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 second ary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir cu rrents were observed in cerebral artery myocytes isolated from control neon atal animals but were absent in myocytes from Kir2.1(-/-)animals. Voltage-d ependent 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 Ba2+-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animal s did not dilate when the extracellular K+ concentration was increased to 1 5 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is r equired for Kir currents and Kc-induced dilations in cerebral arteries.