title: Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels.
abstract: BACKGROUND
  Acidosis is a powerful vasodilator signal in the brain circulation. However, the mechanisms by which this response occurs are not well understood, particularly in the cerebral microcirculation. One important mechanism to dilate cerebral (pial) arteries is by activation of large-conductance, calcium-sensitive potassium (BK(Ca)) channels by local Ca(2+) signals (Ca(2+) sparks) through ryanodine receptors (RyRs). However, the role of this pathway in the brain microcirculation is not known.
  
  
  OBJECTIVE
  The objectives of this study were to determine the mechanism by which acidosis dilates brain parenchymal arterioles (PAs) and to elucidate the roles of RyRs and BK(Ca) channels in this response.
  
  
  RESULTS
  Internal diameter and vascular smooth muscle cell Ca(2+) signals were measured in isolated pressurized murine PAs, using imaging techniques. In physiological pH (7.4), vascular smooth muscle cells exhibited primarily RyR-dependent Ca(2+) waves. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca(2+) wave activity, and dramatically increased Ca(2+) spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% by BK(Ca) channel or RyR blockers, in a nonadditive manner. Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BK(Ca) channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of K(ATP) channels or nitric oxide synthase.
  
  
  CONCLUSIONS
  These results support the novel concept that acidification, by converting Ca(2+) waves to sparks, leads to the activation of BK(Ca) channels to induce dilation of cerebral PAs.
authors.affiliation: University of Vermont College of Medicine, Department of Pharmacology, 89 Beaumont Avenue, B-303 Given Building, Burlington, VT 05405-0068, USA.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Dabertrand
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Brayden
mesh_terms: D000138:Acidosis / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D054086:KATP Channels; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
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