Ca2+ responses of pulmonary arterial myocytes to acute hypoxia require release from ryanodine and inositol trisphosphate receptors in sarcoplasmic reticulum.

In pulmonary arterial smooth muscle cells (PASMC), acute hypoxia increases intracellular Ca(2+) concentration ([Ca(2+)](i)) by inducing Ca(2+) release from the sarcoplasmic reticulum (SR) and Ca(2+) influx through store- and voltage-operated Ca(2+) channels in sarcolemma. To evaluate the mechanisms of hypoxic Ca(2+) release, we measured [Ca(2+)](i) with fluorescent microscopy in primary cultures of rat distal PASMC. In cells perfused with Ca(2+)-free Krebs Ringer bicarbonate solution (KRBS), brief exposures to caffeine (30 mM) and norepinephrine (300 μM), which activate SR ryanodine and inositol trisphosphate receptors (RyR, IP(3)R), respectively, or 4% O(2) caused rapid transient increases in [Ca(2+)](i), indicating intracellular Ca(2+) release. Preexposure of these cells to caffeine, norepinephrine, or the SR Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA; 10 μM) blocked subsequent Ca(2+) release to caffeine, norepinephrine, and hypoxia. The RyR antagonist ryanodine (10 μM) blocked Ca(2+) release to caffeine and hypoxia but not norepinephrine. The IP(3)R antagonist xestospongin C (XeC, 0.1 μM) blocked Ca(2+) release to norepinephrine and hypoxia but not caffeine. In PASMC perfused with normal KRBS, acute hypoxia caused a sustained increase in [Ca(2+)](i) that was abolished by ryanodine or XeC. These results suggest that in rat distal PASMC 1) the initial increase in [Ca(2+)](i) induced by hypoxia, as well as the subsequent Ca(2+) influx that sustained this increase, required release of Ca(2+) from both RyR and IP(3)R, and 2) the SR Ca(2+) stores accessed by RyR, IP(3)R, and hypoxia functioned as a common store, which was replenished by a CPA-inhibitable Ca(2+)-ATPase.
AuthorsJian Wang, Larissa A Shimoda, J T Sylvester
JournalAmerican journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 2 Pg. L161-8 (Jul 2012) ISSN: 1522-1504 [Electronic] United States
PMID22582116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Indoles
  • Inositol 1,4,5-Trisphosphate Receptors
  • Macrocyclic Compounds
  • Oxazoles
  • Ryanodine Receptor Calcium Release Channel
  • xestospongin C
  • Ryanodine
  • Caffeine
  • Calcium-Transporting ATPases
  • Calcium
  • Norepinephrine
  • cyclopiazonic acid
  • Animals
  • Caffeine (pharmacology)
  • Calcium (physiology)
  • Calcium Channel Agonists (pharmacology)
  • Calcium Channel Blockers (pharmacology)
  • Calcium Signaling
  • Calcium-Transporting ATPases (antagonists & inhibitors, metabolism)
  • Cell Hypoxia
  • Cells, Cultured
  • Indoles (pharmacology)
  • Inositol 1,4,5-Trisphosphate Receptors (agonists, antagonists & inhibitors, metabolism)
  • Macrocyclic Compounds (pharmacology)
  • Male
  • Myocytes, Smooth Muscle (drug effects, metabolism, physiology)
  • Norepinephrine (pharmacology)
  • Oxazoles (pharmacology)
  • Pulmonary Artery (cytology)
  • Rats
  • Rats, Wistar
  • Ryanodine (pharmacology)
  • Ryanodine Receptor Calcium Release Channel (metabolism)
  • Sarcoplasmic Reticulum (drug effects, metabolism)

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