Carbon monoxide dilates cerebral arterioles by enhancing the coupling of Ca2+ sparks to Ca2+-activated K+ channels.
Carbon monoxide (CO) is generated endogenously by the enzyme heme oxygenase. Although CO is a known vasodilator, cellular signaling mechanisms are poorly understood and are a source of controversy. The goal of the present study was to investigate mechanisms of CO dilation in porcine cerebral arterioles. Data indicate that exogenous or endogenously produced CO is a potent activator of large-conductance Ca2+-activated K+ (K(Ca)) channels and Ca2+ spark-induced transient K(Ca) currents in arteriole smooth muscle cells. In contrast, CO is a relatively poor activator of Ca2+ sparks. To understand the apparent discrepancy between potent effects on transient K(Ca) currents and weak effects on Ca2+ sparks, regulation of the coupling relationship between these events by CO was investigated. CO increased the percentage of Ca2+ sparks that activated a transient K(Ca) current (ie, the coupling ratio) from approximately 62% in the control condition to 100% and elevated the slope of the amplitude correlation between these events approximately 2.6-fold, indicating that Ca2+ sparks induced larger amplitude transient K(Ca) currents in the presence of CO. This signaling pathway for CO is physiologically relevant because ryanodine, a ryanodine-sensitive Ca2+ release channel blocker that inhibits Ca2+ sparks, abolished CO dilation of pial arterioles in vivo. Thus, CO dilates cerebral arterioles by priming K(Ca) channels for activation by Ca2+ sparks. This study presents a novel dilatory signaling pathway for CO in the cerebral circulation and appears to be the first demonstration [corrected] of a vasodilator that acts by increasing the effective coupling of Ca2+ sparks to K(Ca) channels.
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D002248:Carbon Monoxide / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000502:physiology*; D046508:Culture Techniques; D004553:Electric Conductivity; D006418:Heme / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D019837:Ryanodine Receptor Calcium Release Channel; D014665:Vasodilator Agents; C106087:heme lysinate; D012433:Ryanodine; D006418:Heme; D002248:Carbon Monoxide; D008239:Lysine