Ca2+ release from ryanodine-sensitive store contributes to mechanism of hypoxic vasoconstriction in rat lungs

Abstract

Studies of thapsigargin, cyclopiazonic acid, and ryanodine in isolated pulmonary arteries and smooth muscle cells suggest that release of Ca2+ from inositol 1,4,5-trisphosphate (IP3)- and/or ryanodine-sensitive sarcoplasmic reticulum Ca2+ stores is a component of the mechanism of acute hypoxic pulmonary vasoconstriction (HPV). However, the actions of these agents on HPV in perfused lungs have not been reported. Thus we tested effects of thapsigargin and cyclopiazonic acid, inhibitors of sarcoplasmic reticulum Ca2+-ATPase, and of ryanodine, an agent that either locks the ryanodine receptor open or blocks it, on HPV in salt solution-perfused rat lungs. After inhibition of cyclooxygenase and nitric oxide synthase, thapsigargin (10 nM) and cyclopiazonic acid (5 μM) augmented the vasoconstriction to 0% but not to 3% inspired O2. Relatively high concentrations of ryanodine (100 and 300 μM) blunted HPV in nitric oxide synthase-inhibited lungs. The results indicate that release of Ca2+ from the ryanodine-sensitive, but not the IP3-sensitive, store, contributes to the mechanism of HPV in perfused rat lungs and that Ca2+-ATPase-dependent Ca2+ buffering moderates the response to severe hypoxia.