Independence of prostaglandin synthesis and bradykinin-induced oedema formation during caerulein-induced acute pancreatitis in rats T. Griesbacher, R. Schuligoi & B.A. Peskar, Institute for Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.

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Oedema formation during acute caerulein-induced pancreatitis is due to the release of bradykinin within the pancreas (Griesbacher et al., 2002). In many tissues, bradykinin releases prostaglandins (PG), such as PGE₂, which in turn can contribute to the bradykinin-mediated increases in vascular permeability. We have studied the PGE₂ release during acute pancreatitis with respect to its time course, its dependence on bradykinin action, and its contribution to oedema formation.

Female Sprague-Dawley rats (200-250 g) were anaesthetized with pentobarbitone sodium and phenobarbitone sodium (each 40 mg kg^-1, i.p.). Caerulein (4 nmol kg^-1-1 h^-1 for 2 h) was infused via a jugular vein; control animals received phosphate-buffered saline (8 ml kg^-1 h^-1). Tissue samples excised at 2 h, 4 h, or 24 h after the start of the experiments were washed in cold (4°C) Krebs-Ringer buffer and were incubated for 10 min at 37°C. PGE₂ synthesis was measured by radioimmunoassay (Jobke et al., 1973). Indomethacin (10 mg kg^-1), the kinin B₂ antagonist icatibant (100 nmol kg^-1) or the B₁ antagonist des-Arg¹⁰-[Leu⁹]-kallidin (DALKD; 300 nmol kg^-1 were injected s.c. 30 min prior to the experiments; vehicle controls received an appropriate volume (1 ml kg^-1) of the vehicle (154 mM NaCl). The cyclooxygenase-1 (COX-1) inhibitor SC-560 (1 mg kg^-1; Smith et al., 1998) and the COX-2 inhibitor DFU (2 mg kg^-1; Riendeau et al., 1997), also were given s.c. at -30 min while control animals were injected with the solvent (10% v/v Tween 80 in 154 mM NaCl). For measurements at 24 h the inhibitors were given 1 h before excision of the tissue samples.

The oedema reached peak values of 11.1 ± 0.8 g g^-1 dry wt (n = 12) within 2 h and was resolved completely at 24 h. Icatibant significantly (P<0.05) reduced the oedema to values (4.8 ± 0.2 g g^-1 dry wt, n = 10) not significantly different from control tissues from animals without pancreatitis (2.7 ± 0.1 g g^-1 dry wt, n = 10). Neither DALKD, nor indomethacin, SC-560 or DFU had an effect on oedema formation.

PGE₂ synthesis during pancreatitis was increased to 16.2 ± 2.4 pg g-1 dry wt 10-1 min^-1 (n = 12) within 2 h while control tissues showed values of only 6.7 ± 0.6 pg g-1 10^-1 min^-1 (n= 10, P<0.05). PGE₂ synthesis did not return to baseline on the day after induction of pancreatitis and amounted to 44.7 ± 9.6 pg g-1 10-1 min^-1 (n = 13) at 24 h. PGE₂ synthesis was abolished (P<0.05) after indomethacin treatment at all time points (6.3 ± 0.7 pg g^-1 10^-1 min^-1, n = 12, at 2 h). A similar inhibition was seen after treatment with SC-560 (11.9 ± 2.7 pg g^-1 10^-1 min^-1, n = 6, P<0.05 vs 35.4 ± 6.1 pg g^-1 10^-1 min^-1, n = 7, in rats pretreated with the solvent, Tween 80/NaCl). DFU, icatibant and DALKD had no effect on PGE₂ synthesis.

In summary, in acute caerulein-induced pancreatitis (i) oedema formation and PGE₂ release in the pancreas have different time courses, (ii) the release of PGE2 is independent from the action of kinins released during the inflammation, (iii) cyclooxygenase products do not contribute to oedema formation, and (iv) PGE₂ is generated by COX-1 only.

Griesbacher et al. (2003). Br. J. Pharmacol., 139, 299-308.
Jobke et al. (1973). FEBS Lett., 37, 192-196.
Riendeau et al. (1997). Br. J. Pharmacol., 121, 105-117.
Smith et al. (1998). Proc. Natl. Acad. Sci. USA, 95, 13313-13318.

Supported by the Austrian National Bank, grant 9314.