Haemodynamic influence and endothelin-1 plasma concentrations by selective or non-selective endothelin receptor antagonists in the pig in vivo.
In the present study the haemodynamical effects of endothelin (ET)-receptor antagonism was evaluated using selective and non-selective ET(A)- and ET(B)-receptor blockade in normoxic pigs in vivo. In addition, the influence of the ET-antagonists on circulating plasma ET-1 levels was determined. BMS-182874 (10 and 30 mg kg(-1) i.v.), a selective ET(A)-receptor antagonist decreased the pulmonary and systemic vascular resistances. bosentan (10 and 30 mg(-1) i.v.), a non-selective ET(A)- and ET(B)-receptor antagonist caused principally similar effects as ETA-antagonism alone. No effects were observed by selective ET(B)-blockade using BQ-788 (30 microg kg(-1) i.v.). Of the three antagonists used only bosentan increased the circulating plasma ET-1 levels. It may therefore be concluded that ET contributes to basal systemic and pulmonary vascular tone through ET(A)-receptor activation. ET(B)-receptors are likely to cause the elevated plasma levels of ET-1 observed after bosentan administration. Furthermore, circulating plasma levels of ET-1 do not reflect the physiological effects of ET-1.
Holm
P
P
Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.
Franco-Cereceda
A
A
D000818:Animals; D000077300:Bosentan; D003619:Dansyl Compounds / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011863:Radioimmunoassay; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine
D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; C086539:BQ 788; D000077300:Bosentan