Premium
Synergism between Ca 2+ and Rho‐kinase signaling during pulmonary arterial vasoconstriction in chronic hypoxic newborn lamb
Author(s) -
Papamatheakis Demosthenes G,
Vemulakonda Srilakshmi,
Merritt Travis,
Longo Lawrence D.,
Blood Arlin B.,
Wilson Sean M.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.16
Subject(s) - fasudil , rho associated protein kinase , myosin light chain kinase , contractility , nifedipine , vasoconstriction , chemistry , hypoxic pulmonary vasoconstriction , medicine , endocrinology , myosin , kinase , pharmacology , calcium , biochemistry
Pulmonary artery (PA) contractility is mediated in large part by increases in cytosolic Ca 2+ , which activates myosin light chain (MLC) kinase and in turn phosphorylates myosin light chain 20 (MLC 20 ). Rho‐kinase further enhances phosphorylation of MLC 20 and contractility through inhibition of MLC phosphatase. We hypothesized that Ca 2+ and Rho‐kinase signaling synergistically regulate pulmonary vascular tone in chronically hypoxic (CH) newborn lambs. This hypothesis was tested by performing wire myography on serotonin (5‐HT) stimulated PA rings isolated from 12 to 17 day old lambs maintained at high altitude (3801 m) for the final 100 days of gestation and after birth (CH). 5‐HT elicited dose‐dependent contractions were attenuated with various Ca 2+ entry or Rho‐kinase blockers. Voltage dependent and independent Ca 2+ entry was inhibited with 30 μM KB‐R7943 (KBR), 100 μM flufenamate (FFA), 30 μM SN‐6, or 10 μM nifedipine (NIF) in the absence or presence of 50 μM SKF‐96365 (SKF). Rho‐kinase was inhibited with 10 μM fasudil or Y27632. The potency order for the Ca 2+ entry antagonists was KBR ≥ NIF+SKF ≫ NIF > FFA ≫ SN‐6, whileY27632 > fasudil. Fasudil substantially augmented the inhibitory action of the Ca 2+ entry blockers. These findings support the rationale for treating pulmonary hypertension with medications that target both Ca 2+ and Rho‐kinase pathways. NIH P01HD031226, R01HD003807 (LDL), R01HL95973 (AB)