title: Depolarization-dependent contraction increase after birth and preservation following long-term hypoxia in sheep pulmonary arteries.
abstract: Membrane depolarization is critical to pulmonary arterial (PA) contraction. Both L-type Ca(2+) channels (Ca(L)) and Rho-kinase are important signaling components of this process and mitochondrial and non-mitochondrial generated superoxides can be part of the signaling process. Maturation and long-term hypoxia (LTH) each can modify depolarization-dependent contraction and the role of superoxides. By the use of wire myography, we tested the hypothesis that maturation and LTH increase pulmonary arterial reactivity to high-K(+)-induced membrane depolarization through enhancements in the importance of Ca(L)and Rho-kinase-dependent pathways. The data show that maturation, but not LTH, increases contraction to 125 mM KCl (high-K(+)) without altering the EC(50). High-K(+)-dependent contraction was inhibited to a similar extent in fetal and adult PA by multiple Ca(L) blockers, including 10 μM diltiazem, 10 μM verapamil, and 10 μM nifedipine. Postnatal maturation increased the role for 10 μM nifedipine-sensitive Ca(L), and decreased that for 10 μM Y-27632-sensitive Rho-kinase. In all groups, the combination of nifedipine and Y-27632 effectively inhibited high-K(+) contraction. Tempol (3 mM) but not 100 μM apocynin slightly reduced contraction in arteries from fetal hypoxic and adult normoxic and hypoxic sheep, indicating a limited role for non-mitochondrial derived superoxide to high-K(+)-induced contraction. Western immunoblot for alpha smooth muscle actin indicated small increases in relative abundance in the adult. The data suggest that while Ca(L) therapies more effectively vasodilate PA in adults and rho-kinase therapies are more effective in newborns, combination therapies would provide greater efficacy in both young and mature patients regardless of normoxic or hypoxic conditions.
authors.affiliation: Division of Pulmonary and Critical Care, University of California San Diego Health System, La Jolla, California, USA.
authors.forename: Demosthenes G
authors.initials: DG
authors.lastname: Papamatheakis
authors.forename: Jay J
authors.initials: JJ
authors.lastname: Patel
authors.forename: Quintin
authors.initials: Q
authors.lastname: Blood
authors.forename: Travis T
authors.initials: TT
authors.lastname: Merritt
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson