This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Relton, J. K. Articles by Whalley, E. T. Search for Related Content PubMed PubMed Citation Articles by Relton, J. K. Articles by Whalley, E. T.

(Stroke. 1997;28:1430-1436.)
© 1997 American Heart Association, Inc.

Articles

CP-0597, a Selective Bradykinin B₂ Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Jane K. Relton, PhD; Virginia E. Beckey, MS; Wendy L. Hanson, BA; E. T. Whalley, PhD

From Cortech Inc, Denver, Colo.

Correspondence to Virginia Beckey, Cortech Inc, Denver, CO 80221. E-mail gbeckey{at}crtq.com

Background and Purpose Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B₂ receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat.

Methods Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n=14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-µm sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight.

Results Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6±4.3% versus CP-0597, 20.8±5.3%; P<.001), total infarct volume (vehicle, 206.5±7.7 mm³ versus CP-0597, 94.0±19.2 mm³; P<.001), cortical infarct volume (vehicle, 145.5±4.5 mm³ versus CP-0597, 64.0±15.1 mm³; P<.001), subcortical infarct volume (vehicle, 55.8±4.1 mm³ versus CP-0597, 27.5±4.5 mm³; P<.001), and the number of necrotic neurons (vehicle, 42.9±3.8 versus CP-0597, 23.6±4.7 per field; P<.01). Neurological score (vehicle, 2.78±0.36 versus CP-0597, 6.29±0.87; P<.01) and change in body weight (vehicle, -28.7±2.0 g versus CP-0597, -18.2±2.8 g; P<.01) were also significantly improved.

Conclusions The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such a bradykinin B₂ receptor antagonist in the treatment of stroke.

Key Words: bradykinin • brain edema • cerebral ischemia, focal • neuroprotection • rats

This article has been cited by other articles:

				C. Storini, L. Bergamaschini, R. Gesuete, E. Rossi, D. Maiocchi, and M. G. De Simoni Selective Inhibition of Plasma Kallikrein Protects Brain from Reperfusion Injury J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 849 - 854. [Abstract] [Full Text] [PDF]

				D. J. Kozik and J. S. Tweddell Characterizing the Inflammatory Response to Cardiopulmonary Bypass in Children Ann. Thorac. Surg., June 1, 2006; 81(6): S2347 - S2354. [Abstract] [Full Text] [PDF]

				L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]

				M. G. De Simoni, E. Rossi, C. Storini, S. Pizzimenti, C. Echart, and L. Bergamaschini The Powerful Neuroprotective Action of C1-Inhibitor on Brain Ischemia-Reperfusion Injury Does Not Require C1q Am. J. Pathol., May 1, 2004; 164(5): 1857 - 1863. [Abstract] [Full Text] [PDF]

				T. Matsuda, N. Arakawa, K. Takuma, Y. Kishida, Y. Kawasaki, M. Sakaue, K. Takahashi, T. Takahashi, T. Suzuki, T. Ota, et al. SEA0400, a Novel and Selective Inhibitor of the Na+-Ca2+ Exchanger, Attenuates Reperfusion Injury in the in Vitro and in Vivo Cerebral Ischemic Models J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 249 - 256. [Abstract] [Full Text]

				M H Sarker, D-E Hu, and P A Fraser Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat J. Physiol., October 1, 2000; 528(1): 177 - 187. [Abstract] [Full Text] [PDF]

				G. J DEL ZOPPO, R. VON KUMMER, and G. F HAMANN Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke J. Neurol. Neurosurg. Psychiatry, July 1, 1998; 65(1): 1 - 9. [Full Text]