Blockade of thromboxane/endoperoxide receptor-mediated responses in the pulmonary vascular bed of the cat by sulotroban.
The effects of sulotroban (BM13.177; SK & F 95587), a thromboxane (TX) A2/endoperoxide (PGH2) receptor blocking agent on responses to the TXA2/PGH2 mimics, U46619 and U44069, were investigated in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Injections of U46619 and U44069 directly into the perfused lobar artery caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following administration of sulotroban in a dose of 5 mg/kg i.v., dose-response curves for U46619 and U44069 were shifted to the right in a parallel manner. The duration of the blocking effect of sulotroban was investigated, and responses to U46619 returned to approximately 50% of control in 120 min and were not significantly different from control 240 min after administration of the receptor antagonist. Sulotroban was without significant effect on responses to prostaglandin (PG) D2 or F2 alpha or serotonin, histamine, norepinephrine, angiotensin II or BAY K8644, an agent which enhances calcium entry. Sulotroban was without effect on responses to endothelin (ET)-1, sarafotoxin (S) 6a or S6c and platelet-activating factor (PAF). Sulotroban did not alter baseline vascular pressures in the cat and responses to the PG and TXA2/PGH2 precursor, arachidonic acid, were reduced. The present data show that sulotroban selectively blocks TXA2/PGH2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)
Nossaman
B D
BD
Department of Anesthesiology, Tulane University School of Medicine, New Orleans, LA 70112.
McMahon
T J
TJ
Ragheb
M S
MS
Ibrahim
I N
IN
Babycos
C R
CR
Hood
J S
JS
Kadowitz
P J
PJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002415:Cats; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D012701:Serotonin / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D016232:Endothelins; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D000804:Angiotensin II; D016718:Arachidonic Acid; D012701:Serotonin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C040624:sulotroban; D006632:Histamine; D009638:Norepinephrine