Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1.
The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.
Miki
Takashi
T
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Suzuki
Masashi
M
Shibasaki
Tadao
T
Uemura
Hiroko
H
Sato
Toshiaki
T
Yamaguchi
Kaori
K
Koseki
Haruhiko
H
Iwanaga
Toshihiko
T
Nakaya
Haruaki
H
Seino
Susuma
S
D000788:Angina Pectoris, Variant / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D001013:Aorta, Thoracic; D001794:Blood Pressure; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D005420:Flavoproteins / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D010084:Oxidation-Reduction; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D005420:Flavoproteins; D024661:Potassium Channels, Inwardly Rectifying; D005905:Glyburide