Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.
The molecular bases of inwardly rectifying K(+) (Kir) currents and K(+)-induced dilations were examined in cerebral arteries of mice that lack the Kir2.1 and Kir2.2 genes. The complete absence of the open reading frame in animals homozygous for the targeted allele was confirmed. Kir2.1(-/-) animals die 8 to 12 hours after birth, apparently due to a complete cleft of the secondary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals. Voltage-dependent K(+) currents were similar in cells from neonatal control and Kir2.1(-/-) animals. An increase in the extracellular K(+) concentration from 6 to 15 mmol/L caused Ba(2+)-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animals did not dilate when the extracellular K(+) concentration was increased to 15 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries.
Zaritsky
J J
JJ
Department of Molecular and Cellular Physiology, Beckman Center, Stanford University Medical Center, CA, USA.
Eckman
D M
DM
Wellman
G C
GC
Nelson
M T
MT
Schwarz
T L
TL
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology*; D002972:Cleft Palate / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D016366:Open Reading Frames; D010641:Phenotype; D011188:Potassium / Q000494:pharmacology / Q000502:physiology*; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D014664:Vasodilation / Q000502:physiology*
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D005576:Colforsin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011188:Potassium