Circulation Research. 2002;91:610-617
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036900.76780.95
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036900.76780.95
© 2002 American Heart Association, Inc.
Cellular Biology |
Carbon Monoxide Dilates Cerebral Arterioles by Enhancing the Coupling of Ca2+ Sparks to Ca2+-Activated K+ Channels
From the Department of Physiology, University of Tennessee Health Science Center, Memphis.
Correspondence to Jonathan H. Jaggar, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163. E-mail jjaggar{at}physio1.utmem.edu
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+ (KCa) channels and Ca2+ spark–induced transient KCa 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 KCa 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 KCa 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 Ca2+ sparks induced larger amplitude transient KCa 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 KCa 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 presents of a vasodilator that acts by increasing the effective coupling of Ca2+ sparks to KCa channels.
Key Words: ryanodine-sensitive Ca2+ release channels • Ca2+-sensitive K+ channels • heme oxygenase
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