Molecular mechanisms of diabetic coronary dysfunction due to large conductance Ca2⁺-activated K⁺ channel impairment / 中华医学杂志(英文版)
Chinese Medical Journal
;
(24): 2548-2555, 2012.
Article
in English
| WPRIM
| ID: wpr-283724
ABSTRACT
<p><b>BACKGROUND</b>Diabetes mellitus is associated with coronary dysfunction, contributing to a 2- to 4-fold increase in the risk of coronary heart diseases. The mechanisms by which diabetes induces vasculopathy involve endothelial-dependent and -independent vascular dysfunction in both type 1 and type 2 diabetes mellitus. The purpose of this study is to determine the role of vascular large conductance Ca(2+)-activated K(+) (BK) channel activities in coronary dysfunction in streptozotocin-induced diabetic rats.</p><p><b>METHODS</b>Using videomicroscopy, immunoblotting, fluorescent assay and patch clamp techniques, we investigated the coronary BK channel activities and BK channel-mediated coronary vasoreactivity in streptozotocin-induced diabetic rats.</p><p><b>RESULTS</b>BK currents (defined as the iberiotoxin-sensitive K(+) component) contribute (65 ± 4)% of the total K(+) currents in freshly isolated coronary smooth muscle cells and > 50% of the contraction of the inner diameter of coronary arteries from normal rats. However, BK current density is remarkably reduced in coronary smooth muscle cells of streptozotocin-induced diabetic rats, leading to an increase in coronary artery tension. BK channel activity in response to free Ca(2+) is impaired in diabetic rats. Moreover, cytoplasmic application of DHS-1 (a specific BK channel b(1) subunit activator) robustly enhanced the open probability of BK channels in coronary smooth muscle cells of normal rats. In diabetic rats, the DHS-1 effect was diminished in the presence of 200 nmol/L Ca(2+) and was significantly attenuated in the presence of high free calcium concentration, i.e., 1 mmol/L Ca(2+). Immunoblotting experiments confirmed that there was a 2-fold decrease in BK-b(1) protein expression in diabetic vessels, without altering the BK channel α-subunit expression. Although the cytosolic Ca(2+) concentration of coronary arterial smooth muscle cells was increased from (103 ± 23) nmol/L (n = 5) of control rats to (193 ± 22) nmol/L (n = 6, P < 0.05) of STZ-induced diabetic rats, reduced BK-b(1) expression made these channels less sensitive to intracellular Ca(2+), which in turn led to enhanced smooth muscle contraction.</p><p><b>CONCLUSIONS</b>Our results indicated that BK channels are the key determinant of coronary arterial tone. Impaired BK channel function in diabetes mellitus is associated with down-regulation of BK-b(1) expression and reduction of the b(1)-mediated BK channel activation in diabetic vessels.</p>
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Blotting, Western
/
Rats, Sprague-Dawley
/
Coronary Vessels
/
Diabetes Mellitus, Experimental
/
Diabetes Mellitus, Type 1
/
Electrophysiology
/
Large-Conductance Calcium-Activated Potassium Channels
/
Metabolism
/
Muscle, Smooth, Vascular
Limits:
Animals
Language:
English
Journal:
Chinese Medical Journal
Year:
2012
Type:
Article
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