Hypoxic and metabolic regulation of voltage‐gated K+ channels in rat pulmonary artery smooth muscle cells

XJ Yuan, ML Tod, LJ Rubin, MP Blaustein

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Inhibition of voltage‐gated K+ (Kv) channels by 4‐aminopyridine (4‐AP) depolarizes pulmonary artery (PA) smooth muscle cells, induces Ca(2+)‐dependent action potentials and increases [Ca2+]i. Neither charybdotoxin, which blocks Ca(2+)‐activated K+ channels, nor glibenclamide, which blocks ATP‐sensitive K+ channels, has such effects on membrane potential (Em) and [Ca2+]i. Hypoxia reversibly decreases the 4‐AP‐sensitive KV currents (IK(V)) in PA myocytes. The resulting membrane depolarization caused by decreased IK(V) induces Ca(2+)‐dependent action potentials and thereby raises [Ca2+]i. Thus, KV channel activity plays a critical role in: (a) regulating Em and [Ca2+]i under physiological conditions; and (b) sensing O2 alteration and transducing the hypoxic stimulus to changes of Em and [Ca2+]i. The metabolic inhibitors 2‐deoxy‐D‐glucose (2‐DOG; 10 mM) and carbonyl cyanide‐p‐trifluoromethoxyphenyl‐hydrazone (FCCP; 3‐5 microM), the reducing agent reduced glutathione and inhibitors of cytochrome P‐450, all mimic the effects of hypoxia on IK(V) and Em in PA myocytes. Furthermore, hypoxia and 2‐DOG negligibly affect IK(V) and Em in mesenteric artery smooth muscle cells. These results suggest that hypoxia, perhaps via a localized reduction of ATP, triggers the block of KV channels and depolarizes PA myocytes. This blockade may also be mediated by a change in cellular redox status, perhaps via a conformational change of a haem‐ (or metal‐) containing regulatory moiety that is attached to the channel protein.

Original languageEnglish (US)
Pages (from-to)803-813
Number of pages11
JournalExperimental physiology
Volume80
Issue number5
DOIs
StatePublished - Sep 1 1995

ASJC Scopus subject areas

  • Physiology
  • Nutrition and Dietetics
  • Physiology (medical)

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