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CARDIOVASCULAR
Departments of Medicine (Y.W., D.H.W.) and Pharmacology and Toxicology (N.E.K.), Michigan State University, East Lansing, Michigan
Received August 23, 2006; accepted February 13, 2007.
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Abstract |
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; Julius and Basbaum, 2001). In addition, TRPV1 can be activated by endogenous fatty acid-derived mediators such as anandamide (Di Marzo et al., 2002). It is well known that TRPV1 is mainly expressed in primary sensory nerves including unmyelinated C-fibers or thinly myelinated A
-fibers (Wimalawansa, 1996). The basis for the capsaicin sensitivity of primary sensory nerves is the expression of the TRPV1 receptors. Activation of the TRPV1 expressed in sensory nerves causes release of a number of sensory neurotransmitters, including calcitonin gene-related peptide (CGRP) and substance P, which are potent vasodilators in various vascular beds (Wimalawansa, 1996). There is histological evidence documenting the presence of TRPV1-containing sensory nerve endings innervating the cardiovascular system and kidney.
Anandamide, an endogenous cannabinoid receptor agonist, was isolated from porcine brain and found to be produced in endothelial cells, macrophages, and other peripheral cells (Devane et al., 1992). The endocannabinoid system comprises two G protein-coupled receptors including cannabinoid receptor type 1 (CB1) and 2 (CB2). CB1 receptors are present in the central nervous system and peripheral tissues, whereas CB2 receptors are mainly expressed in immune cells (Matsuda et al., 1990; Munro et al., 1993). The CB1 and CB2 receptor subtypes have been implicated in neurobehavioral as well as cardiovascular effects of cannabinoids (Varga et al., 1996; Lake et al., 1997a,b; Bátkai et al., 2004). Moreover, it has been reported that anandamide excites peripheral terminals of capsaicin-sensitive primary sensory neurons via CB-receptor-independent mechanisms (Zygmunt et al., 1999). It has been shown that the TRPV1 antagonist, capsazepine (CAPZ), selectively abolished anandamide-induced release of CGRP in rodent peripheral arteries, indicating that anandamide stimulates capsaicin-sensitive primary sensory neurons via activation of the TRPV1 receptors. These results were confirmed by Smart et al. (2000), showing that anandamide acted as an agonist for the TRPV1 in humans. Moreover, we have shown in vivo that the anandamide-induced depressor effect was partially attenuated by the TRPV1 receptor antagonist, CAPZ, in spontaneously hypertensive rats or rats fed a high-salt diet, suggesting that anandamide may regulate cardiovascular function via modulating the TRPV1 receptor (Li and Wang, 2003; Wang et al., 2005b).
Although clinical and genetic investigation in humans and animals has provided evidence showing that a linkage exists between chronic high sodium (HS) intake and development of hypertension, the molecular mechanisms underlying salt-induced increases in blood pressure are poorly understood. Our data showed that capsaicin-induced degeneration of sensory nerves renders a rat sensitive to a salt load with a significant increase in blood pressure (Wang et al., 1998), indicating that sensory nerves are important in preventing salt-induced increases in blood pressure. However, it is unknown what mechanisms are responsible for activation of sensory nerves and whether HS intake modulates the production of the compounds targeting the TRPV1. Therefore, this study was designed to test the hypotheses that: 1) HS intake increases anandamide production and 2) anandamide serves as an activator of the TRPV1 in response to HS intake.
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Materials and Methods |
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Surgical Preparation
The rats were anesthetized with ketamine and xylazine (80 and 4 mg/kg i.p., respectively) for implantation of artery and vein catheters. The left jugular vein and carotid artery were cannulated for administration of drugs or for monitoring of mean arterial pressure (MAP) and heart rate (HR) with a Statham 231D pressure transducer coupled to a Gould 2400s recorder (Gould Instruments, Dayton, OH). For conscious animal experiments, catheters were routed s.c. and exteriorized between the scapulae. Rats were quietly brought to home cages 3 h after surgery, and MAP and HR were continuously recorded. Regular room light was turned on during experiments. The rats were allowed to acclimate to their surroundings for 15 to 30 min in their cages, i.e., until which time they ceased exploring the new environment and their blood pressures stabilized. Baseline MAP and HR were recorded for 15 min before administration of drugs (Supowit et al., 1997; Wang and Wang, 2004).
