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<0.05 compared to sham, n=10/group. B2Rago (720 nmol/kg.day-1) increased ND to 27 ± 1.8 at day 1 and mortality to 60% at day 2 (both p<0.05, n=10) while decreasing brain infarct size by 66% (p<0.01). B2Rago reduced BP by 16 mmHg and increased plasma creatinine (73 ± 25 μmol/l, p<0.05). Although B1R mRNA level increased by 1.3 fold in the ischemic brain B1Rago had no effect on ND, mortality or brain infarction.
In diabetic mice MCAO increased ND (28 ± 1), mortality (25%) and infarct size (40 ± 3 %) more than in non-diabetic mice (n=8, p<0.05). B2Rago increased mortality to 80% (p<0.05, n=9). B1Rago, tested at two different dosages (720 or 240 nmol/kg.day-1, n= 8/group) reduced ND (22 ± 2 at day 2 for the low dosage, p< 0.05) and did not increase mortality or alter renal function. B1Rago reduced infarct size by 66 and 71 %, at the two dosages, respectively (p<0.01).
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.
Author Disclosures: D. Desposito: None. C. Taveau: None. G. Zadigue: None. C. Adam: None. N. Bouby: None. F. Alhenc-Gelas: None. R. Roussel: None.
- © 2015 by American Heart Association, Inc.