Salt Intake Augments Hypotensive Effects of Transient Receptor Potential Vanilloid 4

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