The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs

Frontiers in Physiology

Rodrigo Iturriaga¹  Marcela Díaz²  Aníbal J. Llanos³  Germán Ebensperger³  Roberto V. Reyes³  Emilio A. Herrera³  Fernando A. Moraga⁴  Sebastián Castillo-Galán⁵  Sebastián Quezada⁶  Daniela Parrau⁷  Ismael Hernández⁷ 

[1] Centro de Excelencia en Biomedicina de Magallanes, Universidad de Magallanes, Punta Arenas, Chile;Departamento de Promoción de la Salud de la Mujer y el Recién Nacido, Facultad de Medicina, Universidad de Chile, Santiago, Chile;International Center for Andean Studies, Universidad de Chile, Santiago, Chile;Laboratorio de Fisiología, Hipoxia y Función Vascular, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile;Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile;School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia;Unidad de Fisiología y Fisiopatología Perinatal, Programa de Fisiopatología, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile;

关键词: neonatal pulmonary hypertension;    hypoxia;    high altitude;    2-APB;    store operated channels;   

DOI  :  10.3389/fphys.2021.765281

来源: DOAJ

【 摘 要 】

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg–1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.

【 授权许可】

Unknown