Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage-gated potassium channel Kv1.5
Abstract
Hypoxic pulmonary vasoconstriction (HPV) is initiated by the inhibition of several 4-aminopyridine (4-AP)-sensitive, voltage-gated, K+ channels (Kv). Several O-2-sensitive candidate channels (Kv1.2, Kv1.5, Kv2.1, and Kv3.1b) have been proposed, based on similarities between their characteristics in expression systems and the properties of the O-2-sensitive K+ current (I-K) in pulmonary artery smooth muscle cells (PASMCs).
We used gene targeting to delete Kv1.5 in mice by creating a SWAP mouse that is functionally a Kv1.5 knockout. We hypothesized that SWAP mice would display impaired HPV.
The Kv1.5 alpha -subunits present in the endothelium and PASMCs of wild-type mice were absent in the lungs of SWAP mice, whereas expression of other channels Kv (1.1, 1.2, 2.1, 3.1, 4.3), Kir 3.1, Kir 6.1, and BKCa was unaltered. In isolated lungs and resistance PA rings, HPV was reduced significantly in SWAP versus wild-type mice.
Consistent with this finding, PASMCs from SWAP PAs were slightly depolarized and lacked I-Kv1.5, a 4-AP and hypoxia-sensitive component of I-K that activated between -50 mV and -30 mV. We conclude that a K+ channel containing Kv1.5 alpha -subunits is an important effector of HPV in mice.