Selective or nonselective endothelin antagonists in porcine hypoxic pulmonary hypertension?
We evaluated the hemodynamic effects of various endothelin (ET) receptor antagonists using selective and non-selective ETA and ETB receptor blockade in hypoxic pigs in vivo. BMS-182874 (10 mg/kg i.v.) TBC-11251z (10 mg/kg i.v.), selective ETA receptor antagonists, attenuated hypoxia (FiO2 0.1)-evoked increase in pulmonary arterial pressure and pulmonary vascular resistance. Bosentan (10 mg/kg i.v.) a non-selective ETA and ETB receptor antagonist, cause essentially similar effects as ETA antagonism alone. No effects were observed after selective ETB blockade using BQ-788 (total dose 1 mg i.v.). The vasoconstrictor effect of exogenous ET was most effectively antagonized by TBC-11251z, followed by BMS-182874 and bosentan. The pulmonary vasodilator effect exerted by exogenous ET during hypoxia was reversed by BQ-788 and bosentan but not by TBC-11251z or BMS-182874. We can therefore conclude that ET contributes to hypoxic pulmonary vasoconstriction primarily through ETA receptor activation.
Franco-Cereceda
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A
Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.
Holm
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P
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013552:Swine
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B