Carbon Monoxide Dilates Cerebral Arterioles by Enhancing the Coupling of Ca 2+ Sparks to Ca 2+ -Activated K + Channels

Abstract

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 Ca 2+ -activated K + (K Ca ) channels and Ca 2+ spark–induced transient K Ca currents in arteriole smooth muscle cells. In contrast, CO is a relatively poor activator of Ca 2+ sparks. To understand the apparent discrepancy between potent effects on transient K Ca currents and weak effects on Ca 2+ sparks, regulation of the coupling relationship between these events by CO was investigated. CO increased the percentage of Ca 2+ sparks that activated a transient K Ca current (ie, the coupling ratio) from ≈62% in the control condition to 100% and elevated the slope of the amplitude correlation between these events ≈2.6-fold, indicating that Ca 2+ 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 Ca 2+ release channel blocker that inhibits Ca 2+ sparks, abolished CO dilation of pial arterioles in vivo. Thus, CO dilates cerebral arterioles by priming K Ca channels for activation by Ca 2+ sparks. This study presents a novel dilatory signaling pathway for CO in the cerebral circulation and appears to be the first presents of a vasodilator that acts by increasing the effective coupling of Ca 2+ sparks to K Ca channels.