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Salt intake augments hypotensive effects of transient receptor potential vanilloid 4: functional significance and implication Gao F; Sui D; Garavito RM; Worden RM; Wang DHHypertension 2009[Feb]; 53 (2): 228-35To test the hypothesis that activation of the transient receptor potential vanilloid 4 (TRPV4) channel conveys a hypotensive effect that is enhanced during salt load, male Wistar rats fed a normal-sodium (0.5%) or high-sodium (HS; 4%) diet for 3 weeks were given 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), a specific TRPV4 activator, in the presence or absence of capsazepine, a selective TRPV1 blocker, ruthenium red, a TRPV4 blocker, or TRPV4 small hairpin RNA that selectively knockdowns TRPV4. 4 alpha-PDD (1, 2.5, or 5 mg/kg IV) dose-dependently decreased mean arterial pressure (P<0.05). HS enhanced 4 alpha-PDD-induced depressor effects as well as 4 alpha-PDD-mediated release of calcitonin gene-related peptide and substance P (P<0.001). Ruthenium red markedly blunted (P<0.001), whereas capsazepine slightly attenuated (P<0.05) 4 alpha-PDD-induced depressor effects in HS and normal-sodium diet rats. Ruthenium red alone increased baseline mean arterial pressure in both HS and normal-sodium diet rats with a greater magnitude in the former (P<0.05). Western blot analysis showed that HS increased TRPV4 expression in dorsal root ganglia and mesenteric arteries (P<0.05) but not the renal cortex and medulla. Gene-silencing approach revealed that TRPV4 small hairpin RNA downregulated TRPV4 expression leading to blunted 4 alpha-PDD-induced hypotension (P<0.05). Thus, TRPV4 activation decreases blood pressure in rats given a normal-sodium diet. HS enhances TRPV4 expression in sensory nerves/mesenteric arteries and TRPV4-mediated depressor effects and calcitonin gene-related peptide/substance P release such that HS causes a greater increase in blood pressure when TRPV4 is blocked. Our data indicate that TRPV4 activation may constitute a compensatory mechanism in preventing salt-induced increases in blood pressure.|Animals[MESH]|Blood Pressure/*drug effects/physiology[MESH]|Calcitonin Gene-Related Peptide/metabolism[MESH]|Capsaicin/analogs & derivatives/pharmacology[MESH]|Disease Models, Animal[MESH]|Dose-Response Relationship, Drug[MESH]|Ganglia, Spinal/metabolism[MESH]|Hypertension/physiopathology/*prevention & control[MESH]|Hypotension/etiology/*physiopathology[MESH]|Kidney/metabolism[MESH]|Male[MESH]|Mesenteric Arteries/metabolism[MESH]|Phorbol Esters/pharmacology[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Ruthenium Red/pharmacology[MESH]|Salt Tolerance/physiology[MESH]|Sodium Chloride, Dietary/*pharmacology[MESH]|Substance P/metabolism[MESH]|TRPV Cation Channels/agonists/antagonists & inhibitors/*physiology[MESH] |
