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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

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

¹Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, and ²SRI International, Menlo Park, California

Submitted 27 April 2007 ; accepted in final form 21 July 2007

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.

normoxia; hypoxia; oxygen concentration; Y27632; tyrosine kinase; calcium channels; gestation; calcium L-channels; store-operated calcium channels; RhoA; RhoB; Rho kinase

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