R 715

Kinin B1 receptor (B1R) is virtually absent under physiological condition, yet it is highly expressed in models of diabetes mellitus. This study aims at determining: (1) whether B1R is induced in the brain of insulin-resistant rat through the oxidative stress; (2) the consequence of B1R activation on stereotypic nocifensive behavior; (3) the role of downstream putative mediators in B1R-induced behavioral activity. Sprague-Dawley rats were fed with 10% D-glucose in their drinking water or tap water (controls) for 4 or 12 weeks, combined either with a standard chow diet or a diet enriched with α-lipoic acid (1 g/kg feed) for 4 weeks. The distribution and density of brain B1R binding sites were assessed by autoradiography. Behavioral activity evoked by i.c.v. injection of the B1R agonist Sar-[D-Phe(8)]-des-Arg(9)-BK (10 μg) was measured before and after i.c.v. treatments with selective antagonists (10 μg) for kinin B1 (R-715, SSR240612), tachykinin NK1 (RP-67580) and glutamate NMDA (DL-AP5) receptors or with the inhibitor of NOS (L-NNA). Results showed significant increases of B1R binding sites in various brain areas of glucose-fed rats that could be prevented by the diet containing α-lipoic acid.

1 The function and autoradiographic binding expression of kinin B(1) receptors were evaluated in the lungs of Streptozotocin (STZ)-diabetic rats. 2 The intrapleural injection (i.pl.) of des-Arg(9)-bradykinin (des-Arg(9)-BK) (50 and 100 nmol per site), a selective B(1) receptor agonist, increased time-dependently the mononuclear and neutrophil cells influx in the pleural cavity of rats treated with STZ (65 mg kg(-1), i.p., 4 days earlier). This effect was significantly less in control rats. 3 The influx of mononuclear and polymorphonuclear neutrophil cells induced by des-Arg(9)-BK was significantly inhibited by two B(1) receptor antagonists (des-Arg(10)-Hoe140 or R-715, 100 nmol per site, 5 min earlier), but not by two B(2) receptor antagonists (Hoe140, 10 nmol or NPC 18884, 100 nmol per site, 5 min earlier). However, Hoe140 prevented the higher basal leukocyte influx seen in STZ-diabetic rats. 4 Leukocyte infiltration induced by des-Arg(9)-BK in STZ-diabetic rats was significantly 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 Specific 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.

This study investigates whether bradykinin (BK) B(2) receptor binding sites are increased in the brain and thoracic spinal cord of streptozotocin (STZ)-diabetic rats at 2, 7, and 21 days posttreatment by in vitro autoradiography with the radioligand [(125)I]HPP-Hoe 140. In control and diabetic rats, specific binding sites for B(2) receptors were detected in the brain and in various laminae of the spinal cord, predominantly in superficial laminae (K(d)=34 pM). In diabetic rats, B(2) receptor densities were significantly increased in lamina l of the dorsal horn (+35% at 7 and 21 days), spinal trigeminal nucleus (+70% at 7 and 21 days) and nucleus tractus solitarius (+100% at 2 and 7 days). B(2) receptor analogues D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140), 3-(4 hydroxyphenyl)propionyl-Hoe 140 (HPP-Hoe 140), LF16-0687 mesylate ((2-Pyrrolidinecarboxamide, N-[3-[[4-aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichoro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl]sulfonyl]-(2S)-(9Cl)), and BK decreased binding of [(125)I]-HPP-Hoe 140 in the spinal dorsal horn, with K(i) values of 0.5, 1.5, 3.2, and 3.7 nM, respectively. These values were not significantly different in diabetic rats at 7 days (0.