Targeted Disruption of a B2 Bradykinin Receptor Gene in Mice Eliminates Bradykinin Action in Smooth Muscle and Neurons

Borkowski, Joseph A.; Ransom, Richard W.; Seabrook, Guy R.; Trumbauer, Myrna E.; Chen, H; Hill, R.G.; Strader, Catherine D.; Hess, J. Fred

doi:10.1074/jbc.270.23.13706

Cited by 230 publications

(130 citation statements)

References 38 publications

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“…Male (2 ± 3 months of age) J129 Sv wild-type mice (B 2 +/+ ) were obtained from Jackson Laboratory (Bar Harbor, MN, U.S.A.). B 2 7/7 , generated by gene targeting and homologous recombination on a J129 Sv genetic background (Borkowski et al, 1995), were kindly provided by Dr Fred Hess (Merck Laboratories, West Point, PA, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

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Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Emanueli¹,

Salis²,

Figueroa³

et al. 2000

British J Pharmacology

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1 In the rat balloon injury model, angiotensin-converting enzyme (ACE) inhibitors prevent vascular remodelling by inhibiting angiotensin II generation and kinin breakdown. We investigated if ACE inhibition also prevents the structural vascular responses to disruption of carotid artery blood¯ow and if kinin potentiation plays a role in such a protection. 2 Morphometric analysis of the structural alterations caused by ligation of the left carotid artery was performed 14 days after surgery in J129Sv wild-type mice (B 2 +/+ ) drinking normal tap water or water containing captopril (120 mg kg 71 per day). In addition, the e ect of captopril on vascular remodelling was tested in B ). 3 Interruption of blood¯ow resulted in carotid artery intimal hyperplasia and media thickening in untreated B 2 +/+ , these responses being partially suppressed by captopril. The inhibition of intimal thickening exerted by captopril was reduced in B 2 +/+ given DALBK or icatibant (P50.05 for both comparisons) as well as in B 2 7/7 (P50.05). Neither antagonism of kinin receptors nor disruption of the B 2 receptor gene altered the suppressive e ect of captopril on media thickening. The protection of vascular wall structure was independent of the reduction in blood pressure by captopril. 4 These results demonstrate that kinins participate in the inhibitory e ect of captopril on intimal hyperplasia via B 1 and B 2 receptor signalling. Our ®ndings may have important implications in treating vascular remodelling evoked by altered shear stress conditions.

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Section: Methodsmentioning

confidence: 99%

“…The preventive e ect of captopril on vascular remodelling was also evaluated in mice in which the gene encoding for the B 2 receptor was knockedout by gene targeting and homologous recombination (B 2 7/7 ) (Borkowski et al, 1995;Madeddu et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Emanueli¹,

Salis²,

Figueroa³

et al. 2000

British J Pharmacology

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“…Male C57/BL6 (body weight 18 to 22 g, Charles River, Sulzfeld, Germany) and bradykinin B 2 receptor knockout (B 2 À/À ) mice (body weight 18 to 22 g, Jackson Laboratory, Bar Harbor, ME, USA) initially generated by Borkowski et al (1995) were used for the current experiments. To reduce genetic variability, B 2 À/À mice were backcrossed with one of their genetic background strains, C57/BL6, for eight generations.…”

Section: Transient Focal Cerebral Ischemiamentioning

confidence: 99%

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Gröger¹,

Lebesgue

Pruneau

et al. 2005

J Cereb Blood Flow Metab

127

112

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Pharmacological studies using bradykinin B 2 receptor antagonists suggest that bradykinin, an early mediator of inflammation and the main metabolite of the kallikrein-kinin system, is involved in secondary brain damage after cerebral ischemia. However, the time-course of bradykinin production and kinin receptor expression as well as the conclusive role of bradykinin B 2 receptors for brain damage after experimental stroke have not been elucidated so far. C57/Bl6 mice were subjected to 45 mins of middle cerebral artery occlusion (MCAO) and 2, 4, 8, 24, and 48 h later brains were removed for the analysis of tissue bradykinin concentration and kinin B 2 receptor mRNA and protein expression. Brain edema, infarct volume, functional outcome, and long-term survival were assessed in WT and B 2 À/À mice 24 h or 7 days after MCAO. Tissue bradykinin was maximally increased 12 h after ischemia (three-fold), while kinin B 2 receptor mRNA upregulation peaked 24 to 48 h after MCAO (10-to 12-fold versus naïve brain tissue). Immunohistochemistry revealed that kinin B 2 receptors were constitutively and widely expressed in mouse brain, were upregulated 2 h after ischemia in cells showing signs of ischemic damage, and remained upregulated in the penumbra up to 24 h after ischemia. B 2 À/À mice had improved motor function (Po0.05), smaller infarct volumes (À38%; Po0.01), developed less brain edema (À87%; Po0.05), and survived longer (Po0.01) as compared with wild-type controls. The current results show that bradykinin is produced in the brain, kinin B 2 receptors are upregulated on dying cells, and B 2 receptors are involved in cell death and brain edema formation after experimental stroke.

