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(Hypertension. 2009;53:228.)
© 2009 American Heart Association, Inc.

Original Articles

Salt Intake Augments Hypotensive Effects of Transient Receptor Potential Vanilloid 4

Functional Significance and Implication

Feng Gao; Dexin Sui; R. Michael Garavito; R. Mark Worden; Donna H. Wang

From the Departments of Medicine (F.G., D.H.W.), Biochemistry and Molecular Biology (D.S., R.M.G.), Chemical Engineering and Materials Science (R.M.W.), Neuroscience Program (D.H.W.), and Cell and Molecular Biology Program (D.H.W.), Michigan State University, East Lansing.

Correspondence to Donna H. Wang, MD, FAHA, Division of Nanomedical and Molecular Intervention, Department of Medicine, B316B Clinical Center, Michigan State University, East Lansing, MI 48824. E-mail donna.wang{at}ht.msu.edu

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-phorbol 12,13-didecanoate (4-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-PDD (1, 2.5, or 5 mg/kg IV) dose-dependently decreased mean arterial pressure (P<0.05). HS enhanced 4-PDD–induced depressor effects as well as 4-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-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-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.

Key Words: salt intake • gene-targeting • gene-silencing • sensory nerves • blood pressure transient receptor potential channel

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