A Novel Mechanism Contributing to Development of Dahl Salt–Sensitive Hypertension

Abstract

Abstract-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 DSϩHS rats compared with DSϩLS, DRϩHS, and DRϩLS rats. Intravenous bolus injection of capsazepine (3 mg/kg), a selective TRPV1 antagonist, significantly increased mean arterial pressure in conscious DRϩHS rats compared with DRϩLS, DSϮHS, and DSϮLS rats. In contrast, capsaicin (10 or 30 g/kg), a selective TRPV1 agonist, dose-dependently decreased mean arterial pressure in all of the groups with the most profound magnitude in DRϩHS 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 DSϩHS rats compared with DSϩLS, DRϩHS, and DRϩLS 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 Ⅲ rats, Dahl Ⅲ hypertension, sodium-dependent Ⅲ blood pressure B oth 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 hypertension 4,5 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...

Endocannabinoid Regulates Blood Pressure via Activation of the Transient Receptor Potential Vanilloid Type 1 in Wistar Rats Fed a High-Salt Diet

“…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.…”

“…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.…”

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

“…21 Reduced TRPV1 expression has been reported in Dahl salt-sensitive rats, which renders them sensitive to salt load in blood pressure regulation. 22 Capsaicininduced TRPV1 activation enhances endothelium-dependent relaxation and lowers blood pressure in genetic hypertensive rats. 16 TRPV4 activation decreases blood pressure in rats on a normal salt diet, and TRPV4 inhibition increased blood pressure in rats on a high-salt diet.…”

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

“…Moreover, the depressor effect of TRPV1 activation after capsaicin administration was much greater in HS rats compared with NS rats, supporting the notion that TRPV1 plays a counter-regulatory role against salt-induced increases www.chinaphar.com Yu SQ et al Acta Pharmacologica Sinica npg in blood pressure. The counter-regulatory effect of TRPV1 has been shown to involve enhanced CGRP release from sensory nerves that cause vasodilation, sodium and water excretion, and decreases in blood pressure [39][40][41][42][43] . TRPV1 shRNA treatment resulted in enhanced suppression of mesenteric TRPV1 levels but enhanced up-regulation of mesenteric tyrosine hydroxylase contents.…”