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In utero hypoxia augments hypoxic pulmonary vasoconstriction in newborn lamb
Author(s) -
Wilson Sean M,
Papamatheakis Demosthenes G,
Terry Michael R,
Merritt Travis,
MerrillHenry Jeanette,
Schroeder Hobe,
Longo Lawrence D,
Blood Arlin B
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.1023.15
Subject(s) - fasudil , hypoxic pulmonary vasoconstriction , pulmonary hypertension , hypoxia (environmental) , rho associated protein kinase , medicine , in utero , vasoconstriction , pulmonary artery , rho kinase inhibitor , endocrinology , fetus , kinase , pregnancy , chemistry , biology , oxygen , biochemistry , organic chemistry , genetics
Chronic hypoxia (CH) is a risk factor in the development of pulmonary hypertension (PH) and recent evidence shows in utero hypoxic stress alters pulmonary structure and function in fetal lambs. Yet, it is unknown whether gestational CH causes pulmonary hypertension in newborn lambs. Reports also indicate Rho‐kinase pathways hold therapeutic promise for the treatment of pulmonary hypertension. Thus, we tested the hypotheses that in utero CH would increase pulmonary arterial pressure (PAP) and that Rho‐kinase inhibition would reduce PH caused by hypoxia. These hypotheses were tested on 12 to 17 day old lambs born at low altitude (LA) or following 100+ days of in utero and postnatal high altitude exposure (HA) at 3801 m. Pulmonary and systemic arterial pressures were measured on anesthetized and ventilated lambs and myography performed on isolated pulmonary arteries (PA). HA did not change baseline PAP, however it significantly augmented hypoxic pulmonary vasoconstriction (HPV). Rho‐kinase inhibition with 2 mg/kg fasudil (intravenous) reduced PAP and blunted HPV in both LA and HA lambs. Rho‐kinase inhibition with 10 μM fasudil or Y27632 also attenuated serotonin mediated PA contractility. Augmentation of HPV in HA lambs and alleviation by fasudil supports the relevance of Rho‐kinase pathways in the treatment of PH in newborns. NIH P01HD031226, R01HD003807 (LDL), R01HL95973 (AB)