Urodilatin reverses the detrimental influence of bradykinin in acute ischemic stroke

• Published in: Experimental neurology 2016-10, Vol.284 (Pt A), p.1-10
• Main Authors: Dobrivojević, Marina, Špiranec, Katarina, Gorup, Dunja, Erjavec, Igor, Habek, Nikola, Radmilović, Marin, Unfirer, Sanela, Ćosić, Anita, Drenjančević, Ines, Gajović, Srećko, Sinđić, Aleksandra
• Format: Article
• Language: English
• Subjects: Atrial natriuretic peptide; Brain natriuretic peptide; C type natriuretic peptide; cGMP; Urodilatin
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2016.07.007

Occlusion of cerebral arteries leads to ischemic stroke accompanied by subsequent brain edema. Bradykinin (BK) is involved in the formation of cerebral edema, and natriuretic peptides (NPs) potentially have beneficial effects on brain edema formation via a still unknown mechanism. The aim of this study was clarifying the mechanisms of action of NPs on BK signaling, and their interactive effects after ischemic brain injury. We used a mouse model for stroke, the middle cerebral artery (MCA) occlusion. Brain lesion and edema were measured by microcomputerized tomography volumetric measurements. To determine the effects of NPs on the BK signaling pathway in the MCAs we measured changes in vessel diameter and membrane potentials in endothelial cells. To determine the effects of NPs on BK signaling pathway in isolated astrocytes and neurons, membrane potentials and intercellular Ca2+ concentrations were measured. Urodilatin inhibited and when applied together with BK, reduced the formation of the ischemic lesion via activation of G-Protein–Signaling Protein Type 4 at the cellular (atrocities, neurons) and blood vessel (endothelial cells and isolated MCA) level as well as in in vivo experiments. The results of this study show the existence of a natural antagonist of BK in the brain, and the possible use of NPs in the treatment of stroke. •Urodilatin inhibits the effects of bradykinin.•Those inhibitions are shown in neurons and astrocytes, endothelial cells and intact middle cerebral artery.•Action of urodilatin leads to ameliorations of the development of stroke symptoms, brain lesions, and edema after MCAO.