Role Of Bradykinin B1 Receptors Research Articles

Oxidative stress in the optic nerve and cortical visual area of steptozotocin-induced diabetic Wistar rats: Blockade with a selective bradykinin B1 receptor antagonist

The role of bradykinin B1 receptors on the oxidative stress as measured by the levels of Na+/K+ ATPase activity, malondialdehyde (MDA) and glutathione (GSH) in male Wistar rat optic nerve and visual cortex area 1 and 4weeks after STZ treatment was studied. Rats were divided into 4 groups (n=6–7): 1. Controls (non-diabetics); 2. Diabetics (65mg/kg streptozotocin, STZ); 3. Diabetics injected with B1 antagonist R-954 (2mg/Kg) during the last 3days of a one week period; 4. Diabetics injected with B1 antagonist R-954 (2mg/Kg) during the last 3days of a 4week period. The results showed that plasma glucose levels increased by up to 4 fold in diabetic rats 1 or 4weeks following the STZ treatment. R-954 treatment did significantly decrease blood glucose levels. Levels of MDA was increased in the plasma of the 1 and 4week diabetic animals whereas the GSH levels were decreased. Both markers returned to normal following R-954 treatment. Na+/K+ ATPase activity significantly decreased in the optic nerve and visual cortex of diabetic rats at 1 and 4weeks but returned to normal following R-954 treatment. MDA levels increased markedly at 1 and 4weeks compared with control levels in the optic nerve but slightly in the visual cortex and returned to control levels in both tissues following R-954 treatment. GSH levels decreased in both tissues at 1 and 4weeks compared with control levels. Following administration of the selective BKB1R antagonist R-954, the levels of GSH returned to normal in both tissues of the 1 and 4week diabetic animals. These results showed that the inducible BKB1 receptors are associated with the oxidative stress in the optic nerve and cortical visual area of diabetic rats and suggested that BKB1-R antagonist R-954 could have a beneficial role in the treatment of diabetic retinopathy.

Abstract 076: Brain-targeted Bradykinin B1 Receptor Blockade Prevents DOCA-salt Hypertension by Oxidative Stress and ERK1/2 Phosphorylation Mediated Signaling Mechanisms

DOCA-salt hypertension is associated with increased expression of the pro-inflammatory bradykinin B1 receptor (B1R) in the brain. We previously reported that DOCA-salt hypertension is attenuated in global B1R knockout mice. In this study, we further examined the role of B1R within the central nervous system, on hypertension and cardiac hypertrophy, and explored the contribution of downstream signaling mechanisms. DOCA-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of C57Bl6/J male mice produced a significant rise in mean arterial pressure (MAP; telemetry) in these animals (145 ±3 mmHg, n=8, p<0.01). Intracerebroventricular (ICV) infusion of R715 (70 μg/kg/day, 3 weeks), a specific B1R antagonist, attenuated the DOCA-salt-induced hypertension (125 ±3 mmHg, n=8, p<0.01). Moreover, DOCA-salt treatment resulted in cardiac hypertrophy in C57 compared to sham-treated mice (heart weight/tibia length; 9.2 ±0.3 vs. 7.2 ±0.2 mg/mm), which was prevented by B1R blockade with R715 (7.4 ±0.3 mg/mm; P <0.01 vs. DOCA). DOCA-salt-treated mice had increased inflammation (qRT-PCR), as shown by elevated gene expression of TNF, IL-1β and IL-6 (3-, 8- and 5-fold, respectively, n=9, p<0.01 vs. sham) in the hypothalamic paraventricular nucleus (PVN), which was attenuated in R715-treated mice. C57 mice treated with DOCA-salt showed increased oxidative stress, as indicated by increased gene expression of Nox-2 and iNOS (5- and 15-fold increase, respectively, n=4, p<0.01 vs. sham) in the PVN which was prevented by central B1R blockade with R715 (1.9- and 4.4-fold increase, respectively, n=4, p<0.01 vs. DOCA). DOCA-salt-induced increase in PVN Nox-2 protein expression was also prevented by central B1R blockade (2.2 vs. 1.1-fold change, p<0.01). Furthermore, phosphorylation of ERK1/2 was increased in the PVN of DOCA-salt-treated mice (66 ±3 % increase, n=4, p<0.05 vs. sham), which was blunted in R715 treated mice. Taken together, these data provide evidence that blockade of brain B1R attenuates DOCA-salt-induced hypertensive and hypertrophic effects via oxidative stress and ERK1/2 phosphorylation-mediated signaling mechanisms. (Funding: AHA 15SDG25720021 (SS), NIH/NHLBI (HL093178) (EL), and P30GM106392).

