The mechanisms by which active neurons, via astrocytes, rapidly signal intracerebral arterioles to dilate remain obscure. Here we show that modest elevation of extracellular potassium (K+) activated inward rectifier K+ (Kir) channels and caused membrane potential hyperpolarization in smooth muscle cells (SMCs) of intracerebral arterioles and, in cortical brain slices, induced Kir-dependent vasodilation and suppression of SMC intracellular calcium (Ca2+) oscillations. Neuronal activation induced a rapid (<2 s latency) vasodilation that was greatly reduced by Kir channel blockade and completely abrogated by concurrent cyclooxygenase inhibition. Astrocytic endfeet exhibited large-conductance, Ca2+-sensitive K+ (BK) channel currents that could be activated by neuronal stimulation. Blocking BK channels or ablating the gene encoding these channels prevented neuronally induced vasodilation and suppression of arteriolar SMC Ca2+, without affecting the astrocytic Ca2+ elevation. These results support the concept of intercellular K+ channel-to-K+ channel signaling, through which neuronal activity in the form of an astrocytic Ca2+ signal is decoded by astrocytic BK channels, which locally release K+ into the perivascular space to activate SMC Kir channels and cause vasodilation.

BK large conductance voltage-and calcium-activated potassium channels respond to elevations in intracellular calcium and membrane potential depolarization, braking excitability of smooth muscle. BK channels are thought to have a particularly prominent role in urinary bladder smooth muscle function and therefore are candidate targets for overactive bladder therapy. To address the role of the BK channel in urinary bladder function, the gene mSlo1 for the pore-forming subunit of the BK channel was deleted. Slo ؊/؊ mice were viable but exhibited moderate ataxia. Urinary bladder smooth muscle cells of Slo ؊/؊ mice lacked calcium-and voltageactivated BK currents, whereas local calcium transients ("calcium sparks") and voltage-dependent potassium currents were unaffected. In the absence of BK channels, urinary bladder spontaneous and nerve-evoked contractions were greatly enhanced. Consistent with increased urinary bladder contractility caused by the absence of BK currents, Slo ؊/؊ mice demonstrate a marked elevation in urination frequency. These results reveal a central role for BK channels in urinary bladder function and indicate that BK channel dysfunction leads to overactive bladder and urinary incontinence.Overactive urinary bladder and urinary incontinence is a significant health issue occurring in about 51 million (ϳ17%) of the United States population (1), frequently occurring as a secondary consequence of conditions such as diabetes mellitus, stroke, and spinal cord injury. Urge incontinence is caused by overactivity of the urinary bladder smooth muscle (UBSM), 1 often a result of partial urethral outlet obstruction that can occur during prostate hypertrophy. Currently there is a lack of effective therapeutic agents to control urinary bladder function. Antimuscarinic agents, which impair UBSM contraction, are used to treat urinary incontinence but have limited effectiveness and undesirable side effects. More recently, potassium channel opening drugs have been explored as therapeutic agents for urinary incontinence (2-6).BK potassium channels regulate membrane potential and repolarization of UBSM action potentials (7-8). UBSM BK channels are activated by membrane potential depolarization and calcium influx through voltage-dependent calcium channels that occur during the action potential (9). UBSM BK channels are also activated by local intracellular calcium release through ryanodine receptors (calcium sparks) (10). Specific inhibition of BK channels by iberiotoxin (IBTX) causes a pronounced elevation in bladder contractility (8,(11)(12). Deletion of the smooth muscle-specific, modulatory ␤1 subunit decreases the apparent voltage-and calcium-sensitivity of UBSM BK channels, leading to an enhancement of phasic contractility (12). These studies point to a pivotal role of the BK channel in urinary bladder function. EXPERIMENTAL PROCEDURESGeneration of Slo Ϫ/Ϫ Mice-mSlo1 genomic clones were isolated from a 129/SvJ BAC library (Incyte Genomics) using an ϳ1.6-kb EcoRV/XhoI cDNA probe fragment. A 7.8-kb SalI/BamHI geno...