Ca(2+) release from ryanodine-sensitive store contributes to mechanism of hypoxic vasoconstriction in rat lungs.
Studies of thapsigargin, cyclopiazonic acid, and ryanodine in isolated pulmonary arteries and smooth muscle cells suggest that release of Ca(2+) from inositol 1,4,5-trisphosphate (IP(3))- and/or ryanodine-sensitive sarcoplasmic reticulum Ca(2+) 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 Ca(2+)-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 microM) augmented the vasoconstriction to 0% but not to 3% inspired O(2). Relatively high concentrations of ryanodine (100 and 300 microM) blunted HPV in nitric oxide synthase-inhibited lungs. The results indicate that release of Ca(2+) from the ryanodine-sensitive, but not the IP(3)-sensitive, store, contributes to the mechanism of HPV in perfused rat lungs and that Ca(2+)-ATPase-dependent Ca(2+) buffering moderates the response to severe hypoxia.
Morio
Yoshiteru
Y
Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. yoshiteru.morio@uchsc.edi
McMurtry
Ivan F
IF
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D004791:Enzyme Inhibitors; D007211:Indoles; D012433:Ryanodine; D019335:Nitroarginine; D019284:Thapsigargin; D019001:Nitric Oxide Synthase; D002118:Calcium; C000543:cyclopiazonic acid