Thromboxane receptor activation during bronchospasm induced by platelet-activating factor.
The involvement of thromboxane receptors in the responses to platelet-activating factor (PAF) was examined in anesthetized guinea pigs. The thromboxane receptor antagonist SQ 30,741 (1 mg/kg i.v.), aspirin (10 mg/kg i.v.), or vehicle was given 3 min before PAF (0.25 micrograms/kg i.v.). In vehicle-treated animals, PAF reduced dynamic lung compliance (Cdyn, -71 +/- 5%) and increased total airways resistance (Rlung, 497 +/- 108%) (N = 8). Aspirin and SQ 30,741 blocked these responses by greater than 95% (p less than 0.001). However when the PAF dose was increased to 0.5 micrograms/kg, neither drug treatment prevented bronchospasm (-73 +/- 9 and -59 +/- 4% in Cdyn, respectively; N = 5). An intratracheal aerosol of 0.01% PAF was given to other guinea pigs after SQ 30,741 (1 mg/kg i.v. or 0.1% aerosol) or vehicle. In vehicle-treated animals, vaporized PAF reduced Cdyn (-41 +/- 5%) and increased Rlung (72 +/- 16%) (N = 5) and SQ 30,741 (i.v. and intratracheal) did not affect the magnitude of these responses. Intravenous PAF, but not aerosolized PAF, also increased hematocrit (reduced only by aspirin) and decreased circulating platelets (antagonized by SQ 30,741) and leukocytes (unaffected by SQ 30,741 or aspirin). As a positive control, the PAF antagonist WEB 2086 (1 mg/kg i.v.) inhibited all responses to i.v. and intratracheal PAF. These data suggest that thromboxane receptor activation participates in some of the effects of blood borne PAF in vivo.
Schumacher
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Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, 08543-4000.
Steinbacher
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D001986:Bronchial Spasm / Q000139:chemically induced / Q000378:metabolism*; D006168:Guinea Pigs; D007275:Injections, Intravenous; D007442:Intubation, Intratracheal; D008297:Male; D010972:Platelet Activating Factor / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D010976:Platelet Count; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid