title: Salt intake augments hypotensive effects of transient receptor potential vanilloid 4: functional significance and implication.
abstract: To 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.
authors.affiliation: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Dexin
authors.initials: D
authors.lastname: Sui
authors.forename: R Michael
authors.initials: RM
authors.lastname: Garavito
authors.forename: R Mark
authors.initials: RM
authors.lastname: Worden
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control*; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology; D055049:Salt Tolerance / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D010703:Phorbol Esters; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C486577:Trpv4 protein, rat; D012430:Ruthenium Red; C008876:phorbol-12,13-didecanoate; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin