodium excretion. It has been shown that the kidney is innervated by a dense network of capsaicin-sensitive CGRP-containing nerves.16,17 Moreover, several lines of evidence have shown that 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.18–21 It is conceivable that a defect in the sensory nervous system may lead to hypertension associated with reduced sodium excretion. Indeed, sodium excretion in response to sodium loading is impaired in salt–sensitive hypertension induced by sensory nerve degeneration of neonatally capsaicin-treated rats or surgically denervated rats,3,22–24 as well as in DS rats.25–27 Therefore, the susceptibility of DS rats to hypertension may be attributed, at least in part, to the lack of adequate counterregulatory action of sensory nerves, and the resistance to hypertension in DR rats may be related to an enhanced function of sensory nerves.
Perspectives
In addition to angiotensin II and endothelin-1,28,29 which contribute to increased salt sensitivity in DS rats, our findings suggest that salt-induced impairment of the TRPV1 or sensory nerve function may be genetically predisposed in DS rats leading to withdrawing of the protective mechanisms in the face of salt challenge. It follows that the TRPV1 receptor expressed in primary sensory nerves may serve as a candidate gene product in inheriting increased salt sensitivity in DS rats and in humans and that manipulations that modulate TRPV1 function may alter blood pressure. These data may provide a rationale for the search of novel endogenous and/or exogenous TRPV1 agonists for the treatment of salt-dependent hypertension and may contribute to our understandings of an important issue in hypertension research, that is, health disparities.
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Acknowledgments |
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This work was supported in part by the National Institutes of Health (grants HL-57853, HL-73287, and DK67620) and a grant from Michigan Economic Development Corporation. D.H.W. is an Established Investigator of the American Heart Association.
Received October 3, 2005; first decision October 23, 2005; accepted November 10, 2005.
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 B. Nilius, G. Owsianik, T. Voets, and J. A. Peters Transient Receptor Potential Cation Channels in Disease Physiol Rev, January 1, 2007; 87(1): 165 - 217. [Abstract] [Full Text] [PDF]
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Y. Wang, A. F. Chen, and D. H. Wang Enhanced oxidative stress in kidneys of salt-sensitive hypertension: role of sensory nerves Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H3136 - H3143. [Abstract] [Full Text] [PDF]
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 R. Inoue, L. J. Jensen, J. Shi, H. Morita, M. Nishida, A. Honda, and Y. Ito Transient Receptor Potential Channels in Cardiovascular Function and Disease Circ. Res., July 21, 2006; 99(2): 119 - 131. [Abstract] [Full Text] [PDF]
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