Experimental Protocols
Protocol 1. To determine whether the TRPV1 is tonically activated during HS intake, rats fed an NS or HS diet were randomly assigned to two groups for i.v. injection of CAPZ (3 mg/kg), a selective TRPV1 antagonist, in conscious states.
Protocol 2. To determine the role of the CGRP receptor in rats fed an HS diet, MAP responses to injection of CGRP (1 and 5 µg/kg bolus) were measured in conscious rats fed an NS or HS diet. Thirty minutes were allowed for stabilization of blood pressure between injections.
Protocol 3. To determine plasma CGRP concentration in response to methanandamide (MethA; a metabolically stable analog of anandamide), vehicle or MethA (5 mg/kg) was administered into conscious rats fed an NS or HS diet. Fifteen minutes after injection, when the prolonged depressor phase approached to the lowest point, the rats were decapitated for collection of blood for plasma CGRP assay.
Protocol 4. To determine biochemical parameters in plasma and tissues, rats fed an NS or HS diet were sacrificed by decapitation without subjecting to acute experiments. Plasma and mesenteric arteries were collected for analysis of endocannabinoid and Western blot analysis of CGRP receptor components.
Protocol 5. To determine the effect of MethA (0.1 and 10 µM) on CGRP release from mesenteric arteries in vitro, mesenteric arteries from rats fed an NS or HS diet were collected and placed into ice-cold PBS solution. The arteries were dissected free of fat and connective tissues. The preparations were incubated in a Krebs' solution of the following compositions: 119 mM NaCl, 25 mM NaHCO3, 1.2 mM KH2PO4, 1.5 mM MgSO4, 2.5 mM CaCl2, 4.7 mM KCl, and 11 mM D-glucose. The Krebs' solution was maintained at 37°C and gassed with 95% O2 and 5% CO2. After a 1-h stabilization period, the arteries were transferred to another chamber containing 1 ml of Krebs' solution with the addition of 0.05% bovine serum albumin and drugs. In addition, the tissue samples were incubated with CAPZ (10 µM), a selective TRPV1 antagonist, to determine the role of TRPV1 in MethA-induced CGRP release. The tissues were removed after 20-min incubation, and the solutions were collected. At the end of the experiment, the tissues were blotted and weighted. The solution in the tubes was evaporated, and the pellets were stored at –80°C for CGRP immunoassay. The highest concentration of MethA (10 µM) and CAPZ (10 µM) did not show any cross-reactivity with CGRP. The results are expressed as picograms of CGRP per milligram of tissue per 20 min.
Analysis of Endocannabinoid
Plasma was collected and stored at –80°C until lipid extraction. Lipid extracts were isolated from plasma spiked with D4-labeled anandamide as internal standards. The samples were analyzed by liquid chromatography/electrospray tandem mass spectrometry using electrospray positive program designed specific for anandamide as described previously (kindly provided by Drs. Joseph Leykam and Lijun Chen) (Giuffrida et al., 2000; Bátkai et al., 2004). An electrospray-mass spectrometer (LCQ Deca; Thermo Electron, Waltham, MA) equipped with a Nova-Pak C18 column (300 x 3.9 mm, 4 µm; Waters, Milford, MA) was used for analysis. Anandamide standards eluted from the column after approximately 25 min. Diagnostic ions (protonated molecular ions [M + H]+) were detected in the tandem mode. Complete system control and data evaluation were done using the Xcalibur software (Thermo Electron). Values are expressed as picomoles per milliliter of plasma.
Radioimmunoassay
CGRP contents in plasma and tissue incubating buffer were measured using a rabbit anti-rat CGRP radioimmunoassay kit (Phoenix Pharmaceuticals, Belmont, CA) according to the manufacturer's protocol (Wang and Wang, 2006). This antibody has 100% cross-reactivity with rat 
-CGRP and 79% with rat 
-CGRP. There is no cross-reactivity with rat amylin, calcitonin, somatostatin, or substance P.
