Inhibition of prostaglandin synthesis during polystyrene microsphere-induced pulmonary embolism in the rat.
Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 micro m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B(2) (TxB(2)) in bronchoalveolar lavage fluid and increased urinary dinor TxB(2). Furegrelate and ketorolac treatments reduced TxB(2) and dinor TxB(2) to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB(2). Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE.
Jones
Alan E
AE
Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina 28203, USA.
Watts
John A
JA
Debelak
Jacob P
JP
Thornton
Lisa R
LR
Younger
John G
JG
Kline
Jeffrey A
JA
D000792:Angiography; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000096:biosynthesis / Q000652:urine; D015232:Dinoprostone / Q000096:biosynthesis / Q000652:urine; D004195:Disease Models, Animal; D015633:Extravascular Lung Water / Q000378:metabolism; D007022:Hypotension / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D020910:Ketorolac / Q000494:pharmacology; D008565:Membrane Proteins; D008863:Microspheres; D010996:Pleural Effusion / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011137:Polystyrenes; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins / Q000096:biosynthesis* / Q000652:urine; D011652:Pulmonary Circulation; D011655:Pulmonary Embolism / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012126:Respiratory Dead Space / Q000502:physiology; D015996:Survival Rate; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011137:Polystyrenes; D011453:Prostaglandins; D013929:Thromboxane B2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D020910:Ketorolac