Adenosine (ADO) is a potent cerebrovasodilator and has been proposed as a metabolic regulator of cerebral blood flow. However, the mechanism of action by which ADO causes vasodilation in the cerebral circulation is currently unknown. Furthermore, it is not known whether there is a heterogeneity in ADO vasoactivity or receptor subtype vascular tree of the cerebral circulation. This proposal outlines experiments designed to characterize the response of ADO specific to the location in the cerebral circulation and describe the mechanism of action of ADO. Thus, we wish to characterize and define the mechanism of action of ADO dilation in the cerebral circulation in a cell-specific manner, specifically with regard to receptor subtype activation and ion channel activation. Specifically we hypothesize that there is spatial heterogeneity within the cerebral circulation in the 1) vasoactive response to ADO and 2) specific ion channel activation by ADO receptor, and that 3) ADO acts at a specific ADO receptor subtype to cause vasodilation. The proposed experiments will employ techniques of both in vitro isolated perfused vessels and patch clamp studies of isolated vascular smooth muscle (VSM) myocytes as well as pharmacologic and molecular tools to identify specific ADO receptors.
The specific aims are to: 1) Characterize ADO vasoactivity in the arterial network in the rat cerebral circulation in a region-specific manner using an in vitro preparation; 2) Define the functional and molecular anatomy of ADO receptors and the cell-specific spatial distribution of the receptors in cerebrovascular vessels. 3) Define the role of KATP channels and KCa channels of ADO-induced vasodilation in the arterial network using an in vitro isolated perfused vessel with spontaneous tone and isolated single VSM cells.
| Bahjat, Frances Rena; Williams-Karnesky, Rebecca L; Kohama, Steven G et al. (2011) Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. J Cereb Blood Flow Metab 31:1229-42 |
| West, G Alexander; Golshani, Kiarash J; Doyle, Kristian P et al. (2009) A new model of cortical stroke in the rhesus macaque. J Cereb Blood Flow Metab 29:1175-86 |
| Iliff, Jeffrey J; Alkayed, Nabil J; Gloshani, Kiarash J et al. (2005) Cocaine- and amphetamine-regulated transcript (CART) peptide: a vasoactive role in the cerebral circulation. J Cereb Blood Flow Metab 25:1376-85 |
