A B S T R A C T Humoral factors released from platelets during pulmonary embolism may be the cause of several attendant 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 cyclooxygenase 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 qg/kg. min i.v. for 1 h, 1 h after embolization. Within 30 min, embolization led to increases of 6-keto-PGF,a, the stable hydrolysis product of PGI2, from 0.11±0.08 ng/ml (mean±SD) to 0.33±0.10 7g/ml (P < 0.005) and TxB2, the stable product of TxA2, from 0.10±0.04 qg/ml to 0.38±0.0611g/ml (P < 0.001). Increases were observed in total dead space (VD/VT) from 0.46±0.03 to 0.61±0.08 (P < 0.025, physiologic shunting (Qs/(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 4h (P < 0.025). Imidazole pretreatment prevented a rise of TxB2, but not 6-keto-PGFj,; indomethacin blocked both. Both agents maintained VD/VT at base line and limited increases in Qs/QT and PVR. CI was higher after imidazole pretreatment compared with controls (P < 0.025). < 0.025), QS/QT (P < 0.025) and PVR (P < 0.05) within 30 min. During PGI2 infusion, CI was higher than controls. Concentrations of TxB2 correlated with VD/VT, r = 0.79 and Qs/QT, 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 VD/VT is closely allied to TxA2 levels.
Perioperative changes of neutrophil function were investigated in 28 patients who underwent major surgery, particularly focusing on the potential capacity for superoxide and leukotriene production, which seem to be important in host defence. The superoxide-producing capacity of neutrophils, which was examined using N-formyl-peptide or phorbol myristate acetate as an attractant, significantly decreased postoperatively to 55 and 69 per cent of the pre-operative values, respectively. The leukotriene-producing capacity of neutrophils, which was stimulated with calcium ionophore A23187 in the presence of arachidonic acid, significantly changed postoperatively. The leukotriene B4 (LTB4) production increased together with an increment of production of 6-trans 6-trans LTB4, however, increased postoperatively to 1.2 times the (LTC4) production decreased postoperatively. The total production of leukotriene A4 (LTA4) metabolites consisting of LTB4, LTC4, and 6-trans LTB4, however, increased postoperatively to 1.2 times the pre-operative values. This indicates that neutrophils in the postoperative period have a higher capacity for LTA4 production but a lower capacity for superoxide production than those in the pre-operative period.
The importance of prostacyclin (PGI2) and thromboxane (Tx) medication of depressed cardiac performance during abdominal aortic aneurysm operative surgery was studied by contrasting the effects of 650 mg aspirin administered 12 hours before operation to that of a placebo. In 11 patients who received a placebo, the stable metabolite of PGI2, 6-keto-PGF1 alpha rose from 0.050 +/- 0.032 eta grams/ml to 0.419 +/- 0.257 eta grams/ml (p less than 0.01) 30 minutes after the skin incision. The stable metabolite of TxA2, TxB2 did not increase until the aorta was clamped when TxB2 rose from 0.089 +/- 0.054 eta grams/ml to 0.193 +/- 0.138 eta grams/ml (p less than 0.05); this was prior to blood transfusion. During aortic clamping cardiac output decreased 27% (p less than 0.001). In vitro testing of patient plasma showed: 1) depressed developed tension (Tpd) of a rat papillary muscle by 16% (p less than 0.05); 3) reduction of Ca++-ATPase and Mg++-ATPase activity in a rat myocardial subfraction of sarcoplasmic reticulum (p less than 0.05); 3) reduction of Ca++-ATPase in a rat myocardial subfraction of myofibrils (p less than 0.01). Aspirin administered to 11 patients produced no measurable changes in blood loss or fluid requirements. Aspirin lowered preoperative 6-keto-PGF1 alpha and TxB2 levels (p less than 0.01) and prevented an increase of either agent during operation. The low Tx levels were associated with a stable cardiac output during aortic clamping. Further, plasma obtained from aspirin-treated patients did not depress papillary muscle contractility nor decrease ATPase activity of either myocardial subfraction. The observation that TxB2 when added to a papillary muscle or myocardial subfractions, did not decrease Tpd or ATPase suggests that TxB2 plays an indirect role in altering cardiac muscle activity. The results indicate that Txs modulate cardiac depression, which can be prevented with 650 mg aspirin before operation.
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