Western Blot Analysis
Membrane protein of the mesenteric arteries was extracted, separated on a 10% SDS-polyacrylamide gel, and transferred to a polyvinylidene difluoride membrane as described previously (Wang et al., 2005). The membranes were blocked 1 h at room temperature or overnight at 4°C in 5% milk washing solution (50 mM Tris-HCl, 100 mM NaCl, and 0.1% Tween 20, pH 7.5). Subsequently, the membranes were incubated with rabbit anti-rat calcitonin receptor-like receptor (CRLR) antiserum (1:5000; Alpha Diagnostics International Inc., San Antonio, TX) or rabbit anti-human receptor activity-modifying protein (RAMP) 1 polyclonal IgG (1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) in blocking solution overnight at 4°C. After being washed, the membranes were incubated with goat anti-rabbit IgG-HRP (1:5000; Santa Cruz Biotechnology, Inc.) in blocking solution at room temperature for 1 h. The membranes were developed using an enhanced chemiluminescence kit (GE Healthcare, Little Chalfont, Buckinghamshire, UK) and exposed to film (Hyperfilm-ECL; GE Healthcare). The films were scanned and analyzed by using the Image Quantity Program (Scion Corporation, Frederick, MD) to obtain integrated densitometric values. -Actin was used to normalize protein loaded on membranes.
Drugs
CAPZ (Calbiochem, San Diego, CA) was dissolved in dimethyl sulfoxide (10%, v/v), Tween 80 (10%, v/v), and normal saline. CGRP (Sigma) was dissolved in normal saline. MethA (Sigma) was dissolved in ethanol (10%, v/v), Tween 80 (10%, v/v), and normal saline.
Statistical Analysis
All values are expressed as mean ± S.E. Differences between two groups or before and after treatment were analyzed by using the unpaired or paired Student's t test. The differences among groups were analyzed using one-way analysis of variance followed by a Bonferroni's adjustment for multiple comparisons. Comparisons between groups at each experiment time point were determined by the use of two-way analysis of variance followed by a Bonferroni's test. Differences were considered statistically significant at p < 0.05.
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Results |
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To determine whether blockade of the TRPV1 affects blood pressure in 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. As shown in Fig. 1A, the MAP elevation began immediately after injection of CAPZ and reached the peak within 2 min after injection in rats fed an HS diet. The pressor action of CAPZ lasted for about 6 to 7 min. As shown in Fig. 2A, the peak MAP responses to CAPZ injection were significantly increased in HS-treated rats (13 ± 3 mm Hg) compared with the NS-treated rats (4 ± 2 mm Hg, p < 0.05). Therefore, blockade of the TRPV1 leads to a significant increase in blood pressure in rats fed an HS diet but not in rats fed an NS diet, indicating that TRPV1 receptors are activated during HS intake to blunt salt-induced elevation in blood pressure. As shown in Figs. 1B and 2B, no significant change in HR was observed during this experimental period in NS- or HS-treated rats.
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Effects of CGRP on MAP were examined in conscious rats as shown in Fig. 3. CGRP at the doses of 1 and 5 µg/kg caused dose-dependent reductions in MAP in rats fed an NS and HS diet. The magnitude of the CGRP-induced reductions in MAP in HS-treated rats was significantly greater than that in NS-treated rats (19 ± 3 and 43 ± 3 mm Hg in HS-treated rats versus 11 ± 3 and 24 ± 3 mm Hg in NS-treated rats, respectively, p < 0.05).
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Western blotting analysis was performed to determine the effect of HS intake on expression of CGRP receptor proteins. Mesenteric RAMP1, one of the key components of the CGRP receptor, was up-regulated in HS-treated rats compared with NS-treated rats (0.54 ± 0.04 versus 0.41 ± 0.03, p < 0.05). There was no difference in CRLR expression between the two groups (Fig. 7).
