title: 2-AMINOETHYLDIPHENYLBORINATE MODIFIES THE PULMONARY CIRCULATION IN PULMONARY HYPERTENSIVE NEWBORN LAMBS WITH PARTIAL GESTATION AT HIGH ALTITUDE.
abstract: Calcium signaling through store operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, 6 of them received a 2-APB treatment and the other 6 received vehicle treatment, for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure at the third and tenth days, cardiac output between the fourth and eighth days, and pulmonary vascular resistance at the tenth day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-Br-cGMP. The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin and the percentage of Ki67+ nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension, however, further testing of specific blockers is needed.
authors.affiliation: Universidad de Chile, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM).
authors.forename: Sebastián
authors.initials: S
authors.lastname: Castillo-Galán
authors.affiliation: Universidad de Chile, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM).
authors.forename: Sebastián
authors.initials: S
authors.lastname: Quezada
authors.affiliation: Universidad Católica del Norte.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Moraga
authors.affiliation: Facultad de Medicina, Universidad de Chile, Instituto de Ciencias Biomédicas (ICBM), Santiago, Chile.
authors.forename: Germán
authors.initials: G
authors.lastname: Ebensperger
authors.affiliation: Facultad de Medicina, Universidad de Chile.
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Herrera
authors.affiliation: Facultad de Medicina, Universidad de Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Beñaldo
authors.affiliation: Facultad de Medicina, Universidad de Chile, Instituto de Ciencias Biomédicas (ICBM), Santiago, Chile.
authors.forename: Ismael
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Facultad de Medicina, Universidad de Chile, Instituto de Ciencias Biomédicas (ICBM), Santiago, Chile.
authors.forename: Renato
authors.initials: R
authors.lastname: Ebensperger
authors.affiliation: Facultad de Medicina, Universidad de Chile, Instituto de Ciencias Biomédicas (ICBM), Santiago, Chile.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramirez
authors.affiliation: Facultad de Medicina, Universidad de Chile.
authors.forename: Anibal J
authors.initials: AJ
authors.lastname: Llanos
authors.affiliation: Universidad de Chile, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM) vicreyes@med.uchile.cl.
authors.forename: Roberto V
authors.initials: RV
authors.lastname: Reyes
keywords: 2-aminoethyldiophenylborinate; Hypoxia; Neonatal pulmonary hypertension; pulmonary artery remodeling