Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca2+-activated K+ (BK) channels

The cellular events that cause ischemic neurological damage following aneurysmal subarachnoid hemorrhage (SAH) have remained elusive. We report that subarachnoid blood profoundly impacts communication within the neurovascular unit-neurons, astrocytes, and arterioles-causing inversion of neurovascular coupling. Elevation of astrocytic endfoot Ca2+ to similar to 400 nM by neuronal stimulation or to similar to 300 nM by Ca2+ uncaging dilated parenchymal arterioles in control brain slices but caused vasoconstriction in post-SAH brain slices. Inhibition of K+ efflux via astrocytic endfoot large-conductance Ca2+-activated K+ (BK) channels prevented both neurally evoked vasodilation (control) and vasoconstriction (SAH). Consistent with the dual vasodilator/vasoconstrictor action of extracellular K+ ([K+](omicron)), [K+](omicron) <10 mM dilated and [K+](omicron) > 20 mM constricted isolated brain cortex parenchymal arterioles with or without SAH. Notably, elevation of external K+ to 10 mM caused vasodilation in brain slices from control animals but caused a modest constriction in brain slices from SAH model rats; this latter effect was reversed by BK channel inhibition, which restored K+- induced dilations. Importantly, the amplitude of spontaneous astrocytic Ca2+ oscillations was increased after SAH, with peak Ca2+ reaching similar to 490 nM. Our data support a model in which SAH increases the amplitude of spontaneous astrocytic Ca2+ oscillations sufficiently to activate endfoot BK channels and elevate [K+] o in the restricted perivascular space. Abnormally elevated basal [K+](omicron) combined with further K+ efflux stimulated by neuronal activity elevates [K+](omicron) above the dilation/constriction threshold, switching the polarity of arteriolar responses to vasoconstriction. Inversion of neurovascular coupling may contribute to the decreased cerebral blood flow and development of neurological deficits that commonly follow SAH.