Preferential expression and function of voltage-gated, O2-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 O2-sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E(M)), thereby activating Ca2+ influx via voltage-gated Ca2+ 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 O2-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 O2- and correolide-sensitive. The O2-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 O2- and correolide-sensitive I(K) like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O2-sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O2-sensitive Kv-channels.

• Authors: Stephen L Archer, Xi-Chen Wu, Bernard Thébaud, Ali Nsair, Sebastien Bonnet, Ben Tyrrell, M Sean McMurtry, Kyoko Hashimoto, Gwyneth Harry, Evangelos D Michelakis
• Journal: Circulation research (Circ Res) Vol. 95 Issue 3 Pg. 308-18 (Aug 06 2004) ISSN: 1524-4571 [Electronic] United States
• PMID: 15217912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• KCNA5 protein, human
• Kcna5 protein, rat
• Kcnb1 protein, rat
• Kv1.5 Potassium Channel
• Peptides
• Potassium Channels, Voltage-Gated
• Recombinant Fusion Proteins
• Scorpion Venoms
• Shab Potassium Channels
• Triterpenes
• correolide
• tityustoxin
• iberiotoxin
• 4-Aminopyridine
• Acetylcholine
• Potassium
• Oxygen

Topics

• 4-Aminopyridine (pharmacology)
• Acetylcholine (pharmacology)
• Animals
• Cell Hypoxia
• Cells, Cultured (drug effects, physiology)
• Gene Expression Regulation
• Humans
• Hypoxia (physiopathology)
• Ion Channel Gating (drug effects)
• Ion Transport (drug effects)
• Kv1.5 Potassium Channel
• Male
• Membrane Potentials (drug effects)
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (drug effects, physiology)
• Oxygen (pharmacology)
• Patch-Clamp Techniques
• Peptides (pharmacology)
• Potassium (metabolism)
• Potassium Channels, Voltage-Gated (biosynthesis, genetics, physiology)
• Pulmonary Artery (pathology)
• Pulmonary Circulation (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (physiology)
• Scorpion Venoms (pharmacology)
• Shab Potassium Channels
• Transduction, Genetic
• Triterpenes (pharmacology)
• Vascular Resistance (drug effects, physiology)
• Vasoconstriction (drug effects, physiology)