Functional and molecular evidence for impairment of calcium-activated potassium channels in type-1 diabetic cerebral artery smooth muscle cells.
Cerebral vascular dysfunction and associated diseases often occur in type-1 diabetes, but the underlying mechanisms are largely unknown. In this study, we sought to determine whether big-conductance, Ca(2+)-activated K(+) (BK) channels were impaired in vascular (cerebral artery) smooth muscle cells (CASMCs) from streptozotocin-induced type-1 diabetic mice using patch clamp, molecular biologic, and genetic approaches. Our data indicate that the frequency and amplitude of spontaneous transient outward currents (STOCs) are significantly decreased, whereas the activity of spontaneous Ca(2+) sparks is increased, in diabetic CASMCs. The sensitivity of BK channels to voltage, Ca(2+), and the specific inhibitor iberiotoxin are all reduced in diabetic myocytes. Diabetic mice show increased myogenic tone and decreased contraction in response to iberiotoxin in cerebral arteries and elevated blood pressure. The expression of the BK channel beta1, but not alpha-subunit protein, is markedly decreased in diabetic cerebral arteries. Diabetic impairment of BK channel activity is lost in CASMCs from BK channel beta1-subunit gene deletion mice. In conclusion, the BK channel beta1-subunit is impaired in type-1 diabetic vascular SMCs, resulting in increased vasoconstriction and elevated blood pressure, thereby contributing to vascular diseases in type-1 diabetes.
Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA.
Ling
L
Dong
Yun-Min
YM
Zheng
Dee
D
Van Riper
Rakesh
R
Rathore
Qing-Hua
QH
Liu
Harold A
HA
Singer
Yong-Xiao
YX
Wang
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology; D002469:Cell Separation; D002536:Cerebral Arteries / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004594:Electrophysiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology
D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; C064719:iberiotoxin