EFFECTS OF THE BRADYKININ B-2 RECEPTOR ANTAGONIST S-16118 BENZOYL-[HYP(3),THI(5),D-TIC(7),OIC(8)]BRADYKININ) IN DIFFERENT IN-VIVO ANIMAL-MODELS OF INFLAMMATION

The effects of S 16118 {p-guanidobenzoyl-[Hyp(3),Thi(5),D-Tic(7), Oic( 8)]bradykinin (BK)}, a new, potent and long-acting BK B-2 antagonist, were tested in some in vivo models of inflammation. In rats, S 16118 ( 0.1 and 1 mg/kg) given i.v. or s.c. delayed the edema formation induce d by intraplantar carrageenan injections up to 4 hr after administrati on, confirming the involvement of kinins in this inflammatory reaction . In guinea pigs treated with atropine, vagal stimulation induced bron chial microvascular leakage. Aerosolization of S 16118 (5 x 10(-3) M f or 20 sec), 4 min before vagus nerve stimulation, induced a 60% decrea se in the Evans blue extravasation, demonstrating the modulatory role of BK in neurogenic inflammation. In rats, caerulein infusion (4 nmol/ kg/hr) induced hypotension, massive pancreatic edema, hypovolemia due to plasma leakage and an increase in serum lipase and amylase activity . S 16118 (100 nmol/kg s.c.) prevented the hypotension, the pancreatic edema and the hypovolemia and induced a marked increase in the serum lipase and amylase activity. This confirms that BK, acting on BK B-2 r eceptors, is involved in this model of pancreatitis. In rabbits, the i njection of lipopolysaccharides (LPS; 600 mu g/kg i.v.) induced hypote nsion, metabolic acidosis and leukopenia. S 16118 (1.73 mu mol/kg i.v. ) did not influence the effects of LPS injection. In mice, i.p. LPS (2 5 mg/kg) administration induced over 90% mortality in 96 hr. S 16118 ( 1 mg/kg x 4), given 30 min before LPS injection and 4, 8 and 24 hr aft er LPS injection, did not influence the mortality rate. In mice, cecal ligation and puncture induced death (90% in 7 days). S 16118 (1 mg/kg i.v.), given 30 min before the surgical procedure, did not improve th e survival rate. This study demonstrates that S 16118, a potent antago nist of BK B-2 receptors, could be a useful tool for investigating the involvement of kinins in various models of inflammation. Kinins are i nvolved in carrageenan-induced inflammation, vagal stimulation-induced neurogenic inflammation and caerulein-induced pancreatitis. However, in three different models of endotoxic shock, the involvement of BK B- 2 receptor seems to be minimal.