Hypoxic pulmonary endothelial cells release a diffusible contractile factor distinct from endothelin.
Hypoxia (0% O2) evokes a late-phase, endothelium-dependent contractile response in porcine isolated pulmonary arteries that may be caused by a cyclooxygenase-independent, endothelium-derived contractile factor. The aim of this study was to further analyze the mechanism underlying this hypoxic response. Proximal porcine pulmonary arterial rings were suspended for isometric tension recording in organ chambers. Hypoxia (0% O2) caused a late-phase, endothelium-dependent contractile response that was not inhibited by the endothelin (ET)A-receptor antagonist BQ-123 (10(-6) M), by the ETB-receptor antagonist BQ-788 (10(-7) M), or by their combination. In contrast, ET-1 caused a concentration-dependent contraction of arterial rings that was inhibited by BQ-123 (10(-6) M) and a relaxation that was abolished by BQ-788 (10(-7) M) or by endothelial cell removal. Therefore, the endothelium-dependent contraction to hypoxia is not mediated by ET. Hypoxia caused only relaxation in endothelium-denuded rings. However, when a pulmonary valve leaflet, a rich source of pulmonary endothelial cells, was placed into the lumen of endothelium-denuded rings, hypoxia caused a late-phase contractile response that was similar to that observed in arterial rings with native endothelium. This hypoxic contraction persisted in the presence of indomethacin (10(-5) M) and N-nitro-L-arginine methyl ester (3 x 10(-5) M) to block cyclooxygenase and nitric oxide synthase, respectively. These results suggest that hypoxic contraction of pulmonary arteries is mediated by a diffusible, contractile factor released from hypoxic endothelial cells. This contractile mediator is distinct from ET.
Gaine
S P
SP
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Hales
M A
MA
Flavahan
N A
NA
D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011664:Pulmonary Valve / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins