We studied the roles of endothelins in determining ventilation (VA) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a non-specific endothelin antagonist, Tezosentan. Nine anaesthetized piglets (~23 Kg) received autologous clots (~20 gm) via a central venous catheter at time = 0 mins. The distribution of VA and Q at 5 different time points (-30, -5, 30, 60, 120 mins) was mapped by fluorescent microspheres of 10 different colors. 5 piglets (Group 1) received Tezosentan (courtesy Actelion Ltd) starting at time = 40 mins for 2 hours and 4 piglets (Group 2) received only saline and served as control. Our results showed that in all of the animals at 30 mins following APTE but prior to Tezosentan, the mean VA/Q was increased as did VA/Q heterogeneity (Log SD VA/Q), which represented a widening of its main peak. Afterwards Tezosentan attenuated the pulmonary hypertension in Group 1 but also produced moderate systemic hypotension. However, it did not improve PaO2 or VA/Q mismatch. We concluded that endothelins had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high VA/Q regions. Key words: Fluorescent microspheres, Regional ventilation, Regional blood flow, Gas exchange.