Impairment in function and expression of transient receptor potential vanilloid type 4 in Dahl salt-sensitive rats: significance and mechanism.

Abstract

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.

• Authors: Feng Gao, Donna H Wang
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 55 Issue 4 Pg. 1018-25 (Apr 2010) ISSN: 1524-4563 [Electronic] United States
• PMID: 20194297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4alpha-phorbol 12,13-didecanone
• Phorbols
• Potassium Channels, Calcium-Activated
• Sodium Chloride, Dietary
• TRPV Cation Channels
• Trpv4 protein, rat
• Capsaicin
• dihydrocapsaicin

Topics

• Analysis of Variance
• Animals
• Blood Pressure (drug effects, physiology)
• Blotting, Western
• Capsaicin (analogs & derivatives, pharmacology)
• Ganglia, Spinal (drug effects, metabolism)
• Immunohistochemistry
• Kidney (drug effects, metabolism)
• Male
• Mesenteric Arteries (drug effects, metabolism)
• Microscopy, Confocal
• Phorbols (pharmacology)
• Potassium Channels, Calcium-Activated (metabolism)
• Rats
• Rats, Inbred Dahl
• Sodium Chloride, Dietary (administration & dosage)
• TRPV Cation Channels (genetics, metabolism)
• Time Factors