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Discussion |
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Increased Anandamide Levels for TRPV1 and/or CB1 Activation during HS Intake. Our findings may provide a new insight into blood pressure regulatory mechanisms mediated by endocannabinoid anandamide in rats fed an HS diet, which involves TRPV1 as a possible molecular target of salt-induced increases of endocannabinoid. We have shown previously (Wang et al., 2005) that the anandamide-induced depressor response is CAPZ-sensitive, indicating that it is mediated at least in part by activation of the TRPV1. This notion is further confirmed by the present study showing that anandamide stimulates the CAPZ-sensitive release of CGRP in mesenteric arteries. Moreover, HS intake increases the plasma concentration of anandamide, and blockade of the TRPV1 with CAPZ leads to an increase in blood pressure in HS- but not NS-treated rats. These data suggest that TRPV1, possibly activated by salt-induced elevation of anandamide production, may serve as a compensatory mechanism contributing to blunting salt-induced elevation in blood pressure in normal rats. In contrast, we have shown previously (Wang and Wang, 2006) that blockade of TRPV1 during HS intake did not elevate blood pressure in Dahl salt-sensitive rats, indicating that TRPV1 function is impaired in this genetically predisposed strain fed an HS diet given TRPV1 has no protective effect on blunting elevated blood pressure in this strain.
Previous studies (Lake et al., 1997) showed that the prolonged depressor response induced by exogenous anandamide was attenuated by SR141716A, indicating that SR141716A-sensitive CB1 receptors are involved in anandamide-induced depressor response (Lake et al., 1997; Li et al., 2003; Wang et al., 2005). So far, the mechanisms by which cannabinoids elicit the depressor effect have not been well defined. CB1 receptors are abundantly expressed in the central and peripheral nervous system, suggesting that cannabinoids may influence cardiovascular function via modulating autonomic outflow in both the central and peripheral nervous systems. However, several studies have shown that there is no centrally elicited effect of anandamide on the firing rate of presympathetic sympathoexcitatory neurons in the rostral ventrolateral medulla oblongata and splanchnic sympathetic nerve fibers (Varga et al., 1996). These results suggest that peripheral sympathetic nerve actions of anandamide appear to be predominant in cardiovascular regulation. Accumulating evidence has demonstrated that presynaptic CB1 receptors on sympathetic nerve terminals inhibit norepinephrine release (Ishac et al., 1996; Pertwee et al., 1996; Niederhoffer and Szabo, 1999). In addition, CB1 receptors expressed in the vasculature and myocardium directly mediate vasodilation and negative inotropy (Deutsch et al., 1997; Lake et al., 1997; Gebremedhin et al., 1999). All these actions may contribute to the depressor effect of anandamide.
We have shown in vivo that anandamide-induced depressor effect is partially attenuated by the TRPV1 receptor antagonist, CAPZ, in spontaneously hypertensive rats or rats fed an HS diet, suggesting that the TRPV1 receptor may be involved in cardiovascular regulation induced by anandamide (Li et al., 2003; Wang et al., 2005). The results are consistent with the in vitro studies performed by Zygmunt et al. (1999) and Smart et al. (2000) showing that anandamide activates TRPV1 receptors expressed in perivascular sensory nerves, Xenopus oocytes, and HEK293 cells. In addition, structural similarities between anandamide and vanilloids suggest that TRPV1 receptors may serve as a molecular target for anandamide (Di Marzo et al., 1998; Melck et al., 1999).
TRPV1-Mediated Sensory Neuropeptide Release and Its Significance. The TRPV1 antagonist elicited significant increases in blood pressure when an HS but not NS diet was given, suggesting that HS intake is capable of activating the TRPV1. The notion is further supported by an increase in plasma CGRP concentrations associated with HS intake given it is well known that TRPV1 activation leads to CGRP release. TRPV1 activation could result from an increased concentration of endogenous ligand or an up-regulation of TRPV1 receptors expressed in primary sensory nerves. We found that plasma anandamide levels were increased in rats fed an HS diet, which may be responsible for TRPV1 activation during HS intake. Moreover, an increase in TRPV1 expression was evident in mesenteric arteries of HS-treated rats (Li et al., 2003; Wang et al., 2005), which may contribute in part to salt-induced sensitization of the TRPV1 (Li et al., 2003; Wang et al., 2005).
