Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study
Tjen-A-Looi, S.; Ekman, R.; Osborn, J.; Keith, I.
American Journal of Physiology 271(6 Pt 2): H2246-H2253
1996
ISSN/ISBN: 0002-9513 PMID: 8997280 Document Number: 461630
The role of endothelin (ET)-1 in pulmonary arterial pressure (P-pa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol cntdot kg-1-min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O-2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS- 0.25 and 0.5 mu-l cntdot rat -1 cntdot h-1, cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol cntdot kg-1 cntdot min-1). ET-1 (4 pmol) increased P-pa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic P-pa rise at all times, confirming a role for ET-A receptors. ET-AS (0.5 mu-l) was mostly ineffective but exacerbated hypoxic P-pa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (12 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 mu-l) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.