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“…Administration of the B 2 receptor antagonist Hoe-140 blunted the blood pressure-lowering effect of the transgene, whereas intra-arterial bolus injection of BK produced more pronounced blood pressure reduction (7). In contrast, deletion of the B 2 receptor in mice produced an unaltered blood pressure phenotype (8) but led to salt-sensitive hypertension and altered nociception (9,10). Using specific antagonists, the B 1 receptor has been implicated in toxic shock, inflammation, and nociception (11).…”

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confidence: 99%

Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation

Yin

Agata

et al. 2003

Journal of Biological Chemistry

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We demonstrated that rat kinin B 1 receptors displayed a ligand-independent constitutive activity, assessed through inositol phosphate production in transiently or stably transfected human embryonic kidney 293A cells. Substitution of Ala for Asn 130 in the third transmembrane domain resulted in additional constitutive activation of the B 1 receptor. The constitutively active mutant N130A receptor could be further activated by the B 1 receptor agonist des-Arg 9 -bradykinin. To gain insights into the physiological function of the B 1 receptor, we have generated transgenic mice overexpressing wild-type and constitutively active mutant receptors under the control of human cytomegalovirus immediately early gene enhancer/promoter. The rat B 1 receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcriptionpolymerase chain reaction/Southern blot analysis. Transgenic mice were fertile and normotensive. Overexpression of B 1 receptors exacerbated paw edema induced by carrageenan and rendered transgenic mice more susceptible to lipopolysaccharide-induced endotoxic shock. Interestingly, the hemodynamic response to kinins was altered in transgenic mice, with des-Arg 9 -bradykinin inducing blood pressure increase when intravenously administered. Our study supports an important role for B 1 receptors in modulating inflammatory responses and for the first time demonstrates that B 1 receptors mediate a hypertensive response to des-Arg 9 -bradykinin.Kinin peptides are released from kininogen precursors by the action of kallikreins in response to tissue injury (1). Kinins induce smooth muscle contraction, vasodilation, increased vascular permeability, and pain (1). Kinins exert their effects through selective activation of two seven-transmembrane domain (TMD) 1 G protein-coupled receptors (GPCRs), B 1 and B 2 (2-4). The B 2 receptor is constitutively expressed, mediating the actions of intact kinins, bradykinin (BK) in rodents and Lys-BK or kallidin in humans (2). In contrast, the B 1 receptor is expressed at very low levels in normal tissues in most animal species but is induced under the influence of inflammation or exposure of tissues to noxious stimuli, mediating the effects of the carboxypeptidase metabolites of intact kinins, des-Arg 9 -BK (DABK), and des-Arg 10 -kallidin (2). The cellular responses of kinin receptors to agonists are transduced primarily via coupling to either G q protein, which in turn activates phospholipase C to stimulate inositol phosphate production, or the G i protein, acting through phospholipase A 2 to stimulate arachidonic acid pathway (5, 6).Over the past years, transgenic and gene-targeting technologies associated with molecular biology tools have provided important knowledge concerning the role of kinin receptors in vivo. Transgenic mice expressing the human B 2 receptor under the control of the Rous sarcoma virus 3Ј-long terminal repeat promoter were hypotensive compared with control littermates (7). Adm...

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Targeted Disruption of a B2 Bradykinin Receptor Gene in Mice Eliminates Bradykinin Action in Smooth Muscle and Neurons

Cited by 230 publications

References 38 publications

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation

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Targeted Disruption of a B2 Bradykinin Receptor Gene in Mice Eliminates Bradykinin Action in Smooth Muscle and Neurons

Cited by 230 publications

References 38 publications

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

Release of Bradykinin and Expression of Kinin B2Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice

Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation

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Product

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Release of Bradykinin and Expression of Kinin B₂Receptors in the Brain: Role for Cell Death and Brain Edema Formation After Focal Cerebral Ischemia in Mice