Abstract P159: Effect of Pharmacological Kinin Receptor Activation on Brain Damage and Mortality in Experimental Cerebral Ischemia in Non-diabetic and Diabetic Mice

Brain ischemia is a major complication of arterial diseases and has a poorer prognosis in diabetic patients. As activation of the kallikrein-kinin system has been shown to enhance cardiac and renal tolerance to ischemia we tested effect of kinin receptor activation by pharmacological agonists, selective B1R or B2R, in a mouse model of transient middle cerebral artery occlusion [C57bl6 male, 10 week-old, anaesthesia, occlusion 60 min (MCAO)]. Treatment with the B1R agonist NG29 (B1Rago) or the B2R agonist NG291 (B2Rago) was started at reperfusion using osmotic micropumps. Neurological deficit (ND) was evaluated at 1 and 2 days using a panel of 8 established tests combined in a 0-30 deficit score. Brain infarction was quantified at day 2 using TTC and hematoxylin-eosin staining. In some mice diabetes was induced by streptozotocin 8 weeks before MCAO. MCAO induced bradychardia, mild hypotension (mean -11.3 mmHg), ND (19.7 ± 2.4) and resulted in partial brain infarction (18 ± 1.4 %), all p In diabetic mice MCAO increased ND (28 ± 1), mortality (25%) and infarct size (40 ± 3 %) more than in non-diabetic mice (n=8, p Thus, B2R activation reduces brain infarction but paradoxically increases mortality by mechanisms that may involve brain oedema and renal insufficiency. B1R activation has no effect in non-diabetic mice but in diabetic animals it reduces infarct size and improves ND without adverse effect on renal function and survival. Longer follow-up studies are in progress for further evaluating interest and limitation of B1R activation in MCAO.