Phospholipase A2-induced pulmonary and hemodynamic responses in the guinea pig. Effects of enzyme inhibitors and mediators antagonists.
The effect of phospholipase A2 (Naja naja) PLA2) on mean arterial blood pressure and intratracheal pressure was examined in anesthetized guinea pigs. Intracheally administered PLA2 (1 to 10 U) produced acute, dose-dependent increases in mean arterial blood pressure and intracheal pressure. However, Intravenously administered PLA2 (doses as large as 1,000 U) did not alter monitored variables. Acute PLA2-induced morphologic alterations were characterized by airway constriction, airway/alveolar cell damage, and pulmonary sequestration of both leukocytes and platelets. PLA2-induced increases in both mean arterial blood pressure and intratracheal pressure were attenuated to varying degrees by pretreating intravenously with indomethacin (10 mg/kg), a cyclooxygenase inhibitor, and WEB 2086 (0.1 mg/kg), a platelet-activating factor antagonist. Both ICI 198,615 (1 mg/kg), a leukotriene D4, receptor antagonist given intravenously, and dexamethasone (50 mg/kg), a steroidal anti-inflammatory agent given intraperitoneally as a 2-day pretreatment, reduced PLA2-induced increases in intratracheal pressure. Pyrilamine (2 mg/kg), a histamine1-receptor antagonist given intravenously, did not modify PLA2-induced pathophysiologic responses. Guinea pigs exposed to aerosolized PLA2 (100 U/ml) exhibited evidence of increased bronchoalveolar lavage macrophage, leukocyte, and lymphocyte accumulation at 24 h post-PLA2. These studies suggest that in vivo PLA2-induced pathophysiologic changes in the guinea pig involve alterations in resident airway cell populations as well as sequestration and infiltration of inflammatory cells. Both eicosanoids and platelet-activating factor appear to contribute to these PLA2-induced pathophysiologic effects.
Tocker
J E
JE
Department of Pharmacology and Chemotherapy, Hoffmann-La Roche, Nutley, New Jersey 07110.
Durham
S K
SK
Welton
A F
AF
Selig
W M
WM
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010741:Phospholipases A / Q000633:toxicity*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011312:Pressure; D011433:Propranolol / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D013189:SRS-A / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D004791:Enzyme Inhibitors; D007191:Indazoles; D010972:Platelet Activating Factor; D013189:SRS-A; D014230:Triazoles; C054217:ICI 198615; C052518:WEB 2086; D003907:Dexamethasone; D011433:Propranolol; D010741:Phospholipases A; D054467:Phospholipases A2; D011738:Pyrilamine; D007213:Indomethacin