CGRP is one of the most powerful vasodilatory neuropeptides (Kawasaki et al., 1988; Wimalawansa, 1996) via its direct effect or inhibition of sympathetic nervous activity (Ralevic et al., 1995; Oh-hashi et al., 2001). McLatchie et al. (1998) have shown that a functional CGRP receptor derives from CRLR, but the phenotype is determined by coexpression of a particular RAMP. RAMPs are required to transport CRLR to the plasma membrane, determining its glycosylation state, and defining its pharmacological properties (McLatchie et al., 1998). Coexpression of RAMP1 and CRLR is found to form a CGRP receptor, whereas RAMP2 or RAMP3 coexpressed with CRLR produces an adrenomedullin receptor (McLatchie et al., 1998; Fraser et al., 1999). Our data show that chronic high-salt intake causes up-regulation of RAMP1 in mesenteric arteries, suggesting that the mechanisms including up-regulation and sensitization of the CGRP receptor in the target tissues may also be involved in the enhanced responses to anandamide in rats fed an HS diet. Indeed, our data show that the depressor effect of CGRP is greater in rats fed an HS diet than in rats fed an NS diet.
Although modulating peripheral vascular reactivity may underlie acute blood pressure regulation, long-term blood pressure regulation is intrinsically linked to renal excretory function (Guyton, 1961; Borst and Borst-de-Geus, 1963). Much of the previous research on salt-dependent hypertension has focused on the sympathetic nervous system and endocrine regulation of sodium and water balance. In addition to these well investigated systems, sensory nerves and their neurotransmitters facilitate sodium excretion. It has been shown that the kidney is innervated by a dense network of CGRP-positive sensory nerves (Chai et al., 1998). Moreover, CGRP and substance P have direct and indirect effects on tubular ion transport leading to natriuresis and diuresis (Arendshorst et al., 1976; Shekhar et al., 1991). Indeed, several studies have shown that sodium excretion in response to sodium loading is impaired in salt-sensitive hypertension induced by sensory nerve degeneration of neonatally capsaicin treatment or by surgical sensory denervation (Ye and Wang, 2002; Kopp et al., 2003; Wang et al., 2005).
In summary, our results demonstrate that TRPV1 is activated in rats fed an HS diet, probably because of elevated anandamide production leading to CGRP release. These effects, probably involving altered peripheral vascular reactivity and renal function, may play a counterregulatory role in blunting salt-induced increases in blood pressure.
Perspective. There is mounting evidence showing that HS may contribute to the development of hypertension (Haddy and Pamnani, 1995; Kotchen, 2005). However, mechanisms underlying salt-dependent hypertension are unclear. Although previous studies have shown that CGRP release may play a compensatory role in preventing blood pressure elevation in deoxycorticosterone-salt hypertensive rats (Supowit et al., 1997), the identity of the endogenous ligands triggering enhanced CGRP release remains unclear. Our findings of the current study suggest that elevated anandamide concentrations may attenuate the increase in blood pressure via activation of TRPV1 during HS intake. Thus, it is conceivable that activation of the TRPV1 via enhancement of anandamide production/release or blockade of its metabolic degradation or uptake might be an effective approach for future consideration of new therapeutic strategies in treating hypertension.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: TRPV1, transient receptor potential vanilloid type 1; CGRP, calcitonin gene-related peptide; CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; CAPZ, capsazepine; HS, high sodium; NS, normal sodium; MAP, mean arterial pressure; HR, heart rate; MethA, methanandamide; CRLR, calcitonin receptor-like receptor; RAMP, receptor activity-modifying protein.
Address correspondence to: Dr. 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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, p < 0.05 compared with NS-treated rats at the same dose of CGRP.
, p < 0.05 compared with the corresponding rats treated with MethA (10 µM).
