Intrinsic prostacyclin contributes to exudation induced by bradykinin or carrageenin: a study on the paw edema induced in IP-receptor-deficient mice.
To prove that prostaglandin I2 (PGI2) is a major prostaglandin involved in bradykinin-induced exudation, we examined carrageenin- or bradykinin-induced paw edema in prostacyclin receptor-deficient mice (IPKO). Paw volume of wild-type mice (IPWT) increased gradually 5-6 hr after the carrageenin injection in a similar manner as in ICR mice, but the swelling in IPKO mice was significantly smaller (about 60% of the IPWT volume). Indomethacin, at 10 mg/kg, suppressed the swelling of the IPWT paw to the level of the non-pretreated IPKO, which was not affected by indomethacin, confirming the previous result that PGI2 is a major prostaglandin involved in the swelling. The paw edema of IPWT and IPKO was significantly attenuated by the nonpeptide bradykinin B2-receptor antagonist FR173657, at 30 mg/kg, to the same level of swelling, indicating kinin involvement. Injection of bradykinin (1.2 nmole) into the paw caused rapid edema, which peaked around 15 min in both mice. However, the edema induced in IPKO was smaller and almost at the same level as that elicited in the indomethacin-treated IPWT, suggesting that edema induced by bradykinin includes the intrinsic effect of PGI2. Concomitant injection of carbacyclin with bradykinin caused enhancement of edema in IPWT mice but not in IPKO mice, indicating that intrinsic PGI2 could cause enhancement of bradykinin- or even carrageenin-induced edema formation. These results clearly demonstrate that bradykinin released by carrageenin may be a key mediator to induce PGI2 formation, and both autacoids work together to induce enhanced inflammatory exudation.
Ueno
A
A
Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Naraba
H
H
Ikeda
Y
Y
Ushikubi
F
F
Murata
T
T
Narumiya
S
S
Oh-ishi
S
S
D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000633:toxicity; D002351:Carrageenan / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000502:physiology*; D005122:Exudates and Transudates / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D011465:Prostaglandins, Synthetic; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C026678:carboprostacyclin; D002351:Carrageenan; D011464:Epoprostenol; D001920:Bradykinin; D007213:Indomethacin