Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 154; no. 4; pp. 183 - 193
• Main Authors: Giachini, Fernanda R.C., Carneiro, Fernando S., Lima, Victor V., Carneiro, Zidonia N., Dorrance, Anne, Webb, R. Clinton, Tostes, Rita C.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.10.2009; Elsevier
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Acetylcholine - pharmacology; Animals; Biological and medical sciences; Blood Pressure - drug effects; Body Weight; Charybdotoxin - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; General aspects; Indomethacin - pharmacology; Internal Medicine; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Neurology; NG-Nitroarginine Methyl Ester - pharmacology; Potassium Channels, Calcium-Activated - genetics; Potassium Channels, Calcium-Activated - physiology; Rats; Rats, Inbred SHR - genetics; Rats, Inbred SHR - physiology; Rats, Inbred WKY; Up-Regulation; Vascular diseases and vascular malformations of the nervous system; Vasodilation - drug effects; Vasodilation - physiology; NO; L-NAME; WKY; Ach; SHRSP; PGI 2; BK Ca; K Ca; PSS; REST; SK Ca; TRAM-34; E max; IK Ca; EDHF; p D 2; maximum effect elicited by the agonist; endothelium-derived hyperpolarizing factor; repressor element 1-silencing transcription factor; intermediate calcium-activated potassium channels; nitric oxide; N-nitro-L-arginine methyl ester; small calcium-activated potassium channels; prostacyclin; 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole; calcium-activated potassium channels; large-conductance calcium-activated potassium channels; physiologic salt solution; stroke-prone spontaneously hypertensive rat; negative logarithm of the molar concentration of agonist producing 50% of the maximum response; Wistar Kyoto; acetylcholine; Hypertension; Nervous system diseases; Stroke; Calcium; Rat; Rodentia; Cardiovascular disease; Ionic channel; Inorganic element; Vasodilation; Cerebral disorder; Endothelium; Vascular disease; Medicine; Vasomotricity; Vertebrata; Mammalia; Animal; Central nervous system disease; Clinical biology; Potassium; Cerebrovascular disease
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2009.07.003

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; 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 K Ca (BK Ca) 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 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 (10μmol/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.