The effects of
S 16118 (p-guanidobenzoyl-[Hyp3,Thi5,D-Tic7, Oic8]
bradykinin (BK)], a new, potent and long-acting BK B2 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 induced by intraplantar
carrageenan injections up to 4 hr after administration, confirming the involvement of
kinins in this inflammatory reaction. In guinea pigs treated with
atropine, vagal stimulation induced bronchial microvascular leakage. Aerosolization of
S 16118 (5 x 10(-3) M for 20 sec), 4 min before
vagus nerve stimulation, induced a 60% decrease 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 B2 receptors, is involved in this model of
pancreatitis. In rabbits, the injection of
lipopolysaccharides (LPS; 600 micrograms/kg i.v.)
induced hypotension,
metabolic acidosis and
leukopenia.
S 16118 (1.73 mumol/kg i.v.) did not influence the effects of LPS injection. In mice, i.p. LPS (25 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 after LPS injection, did not influence the mortality rate.(ABSTRACT TRUNCATED AT 250 WORDS)