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cGMP amplification of pulmonary arterial myocyte Ca 2+ waves is preferentially impaired in high altitude‐induced hypoxic fetal sheep (1089.7)
Author(s) -
Paez Ricardo,
Romero Monica,
Blood Quintin,
Osman Noah,
Manjunath Chetas,
Glasgow Shane,
Francis Michael,
Taylor Mark,
Longo Lawerence,
Wilson Sean
Publication year - 2014
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.28.1_supplement.1089.7
Subject(s) - medicine , endocrinology , serca , ryanodine receptor , myocyte , ibmx , chemistry , endoplasmic reticulum , fetus , biology , calcium , forskolin , receptor , atpase , biochemistry , enzyme , pregnancy , genetics
High altitude is a risk factor in the development of pulmonary hypertension (PH). Treatment often includes the use of phosphodiesterase (PDE) inhibitors of PDE3 (milrinone, cAMP) and PDE5 (sildenafil, cGMP), which increase cyclic nucleotides and promotes vasodilation in pulmonary arterial (PA) myocytes. With respect to the current studies, c‐AMP and c‐GMP enhance ryanodine receptor (RyR) and Sarco/Endoplasmic Reticulum Ca 2+ ‐ATPase (SERCA) pump activity in myocytes, which regulate intracellular Ca 2+ . To test whether long term hypoxia (LTH) impairs, and maturity enhances the effects of c‐AMP and c‐GMP on myocyte Ca 2+ waves, we selected 3‐isobutyl‐1‐methyl xanthine (IBMX), a PDE inhibitor, as well as 8‐Br‐c‐AMP and 8‐Br‐c‐GMP. We measured cytosolic Ca 2+ in PA myocytes of fetal and adult sheep that lived at low (~353 m) or high altitude (~3801 m) via confocal imaging of fluo‐4. Maturation increased while IBMX, 8‐Br‐c‐AMP, and 8‐Br‐c‐GMP each failed to alter the percentage of responsive cells independent of altitude. LTH fetuses had reduced wave amplitude and area under the curve (AUC), but wave kinetics were unaltered. The AUC was maintained in LTH adults, but waves were faster and larger. c‐GMP increased AUC by lengthening waves in all groups except for hypoxic fetuses. Alterations of Ca 2+ regulatory pathways including SERCAs and RyRs could contribute to LTH impairment in Ca 2+ waves and c‐GMP amplified signals. Grant Funding Source : Supported by NSF MRI 0923559, NIH HD‐069746, P01HD031226, , R01HD003807, 5P20 MD‐006988,LLUSOM