Impairment in Function and Expression of Transient Receptor Potential Vanilloid Type 4 in Dahl Salt-Sensitive Rats

<jats:p> To examine the role of transient receptor potential vanilloid type 4 (TRPV4) channels in the development of salt-sensitive hypertension, male Dahl salt-sensitive (DS) and -resistant (DR) rats were fed a low-salt (LS) or high-salt (HS) diet for 3 weeks. DS-HS but not DR-HS rats developed hypertension. 4α-Phorbol-12,13-didecanoate (a selective TRPV4 activator; 2.5 mg/kg IV) decreased mean arterial pressure in all of the groups with the greatest effects in DR-HS and the least in DS-HS rats ( <jats:italic>P</jats:italic> <0.05). Depressor effects of 4α-phorbol-12,13-didecanoate but not dihydrocapsaicin (a selective TRPV1 agonist; 30 μg/kg IV) were abolished by ruthenium red (a TRPV4 antagonist; 3 mg/kg IV) in all of the groups. Blockade of TRPV4 with ruthenium red increased mean arterial pressure in DR-HS rats only ( <jats:italic>P</jats:italic> <0.05). TRPV4 protein contents were decreased in the renal cortex, medulla, and dorsal root ganglia in DS-HS compared with DS-LS rats but increased in dorsal root ganglia and mesenteric arteries in DR-HS compared with DR-LS rats ( <jats:italic>P</jats:italic> <0.05). Mean arterial pressure responses to blockade of small- and large-/intermediate-conductance Ca <jats:sup>2+</jats:sup> -activated K <jats:sup>+</jats:sup> channels (Maxiκ channels) with apamin and charybdotoxin, respectively, were examined. Apamin (100 μg/kg) plus charybdotoxin (100 μg/kg) abolished 4α-phorbol-12,13-didecanoate–induced hypotension in DR-LS, DR-HS, and DS-LS rats only. Thus, HS-induced enhancement of TRPV4 function and expression in sensory neurons and resistant vessels in DR rats may prevent salt-induced hypertension possibly via activation of Maxiκ channels given that blockade of TRPV4 elevates mean arterial pressure. In contrast, HS-induced suppression of TRPV4 function and expression in sensory neurons and kidneys in DS rats may contribute to increased salt sensitivity. </jats:p>