Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The small (SKCa) and intermediate (IKCa) calcium-activated potassium channels play a key role in endothelium-dependent relaxation. Because the repressor element 1-silencing transcription factor (REST) negatively regulates IKCa expression, we hypothesized that augmented REST and decreased IKCa expression contributes to impaired endothelium-dependent vasodilation associated with hypertension. Acetylcholine (ACh) responses were slightly decreased in small mesenteric arteries from male stroke-prone spontaneously hypertensive rats (SHRSPs) versus arteries from Wistar Kyoto (WKY) rats. Incubation with N-nitro-L-arginine methyl ester (L-NAME; 100μmol/L) and indomethacin (100μmol/L) greatly impaired ACh responses in vessels from SHRSP. Iberiotoxin (0.1μmol/L), which is a selective inhibitor of large-conductance KCa (BKCa) channels, did not modify EDHF-mediated vasodilation in SHRSP or WKY. UCL-1684 (0.1μmol/L), which is a selective inhibitor of SKCa channels, almost abolished EDHF-mediated vasodilation in WKY and decreased relaxation in SHRSP. 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; 10μmol/L) and charybdotoxin (0.1μmol/L), which are both IKCa inhibitors, produced a small decrease of EDHF relaxation in WKY but completely abrogated EDHF vasodilation in SHRSP. EDHF-mediated relaxant responses were completely abolished in both groups by simultaneous treatment with UCL-1684 and TRAM-34 or charybdotoxin. Relaxation to SKCa/IKCa channels agonist NS-309 was decreased in SHRSP arteries. The expression of SKCa was decreased, whereas IKCa was increased in SHRSP mesenteric arteries. REST expression was reduced in arteries from SHRSP. Vessels incubated with TRAM-34 (10μmol/L) for 24h displayed reduced REST expression and demonstrated no differences in IKCa. In conclusion, IKCa channel upregulation, via decreased REST, seems to compensate deficient activity of SKCa channels in the vasculature of spontaneously hypertensive rats.
ASJC Scopus subject areas
- Public Health, Environmental and Occupational Health
- Biochemistry, medical
- Physiology (medical)