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Cyclic Nucleotides Reduce Ryanodine Receptor Mediated Ca 2+ Spark Activation Independent of Long Term Hypoxia in Ovine Fetal Pulmonary Arterial Myocytes
Author(s) -
Guerrero Maria,
Hough Steven,
Romero Monica,
Puglisi Jose,
Zhang Lubo,
Wilson Sean M.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.892.8
Subject(s) - ryanodine receptor , medicine , myocyte , endocrinology , ryanodine receptor 2 , chemistry , biology , calcium
Ryanodine receptors (RyR) release Ca 2+ from smooth muscle sarcoplasmic reticulum in rapid events known as Ca 2+ sparks. These Ca 2+ sparks activate voltage and Ca 2+ gated potassium channels (BK channels) that cause cell repolarization. Ca 2+ spark‐BK channel mediated cell repolarization dilates many types of vessels and is essential to pulmonary arterial (PA) vasodilation during the fetal transition to breathing air. Infants who do not successfully negotiate this transition are at risk of developing pulmonary hypertension, which has significant morbidity and mortality. Previous work shows that long term hypoxia (LTH) decreases Ca 2+ spark events in fetal pulmonary arterial smooth muscle cells (PASMCs) even though the Ca 2+ stores have functional RyRs. Additional studies illustrate that cyclic nucleotides can increase RyR activity, which led us to test the hypothesis that cyclic nucleotides could rescue RyR activity in myocytes of LTH fetuses. This was examined by treating PAs isolated from low (700m; LA) and high altitude (3801m; HA) near‐term fetal sheep with exogenous cyclic AMP (cAMP) and cyclic GMP (cGMP) or the methylxanthine IBMX, a non‐specific cAMP and cGMP phosphodiesterase inhibitor. RyR activity was measured by confocal imaging of Ca 2+ sparks in fluo‐4 labeled PASMCs. The spatial and temporal aspects to the Ca 2+ sparks were evaluated using SparkLab, a custom software package. Contrary to our hypothesis, the prevalence of Ca 2+ sparks decreased in the presence of cAMP, cGMP, and IBMX for PASMC from both LA and HA fetal sheep. These data suggest that cyclic nucleotides reduce instead of increase vasodilatory capacity via RyR‐BK channel coupling mechanisms. Furthermore, increased cyclic nucleotides had no effect on the spatial‐temporal aspects to the Ca 2+ sparks. Even though the signaling pathway remains unclear, the reduction of Ca 2+ sparks by cyclic nucleotides is potentially a novel mechanism of RyR modulation in sheep fetal PASMC. This data suggests that increasing cyclic nucleotides may be contra‐indicated in newborn infants who are at risk of developing pulmonary hypertension. Support or Funding Information This work is supported by The National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development grant number HD083132, by the National Science Foundation under Grant No. MRI 0923559, and the Loma Linda University School of Medicine. SH was a Loma Linda University Summer Undergraduate Research Fellow. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .