Calcium-dependent and calcium-sensitizing pathways in the mature and immature ductus arteriosus

Studies performed in sheep and baboons have shown that after birth, the normoxic muscle media of ductus arteriosus (DA) becomes profoundly hypoxic as it constricts and undergoes anatomic remodeling. We used isolated fetal lamb DA (pretreated with inhibitors of prostaglandin and nitric oxide production) to determine why the immature DA fails to remain tightly constricted during the hypoxic phase of remodeling. Under normoxic conditions, mature DA constricts to 70% of its maximal active tension (MAT). Half of its normoxic tension is due to Ca2+ entry through calcium L-channels and store-operated calcium (SOC) channels. The other half is independent of extracellular Ca2+ and is unaffected by inhibitors of sarcoplasmic reticulum (SR) Ca2+ release (ryanodine) or reuptake [cyclopiazonic acid (CPA)]. The mature DA relaxes slightly during hypoxia (to 60% MAT) due to decreases in calcium L-channel-mediated Ca2+ entry. Inhibitors of Rho kinase and tyrosine kinase inhibit both Ca2+-dependent and Ca2+-independent DA tension. Although Rho kinase activity may increase during gestation, immature DA develop lower tensions than mature DA, primarily because of differences in the way they process Ca2+. Calcium L-channel expression increases with advancing gestation. Under normoxic conditions, differences in calcium L-channel-mediated Ca2+ entry account for differences in tension between immature (60% MAT) and mature (70% MAT) DA. Under hypoxic conditions, differences in both calcium L-channel-dependent and calcium L-channel-independent Ca2+ entry, account for differences in tension between immature (33% MAT) and mature (60% MAT) DA. Stimulation of Ca2+ entry through reverse-mode Na+/Ca2+ exchange or CPA-induced SOC channel activity constrict the DA and eliminate differences between immature and mature DA during both hypoxia and normoxia.