The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP)

An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-beta1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-beta1 through an increase in eNOS activity in a hypertensive condition.

Abstracts

Abstracts

Renal protective role of bradykinin B1 receptor in stroke-prone spontaneously hypertensive rats.

The kallikrein-kinin system plays important roles in blood pressure regulation, metabolism of electrolytes and organ protection. Although the bradykinin B2 receptor (B2R) has been reported to be involved in most of these effects, a role of the bradykinin B1 receptor (B1R) has also been noted recently. The aim of this study was to determine the role of renal B1R in stroke-prone spontaneously hypertensive rats (SHR-SP). Sixteen-week-old SHR-SP and Wistar Kyoto rats (WKY) as a control were used in the experiments. A high level of B1R mRNA was detected in SHR-SP, while the expression in WKY was almost undetectable. Immunohistochemistry revealed a B1R protein in the renal tubules and glomeruli in SHR-SP. The acute injection of a B1 R agonist into SHR-SP increased urinary NOx excretion to a level up to 5-fold higher than that in the SHR-SP treated with vehicle. The infusion of B1 R antagonist for 4 weeks resulted in a significant elevation of blood pressure and urinary albumin excretion and a decrease in urinary NOx excretion in SHR-SP. The administration of B1 R antagonist resulted in renal interstitial and glomerular fibrosis in SHR-SP. Moreover, the expressions of transforming growth factor (TGF) beta1 protein and collagen III mRNA in SHR-SP treated with B1R antagonist were significantly higher than those of SHR-SP treated with a vehicle. The expression and phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38, but not c-Jun N-terminal kinase (JNK), were significantly increased in the SHR-SP treated with B1R antagonist. These results indicated that renal B1R might be over-expressed in a high blood pressure condition, and that this upregulated B1 R may play an important role in renal protection by inhibiting renal fibrosis via an increase of NO production and a suppression of TGFbeta1 expression and mitogen-activated protein kinase (ERK and p38) phosphorylation.

Induction of bradykinin B1 receptors in vivo in a model of ultra-violet irradiation-induced thermal hyperalgesia in the rat.

1. The role of bradykinin B1 receptors in the thermal hyperalgesia following unilateral ultra-violet (u.v.) irradiation of the hindpaw of rats has been investigated. 2. In non-irradiated (naive) animals the B1 receptor agonist des-Arg9-bradykinin and bradykinin (BK) (up to 1 mumol kg-1 i.v.) had no effect on withdrawal latency to a noxious heat stimulus when administered 60 min before testing. 3. Following exposure of one hindpaw to strong u.v. irradiation the withdrawal latency of the u.v.-treated paw to radiant noxious heat fell by a maximum of 50% after 48 h. There was no reduction in latency in the contralateral paw. 4. des-Arg9-BK (1-100 nmol kg-1 i.v.) administered 24 h after u.v. exposure caused a further dose-dependent fall (50 +/- 4% reduction from saline injected animals at 100 nmol kg-1 i.v.) in withdrawal latency in the u.v.-treated paw when measured 60 min after injection. The withdrawal latency of the contralateral paw was also reduced but to a lesser extent following des-Arg9-BK (100 nmol kg-1 i.v.) with a maximum reduction of 19 +/- 3%. 5. Bradykinin also induced a further reduction in withdrawal latency (33 +/- 5% reduction at 1 mumol kg-1) although it was not as effective as des-Arg9-BK. Bradykinin did not reduce the withdrawal latency in the contralateral paw. 6. The hyperalgesic action of both des-Arg9-BK (10 nmol kg-1 i.v.) and bradykinin (100 nmol kg-1 i.v.)were antagonized by the B, receptor antagonist, des-Arg9,Leu8-BK (200 nmol kg-1 i.v.) but not by the B2 receptor antagonist, HOE 140 (0.5 .micromol kg-1 i.v.).7. The results suggest that in conditions of inflammatory hyperalgesia bradykinin B1 receptors are induced both locally and distant to the inflamed area, activation of which leads to further thermal hyperalgesia. In addition, in these conditions bradykinin appears to act predominantly via B1 receptors,presumably after degradation to des-Arg9-BK.