KIR Channel Regulation of Electrical Conduction along Cerebrovascular Endothelium: Enhanced Modulation During Alzheimer's Disease.

Objective: Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K+ (K-IR) channels. This study addressed effects of K-IR channel activity on EC coupling before and during Alzheimer's disease (AD). Methods: Intact EC tubes (width: similar to 90-100 mu m; length: similar to 0.5 mm) were freshly isolated from posterior cerebral arteries of young Pre-AD (1-3 months) and aged AD (13-18 months) male and female 3xTg-AD mice. Dual intracellular microelectrodes applied simultaneous current injections (+/- 0.5-3 nA) and membrane potential (V-m) recordings in ECs at distance similar to 400 mu m. Elevated extracellular potassium ([K+](E); 8-15 mmol/L; reference, 5 mmol/L) activated K-IR channels. Results: Conducted V-m ( increment V-m) responses ranged from similar to-30 to 30 mV in response to -3 to +3 nA (linear regression, R-2 >= .99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased similar to 10%-20% during 15 mmol/L [K+](E) in Pre-AD males and AD females. 15 mmol/L [K+](E) decreased conduction by similar to 10%-20% at lower increment V-m thresholds in AD animals (similar to +/- 20 mV) versus Pre-AD (similar to +/- 25 mV). AD increased conducted hyperpolarization by similar to 10%-15% during 8-12 mmol/L [K+](E). Conclusions: Brain endothelial K-IR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.