Preferential Expression and Function of Voltage-Gated, O 2 -Sensitive K + Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction: Ionic Diversity in Smooth Muscle Cells

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O 2 -sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E M ), thereby activating Ca 2+ influx via voltage-gated Ca 2+ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O 2 -sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kv-inhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K + current (I K ) and a more hyperpolarized E M and were uniquely O 2 − and correolide-sensitive. The O 2 -sensitive current (active at −65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I K 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide’s effects. The hypoxia-sensitive, correolide-insensitive I K (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5>Kv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O 2 − and correolide-sensitive I K like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O 2 -sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O 2 -sensitive Kv-channels.