Effects of putative thromboxane receptor agonists and antagonists on rat small intestinal ion transport.
Effects of a thromboxane mimic, U46619, on electrolyte transport were examined in vitro using stripped segments of rat ileal mucosa mounted in Ussing chambers. Addition of U46619 to the serosal bathing solution elicited a transient increase in short-circuit current (Isc) and decrease in transepithelial conductance (Gt). The increase in Isc was accompanied by a transient increase in Cl- secretion and decrease in Na+ absorption. In the steady-state, Isc was not increased whereas Gt remained decreased and Na+ and Cl- absorption were inhibited. Removal of Cl- or pretreatment with serosal and mucosal indomethacin (1 microM) or the thromboxane receptor antagonist, SK&F 88046, added to the serosal bathing solution, inhibited the increase in Isc stimulated by U46619 (apparent KB approximately 8 nM). The effects of U46619 on both Isc and Gt are qualitatively similar to those resulting from stimulation with leukotriene D4. However, the changes in Isc with leukotriene D4 (10 microM) are antagonized by SK&F 88046 only at high concentrations (1-10 microM). In addition, the secretagogues prostaglandin F2 alpha, lys-bradykinin, serotonin and histamine, produce qualitatively similar changes in Isc to those seen with U46619 without altering Gt. With the exception of prostaglandin F2 alpha, the effects of these secretagogues are not inhibited by SK&F 88046 (10 microM). These results indicate that U46619 acts at a thromboxane receptor to stimulate intestinal Cl- secretion and inhibit Na+ and Cl- absorption. These changes are inhibited selectively by the thromboxane receptor antagonist, SK&F 88046.
Smith
P L
PL
Department of Drug Delivery, Smith Kline & French Laboratories, Philadelphia, Pennsylvania.
McCafferty
G P
GP
Fondacaro
J D
JD
Wasserman
M A
MA
Elton
E
E
Ryan
F M
FM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000378:metabolism*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013189:SRS-A / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D002712:Chlorides; D004573:Electrolytes; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C034339:SK&F 88046; D013189:SRS-A; D013449:Sulfonamides; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D012964:Sodium; D015237:Dinoprost