title: Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels.
abstract: ATP-sensitive K+ channels (K(ATP)) contribute to vasomotor regulation in some species. It is not fully understood the extent to which K(ATP) participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription-polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective K(ATP) opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription-polymerase chain reaction detected mRNA expression for K(ATP) subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90+/-2% versus DM(-) 96+/-1%, P<0.05) and hypoxia (maximum dilation, DM(+) 56+/-8% versus DM(-) 85+/-5%, P<0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to K(ATP) opening, leading to reduced dilation to hypoxia. This reduction in K(ATP) function could contribute to the greater cardiovascular mortality and morbidity in DM.
authors.affiliation: Department of Veterans Affairs Medical Center, Milwaukee, Wis, USA. hmiura@mcw.edu
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Wachtel
authors.forename: Fausto R
authors.initials: FR
authors.lastname: Loberiza
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Mamoru
authors.initials: M
authors.lastname: Miura
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Nicolosi
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008833:Microcirculation / Q000503:physiopathology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012737:Sex Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020030:Nitric Oxide Donors; D010847:Picolines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011714:Pyrans; D012333:RNA, Messenger; D014665:Vasodilator Agents; C061043:aprikalim; D000255:Adenosine Triphosphate; D001920:Bradykinin; D005905:Glyburide