No abstract

1 The characterization of the B 1 kinin receptor, and some mediators involved in the in¯ammatory response elicited by intrathoracic (i.t.) administration of des-Arg 9 -bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg 9 -BK (10 ± 100 nmol per site), a selective B 1 agonist, caused a signi®cant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell in¯ux, mainly neutrophils, and, to a lesser extent, mononuclear cell in¯ux, peaking at 4 h and lasting for up to 48 h. The increase in¯uid leakage caused by des-Arg 9 -BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg 9 -BK (30 nmol per site) caused a similar in¯ammatory response. -BK-induced plasma extravasation (P50.01), without signi®cantly aecting the total and dierential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg 9 -BK (i.t.)-induced neutrophil cell migration (P50.01), and, to a lesser extent, mononuclear cell migration (P50.01). The D-enantiomer D-NAME had no eect on des-Arg 9 -BK-induced pleurisy. At the same dose range, L-NOARG and L-NAME inhibited the total cell migration (P50.01). L-NAME, but not L-NOARG caused signi®cant inhibition of des-Arg 9 -BKinduced¯uid leakage. Indomethacin (1 mg kg 71 , i.p.), administered 1 h before des-Arg 9 -BK (30 nmol per site), inhibited the mononuclear cell migration (P50.05), but, surprisingly, increased the neutrophil migration at 4 h without interfering with plasma extravasation. The administration of terfenadine (50 mg kg 71 , i.p.), 30 min before des-Arg 9 -BK (30 nmol per site), did not interfere signi®cantly with the total cell migration or with the plasma extravasation in the mouse pleurisy caused by i.t. injection of desArg 9 -BK. 6 Pretreatment of animals with the lipopolysaccharide of E. coli (LPS; 10 mg per animal, i.v.) for 24 h did not result in any signi®cant change of the in¯ammatory response induced by i.t. injection of desArg 9 -BK compared with the saline treated group. However, the identical treatment of mice with LPS resulted in a marked enhancement of des-Arg 9 -BK induced paw oedema (P50.01). 7 In conclusion, we have demonstrated that the in¯ammatory response induced by i.t. injection of desArg 9 -BK, in a murine model of pleurisy, is mediated by stimulation of constitutive B 1 receptors. These responses are largely mediated by release of neuropeptides such as substance P or CGRP and also by NO, but products derived from cyclo-oxygenase pathway and histamine seem not to be involved. Therefore, these results further support the notion that the B 1 kinin receptor has an important role in modulating in¯ammatory responses, and it is suggested that selective B 1 antagonists may provide therapeutic bene®t in the treatment of in¯ammatory and allergic conditions.

No abstract

A number of potential anti-diabetic plants were identified through an ethnobotanical survey of the traditional pharmacopeia of the Cree of Eeyou Istchee (CEI—Northeastern Canada) used against symptoms of diabetes and their biological activity assessed by in vitro bioassays. Among these, Sorbus decora C.K.Schneid. (Rosacea) ranked highly and increased the transport of glucose in skeletal muscle cells in culture. The present study thus aimed at confirming the antidiabetic potential of S. decora in in vivo models of insulin resistance and diabetes, notably the streptozotocin Type 1 diabetic rat (STZ), the genetic KK-Ay Type 2 diabetic mouse and the rat rendered insulin resistant with 10% glucose water consumption for 6 weeks. Sorbus decora ethanolic crude extract (SDEE) was administered orally (200 mg kg−1) and compared to metformin (150 or 500 mg kg−1). The intragastric (i.g.) gavage of SDEE transiently decreased glycemia in STZ rats in a bi-phasic manner but the effect was cumulative over several days. In KK-Ay mice, SDEE incorporated in food (0.12%) decreased glycemia by 15% within 1 week as compared to vehicle controls. In pre-diabetic insulin-resistant rats, SDEE fed daily by i.g. gavage for 2 weeks significantly decreased the slight hyperglycemia and hyperinsulinemia, without affecting sugar water intake. Using the HOMA insulin resistance parameter, the effect of SDEE was equivalent to that of metformin. In conclusion, the ethanolic crude extract of S. decora demonstrates both anti-hyperglycemic and insulin-sensitizing activity in vivo, thereby confirming anti-diabetic potential and validating CEI traditional medicine.

1 The function and autoradiographic binding expression of kinin B 1 receptors were evaluated in the lungs of Streptozotocin (STZ)-diabetic rats. -BK in STZ-diabetic rats was signi®cantly reduced after treatment with insulin (2 U per day, s.c. over 4 days) or with an anti-PMN antibody (0.1 ml of a 1 : 20 dilution, i.pl. 5 min earlier). 5 Speci®c B 1 receptor binding sites were seen in lung sections from both control and STZ-diabetic rats, yet the density of labelling was much greater in diabetic rats and particularly after intrapleural injection of des-Arg 9 -BK. Treatment with insulin or with the anti-PMN antibody markedly reduced B 1 receptor binding sites occurring after the injection of des-Arg 9 -BK in STZ-diabetic rats. 6 Data suggest that the B 1 receptor is up-regulated in the lungs of STZ-diabetic rats, and its activation increases leukocyte in®ltration into the pleural cavity. The overexpression of B 1 receptors seems to depend on neutrophils in¯ux and appears to be associated with hyperglycaemia.