Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage-gated potassium channel Kv1.5.

Abstract

SPECIFIC AIMSHypoxic pulmonary vasoconstriction (HPV), a vasomotor mechanism that matches regional perfusion to ventilation, is initiated by the inhibition of 4-aminopyridine (4-AP) -sensitive, voltage-gated, potassium channels (Kv), resulting in membrane depolarization, opening of voltage-gated calcium channels, and vasoconstriction. We used gene targeting to create mice lacking a candidate O2-sensitive channel, Kv1.5, to evaluate the hypothesis that loss of Kv1.5 would impair HPV.PRINCIPAL FINDINGS1. Gene targeting selectively deleted Kv1.5 channelsThe 4-AP-sensitive mouse K + channel gene mKv1.5 was cloned and a targeting construct was engineered by Barry London. The construct consisted of a 5′ arm of the promoter and 5′UTR of mKv1.5, the rat Kv1.1 K + channel (rKv1.1) tagged with the 9 amino acid hemagglutinin tag (HA) and cloned into the SMAI site of mKv1.5 located at position −6, a neomycin resistance cassette (NeoR), mKv1.5 starting at an XbaI site in the 3′UTR, and the thymidine kinase gene for ne...