Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study.
The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.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 O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa 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 Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) 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.
Tjen-A-Looi
S
S
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison 53706, USA.
Ekman
R
R
Osborn
J
J
Keith
I
I
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000378:metabolism; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000276:immunology / Q000494:pharmacology*; D006400:Hematocrit; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D007106:Immune Sera / Q000494:pharmacology; D008137:Longitudinal Studies; D008168:Lung / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007106:Immune Sera; D010456:Peptides, Cyclic; D015740:Calcitonin Gene-Related Peptide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)