RyR function in sheep pulmonary arteries is differentially influenced by postnatal maturation and chronic hypoxia

Abstract

Ryanodine receptors (RYR) and associated Ca2+ spark events are important to pulmonary arterial (PA) tone with potential differences in their role in fetuses as compared to adults. RyRs are implicated in hypoxic pulmonary vasoconstriction (HPV) and ET‐1 dependent contractility. Evidence also indicates HPV and PA tone are dysregulated by chronic hypoxia (CH) in fetuses and adults, and yet their combined influence on Ca2+ sparks and the relationship to PA tone is not known. We therefore tested the hypotheses that Ca2+ sparks are restricted before birth and that CH augments their function. These hypotheses were tested on PA from near term fetal sheep or adult ewes at low altitude or following 100+ days at 3801 m (CH). Ca2+ sparks were measured in fluo‐4 loaded PA strips while myography was performed on isolated PA rings. Ca2+ spark activity was far greater in adults relative to fetuses while CH accentuated spark activity in both groups. Selective RyR1 inhibition with 10 μM dantrolene (DAN) reduced spark activity in normoxic and CH fetuses and in normoxic but not CH adults, where 10 μM ryanodine (RY) restricted spark activity. Interestingly, DAN but not RY moderately reduced serotonin (5‐HT) mediated PA contraction in CH fetuses and adults. Overall, RyR function appears developmentally regulated and augmented by CH, and RyR function has modest influence on 5‐HT dependent contractility. NIH P01HD031226, R01HD003807 (LDL)