Role of reverse‐mode sodium‐calcium exchange to serotonergic contractility in pulmonary arteries of hypoxic sheep

Abstract

Serotonin (5HT) is a prominent vasoactive substance in the lung with increases in intracellular Ca2+ being important to 5HT elicited pulmonary arterial (PA) contractility. L‐type Ca2+ channel (CaL) activation concomitant with membrane depolarization contributes significantly to 5HT dependent PA contractility and Ca2+ signaling. Chronic hypoxia (CH) is a risk factor in the development of pulmonary hypertension (PH) and we find CH reduced the role for CaL during 5HT‐mediated contractility in PA from fetal sheep, even though the contractility was unchanged when normalized to 125 mM KCl. Evidence indicates membrane depolarization sufficient to activate CaL will also shift the sodium‐calcium exchanger (NCX) into “reverse‐mode”, which would augment extracellular Ca2+ entry. Using wire‐myography on endothelium‐denuded PA rings from CH fetal and adult sheep, we tested the hypothesis that CH reduces “reverse‐mode” NCX in PA from fetus. PA rings were stimulated with 10 ?M 5HT and reverse mode NCX selectively inhibited with 10 ?M KB‐R 7943. In adult, 10 ?M KB‐R 7943 reduced 5HT‐elecited PA contractility to 76 ± 7 % of control while in fetal there was no affect on 5HT‐mediated PA contractility, being 97 ± 7 % of control. This work provides evidence that CH reduces “reverse‐mode” NCX activity in PA of fetal sheep, suggesting this process may contribute to CH‐related vascular dysfunction in newborn. (Support from NIH, NSF and UM)