Inhibition of pulmonary thromboxane A2 synthase activity and airway responses by CGS 13080.
The effects of CGS 13080, a thromboxane (TXA2) synthase inhibitor, on airway responses to arachidonic acid (AA) were investigated in the anesthetized cat. Feline and human lung microsomal fraction exhibited prostaglandin I2 (PGI2, prostacyclin), and TXA2 synthase activities, and human platelet microsomal fractions exhibited TXA2 synthase activity. Cat and human lung microsomal fractions, but not human platelets, exhibited the presence of GSH-dependent PGE2 isomerase activity. CGS 13080 inhibited TXA2 synthase activity in all three microsomal fractions in a concentration-dependent manner. The increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance in response to AA were decreased significantly by CGS 13080. These data suggest that the bronchoconstrictor actions of AA are mediated in large part by the formation of TXA2. The data further indicate that cyclooxygenase products other than TXA2 are involved in the bronchoconstrictor response to AA since meclofenamate had greater inhibitory activity than did CGS 13080. Moreover, the effects of CGS 13080 were due to inhibition of TXA2 synthase rather than an effect on TXA2 receptors, since airway responses to the TXA2 mimic, U46619, were not altered. The present data show that CGS 13080 inhibits TXA2 synthase activity without altering cyclooxygenase, PGI2 synthase, or GSH-dependent PGE2 isomerase activities. The data further indicate that in vivo administration of CGS 13080 may selectively increase PGI2 synthase activity.
McNamara
D B
DB
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112.
Harrington
J K
JK
Bellan
J A
JA
Graybar
G B
GB
Underwood
D C
DC
Kadowitz
P J
PJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002415:Cats; D005231:Fatty Acids, Unsaturated; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011725:Pyridines; D008469:Meclofenamic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C037787:pirmagrel; D013930:Thromboxane-A Synthase