Impairment in function and expression of transient receptor potential vanilloid type 4 in Dahl salt-sensitive rats: significance and mechanism.
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. 4alpha-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 (P<0.05). Depressor effects of 4alpha-phorbol-12,13-didecanoate but not dihydrocapsaicin (a selective TRPV1 agonist; 30 microg/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 (P<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 (P<0.05). Mean arterial pressure responses to blockade of small- and large-/intermediate-conductance Ca(2+)-activated K(+) channels (Maxikappa channels) with apamin and charybdotoxin, respectively, were examined. Apamin (100 microg/kg) plus charybdotoxin (100 microg/kg) abolished 4alpha-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 Maxikappa 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.
Gao
Feng
F
Department of Medicine, Michigan State University, East Lansing, Mich 48824, USA.
Wang
Donna H
DH
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D015153:Blotting, Western; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D018613:Microscopy, Confocal; D010704:Phorbols / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
C517592:4alpha-phorbol 12,13-didecanone; D010704:Phorbols; D024681:Potassium Channels, Calcium-Activated; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D002211:Capsaicin; C012906:dihydrocapsaicin