title: Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats.
abstract: Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The small (SK(Ca)) and intermediate (IK(Ca)) calcium-activated potassium channels play a key role in endothelium-dependent relaxation. Because the repressor element 1-silencing transcription factor (REST) negatively regulates IK(Ca) expression, we hypothesized that augmented REST and decreased IK(Ca) 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; 100mumol/L) and indomethacin (100mumol/L) greatly impaired ACh responses in vessels from SHRSP. Iberiotoxin (0.1mumol/L), which is a selective inhibitor of large-conductance K(Ca) (BK(Ca)) channels, did not modify EDHF-mediated vasodilation in SHRSP or WKY. UCL-1684 (0.1mumol/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; 10mumol/L) and charybdotoxin (0.1mumol/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 SK(Ca)/IK(Ca) channels agonist NS-309 was decreased in SHRSP arteries. The expression of SK(Ca) was decreased, whereas IK(Ca) was increased in SHRSP mesenteric arteries. REST expression was reduced in arteries from SHRSP. Vessels incubated with TRAM-34 (10mumol/L) for 24h displayed reduced REST expression and demonstrated no differences in IK(Ca). In conclusion, IK(Ca) channel upregulation, via decreased REST, seems to compensate deficient activity of SK(Ca) channels in the vasculature of spontaneously hypertensive rats.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA. fgiachini@mcg.edu
authors.forename: Fernanda R C
authors.initials: FR
authors.lastname: Giachini
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Carneiro
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.forename: Zidonia N
authors.initials: ZN
authors.lastname: Carneiro
authors.forename: Anne
authors.initials: A
authors.lastname: Dorrance
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D018999:Charybdotoxin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics / Q000502:physiology*; D011921:Rats, Inbred WKY; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D018999:Charybdotoxin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin