Metabolic inhibition with cyanide induces calcium release in pulmonary artery myocytes and Xenopus oocytes

Abstract

We examined the effects of metabolic inhibition on intracellular Ca2+ release in single pulmonary arterial smooth muscle cells (PASMCs). Severe metabolic inhibition with cyanide (CN, 10 mM) increased intracellular calcium concentration ([Ca2+]i) and activated Ca2+-activated Cl− currents [ICl(Ca)] in PASMCs, responses that were greatly inhibited by BAPTA-AM or caffeine. Mild metabolic inhibition with CN (1 mM) increased spontaneous transient inward currents and Ca2+ sparks in PASMCs. In Xenopus oocytes, CN also induced Ca2+ release and activated ICl(Ca), and these responses were inhibited by thapsigargin and cyclopiazonic acid to deplete sarcoplasmic reticulum (SR) Ca2+, whereas neither heparin nor anti-inositol 1,4,5-trisphosphate receptor (IP3R) antibodies affected CN responses. In both PASMCs and oocytes, CN-evoked Ca2+release was inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP) and oligomycin or CCCP and thapsigargin. Whereas hypoxic stimuli resulted in Ca2+release in pulmonary but not mesenteric artery myocytes, CN induced release in both cell types. We conclude that metabolic inhibition with CN increases [Ca2+]i in both pulmonary and systemic artery myocytes by stimulating Ca2+ release from the SR and mitochondria.