CP-0597

The effects of the tachykinin NK(2)receptor antagonist, MEN 11420 (300 nmol/kg) and the bradykinin B(2)receptor antagonist, CP 0597 (17.2 and 172 nmol/kg) were studied in a rabbit model of antigen-induced airway responses. Antigen inhalation induced acute bronchoconstriction, airway hyperresponsiveness to histamine, and pulmonary eosinophil infiltration in 3-month-old rabbits immunized with Alternaria tenuis antigen within 24 h of birth. Treatment with MEN 11420 significantly reduced the acute bronchoconstriction induced by antigen, in terms of lung resistance. Antigen-induced changes in dynamic compliance were unaffected. CP 0597 had no effect on antigen-induced changes in lung function. Neither MEN 11420 nor CP 0597 had a significant effect on the antigen-induced increase in airway responsiveness to inhaled histamine or the pulmonary eosinophil infiltration 24 h after antigen challenge. We conclude that blockade of the NK(2)receptor can alter acute airway responses to antigen, but not antigen-induced eosinophilia or hyperresponsiveness to histamine. We also conclude that bradykinin B(2)receptor-mediated responses do not play a role in airway responses to antigen.

Background and PurposeRecent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B2receptor 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.MethodsMale 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 After 1 hour the filament was retracted and the ischemic tissue reperfused.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.ResultsTreatment 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 mm3versus CP-0597, 94.0±19.2 mm3;P<.001), cortical infarct volume (vehicle, 145.5±4.5 mm3versus CP-0597, 64.0±15.1 mm3;P<.001), subcortical infarct volume (vehicle, 55.8±4.1 mm3versus 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.ConclusionsThe 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 B2receptor antagonist in the treatment of stroke.