DIMINISHED MUSCARINIC RECEPTOR-MEDIATED CEREBRAL BLOOD-FLOW RESPONSE IN STREPTOZOTOCIN-TREATED RATS

Endothelium-dependent vascular relaxation in the brain may be impaired in the streptozotocin-treated chronically hyperglycemic diabetic (D) rat. To study this, we measured regional cerebral blood flow (rCBF) changes induced by intracarotid (ic) or intravenous (iv) infusions of the blood-brain permeant muscarinic receptor (MR) agonist oxotremorine (Oxo). In nondiabetic (ND) rats, both ic and iv Oxo resulted in significant (P < 0.05) rCBF increases from values obtained during saline infusions in the regions analyzed. The maximum rCBF values measured during Oxo (expressed as percent iv or ic saline value) were 358-403% in the cortex (CX), 236-260% in the subcortex (SC), 162-186% in the brain stem (BS), and 143-158% in the cerebellum (CE). The iv or ic Oxo response in D vs. ND rats was reduced by 60-70% in the CX and SC, lost in the BS, and unchanged in the CE. The CBF response was associated with no change in cortical CMRO2 and was completely blocked during ic atropine-Oxo co-infusion or iv co-infusion of Oxo with the nitric oxide (NO) synthesis inhibitor L-nitroarginine methyl ester, demonstrating, respectively, no role for metabolic activation, the exclusive role of MR values, and the critical role for the release of the putative endothelium-dependent relaxation factor NO in mediating this effect. These findings indicate a significant, but regionally variable, impairment of the mechanism for endothelium-dependent vascular relaxation in the diabetic brain.