Thromboxane mediation of cardiopulmonary effects of embolism

Abstract

Humoral factors released from platelets during pulmonary embolism may be the cause of several attendent cardiopulmonary abnormalities. This study examines the role of thromboxanes (Tx) after experimental embolism induced with 0.5 g/kg autologous clot in four groups of five dogs: (a) untreated embolized controls; (b) pretreatment with the Tx synthetase inhibitor, imidazole 25 mg/kg . h i.v., starting 30 min before embolization; (c) pretreatment with the clycooxygenase inhibitor indomethacin, 5 mg/kg, 12 h per os and 1 mg/kg, 1 h i.v. before the experiment; (d) treatment with prostacyclin (PGI2) 100 ηg/kg . min i.v. for 1 h, 1 h after embolization. Within 30 min, embolization led to increases of 6-keto-PGF(1α), the stable hydrolosis product of PGI2, from 0.11±0.08 ηg/ml (mean±SD) to 0.33±0.10 ηg/ml (P < 0.005) and TxB2, the stable product of TxA2, from 0.10±0.04 ηg/ml to 0.38±0.06 ηg/ml (P < 0.001). Increases were observed in total dead space V(D)/V(T) from 0.46±0.03 to 0.61±0.08 (P < 0.025, physiologic shunting (Q(S)/Q(T)) from 16±4% to 38±9% (P < 0.01), pulmonary vascular resistance (PVR) from 2.27±0.59 mm Hg . min/liter to 9.21±1.90 mm Hg . min/liter (P < 0.005) and mean pulmonary arterial pressure from 14±6 mm Hg to 34±1 mm Hg (P < 0.001). Cardiac index (CI) fell from 139±11 ml/kg . min to 95±17 ml/kg . min in 4 h (P < 0.025). Imidazole pretreatment prevented a rise of TxB2, but not 6-keto-PGF(1α); indomethacin blocked both. Both agents maintained V(D)/V(T) at base line and limited increases in Q(S)/Q(T) and PVR. CI was higher after imidazole pretreatemnt compared with controls (P < 0.025). Indomethacin led to intermediate levels of CI. PGI2 lowered TxB2 (P < 0.025), V(D)/V(T) (P < 0.025), Q(S)/Q(T) (P < 0.025) and PVR (P < 0.05) within 30 min. During PGI2 infusion, CI was higher than controls. Concentrations of TxB2 correlated with V(D)/V(T), r = 0.79 and Q(S)/Q(T), r = 0.69 (P < 0.001). Treatment of three dogs with the imidazole derivative ketoconazole, 10 mg/kg IV, 30 min after 0.75 g/kg autologous clot resulted in a lowering of physiologic dead space, but no other improvement of cardiopulmonary function. These results show that a number of cardiopulmonary abnormalities induced by pulmonary embolism are related directly or indirectly to platelet secretions and that V(D)/V(T) is closely allied to TxA2 levels.