Role of calcium to serotonergic mediated contractility in ovine pulmonary arteries: effects of maturation and chronic hypoxia

Abstract

Serotonin (5‐HT) is implicated in idiopathic and hypoxic stress induced pulmonary hypertension (PH) in adult and newborn. However, voltage‐gated L‐type Ca2+ channel (CaL) antagonists are not effective in the treatment of PH. The hypothesis that Ca2+ dependent pulmonary arterial (PA) contractility is reduced with chronic hypoxic (CH) stress and enhanced with maturation was tested by performing wire myography on PA isolated from fetal and adult sheep that were either normoxic or maintained under CH stress. Arterial segments were exposed to blockers of L‐type calcium channels (CaL, 10 μM nifedipine), non selective cation channels (NSCC, 50 μM SKF96365) and IP3 receptors (50 μM 2‐APB) in an additive manner during 10–100 μM 5‐HT elicited contractility. The contribution of CaL and NSCC to 5‐HT elicited contraction increased with maturation and decreased with CH while IP3 mediated contractility was unchanged. As a whole, Ca2+ dependent contractility increased with maturation and decreased with CH, implicating alterations in the pathways that sensitize contractile proteins to elevations in cytosolic Ca2+. CH mediated increases in Ca2+ independent contractility were greatest in adult, possibly because the fetus is under relative hypoxic stress. These dramatic changes in 5‐HT mediated contractility with CH may contribute to vascular reactivity disorders such as PH. (Support from NIH, Sigma Xi and UM)