Published online before print April 7, 2008, doi: 10.1161/HYPERTENSIONAHA.108.110692
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(Hypertension. 2008;51:e42.)
© 2008 American Heart Association, Inc.
Letters to the Editor |
Response to Deficiency of Bradykinin Receptor B2 Is not Detrimental in Experimental Stroke
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
Our response was solicited by the editor based on the article by Kleinschnitz et al.1 We stand by our results that deficiency in the kinin B2 receptor exacerbates ischemic stroke deficits.2 Kleinschnitz et al1 doubt the possibility of dissecting 8 coronal sections from the mouse brain. In fact, it is easy to dissect each mouse brain into 8 serial sections using a 1-mm mouse brain matrix (RBM-2000C, ASI Instruments). We incorrectly identified the thickness as 
2 mm instead of 1 mm per section (page 753), and cubic millimeters per rat instead of cubic millimeters per mouse (page 754).2 The sections were stained with 2% 2,3,5-triphenyltetrazolium chloride and individually photographed by James Nicholson in the Laboratory Medicine Imaging Core Facility at the Medical University of South Carolina. During image assembly, we misplaced 1 of the 8 sections on the bottom of the right panel (first row) in the bradykinin B2 receptor knockout group 3 days after middle cerebral artery occlusion (MCAO; Figure 3; shown here). The correct image of the 2,3,5-triphenyltetrazolium chloride–stained serial section of the bradykinin B2 receptor knockout mouse is indicated by an arrow.
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Kleinschnitz et al1 indicated that the infarct size was small in our study.2 All of the images from the series of 2,3,5-triphenyltetrazolium chloride–stained sections of wild-type and B2R-KO mice were sent to Dr Cesar V. Borlongan (Department of Neurology and Institute of Molecular Medicine and Genetics, Medical College of Georgia) to calculate the infarct volume in a blinded fashion. The reason for the discrepancy is that we measured infarct size and volume corresponding with striatum only, which is the most consistent brain area damaged by MCAO. Our calculated infarct volume in wild-type mice 1 day after MCAO is quite close to the published data.3 The infarct size usually reaches a maximum at day 2 or 3 after MCAO and reduces gradually.4 Moreover, the infarct size is not significantly increased when the occlusion time changes from 60 minutes to 180 minutes.5
We chose to use only mice with neurologic deficit scores 
5 after fully recovering from anesthesia to assure that MCAO was successful.2 Our results showed that the mortality rate and neurologic deficit scores of bradykinin B2 receptor knockout mice (n=48) after MCAO were significantly increased compared with wild-type mice (n=40). The protective role of the kinin B2 receptor in ischemic brain injury was supported by our previous study using a rat MCAO model.6 Delayed systemic kallikrein gene delivery after MCAO was effective in reducing neurologic dysfunction, infarct size, apoptosis, and inflammation and promoting angiogenesis and neurogenesis. Neuroprotective effects of kallikrein were mediated by the kinin B2 receptor, because icatibant blocked the effects of kallikrein.6 Most importantly, a recent clinical report has demonstrated that human tissue (urinary) kallikrein is effective in the treatment of patients with acute brain infarction when intravenously infused within 48 hours of stroke onset.7 Given the current evidence, we are convinced that kallikrein/kinin through kinin B2 receptor activation plays a neuroprotective role in ischemic brain injury.
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Kleinschnitz C, Austinat M, Bader M, Renné T, Stoll G. Deficiency of bradykinin receptor B2 is not detrimental in experimental stroke. Hypertension. 2008; 51: e41.
2. Xia CF, Smith R, Shen B, Yang ZR, Borlongan C, Chao L, Chao J. Post-ischemic brain injury is exacerbated in mice lacking the kinin B2 receptor. Hypertension. 2006; 47: 1–7.
3. Kitano H, Nishimura H, Tachibana H, Yoshikawa H, Matsuyama T. ORP150 ameliorates ischemia/reperfusion injury from middle cerebral artery occlusion in mouse brain. Brain Res. 2004; 1015: 122–128.[CrossRef][Medline] [Order article via Infotrieve]
4. Henrich-Noack P, Baldauf K, Reiser G, Reymann KG. Pattern of time-dependent reduction of histologically determined infarct volume after focal ischaemia in mice. Neurosci Lett. 2008; 432: 141–145.[CrossRef][Medline] [Order article via Infotrieve]
5. Belayev L, Busto R, Zhao W, Fernandez G, Ginsberg MD. Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. Brain Res. 1999; 833: 181–190.[CrossRef][Medline] [Order article via Infotrieve]
6. Xia CF, Yin H, Yao YY, Borlongan CV, Chao L, Chao J. Kallikrein/kinin protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. Hum Gene Ther. 2006; 17: 206–219.[CrossRef][Medline] [Order article via Infotrieve]
7. Ding DY, Lu CZ, Ding MP, Su BH, Chen FA. Multicenter, randomized, double-blinded and placebo-controlled study of acute brain infarction treated by human urinary kallidinogenase. Chin J Neurol. 2007; 40: 306–310.
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  M. Austinat, S. Braeuninger, J. B. Pesquero, M. Brede, M. Bader, G. Stoll, T. Renne, and C. Kleinschnitz Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema * Expanded Materials and Methods Stroke, January 1, 2009; 40(1): 285 - 293. [Abstract] [Full Text] [PDF]
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