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(Circulation Research. 1995;76:53-63.)
© 1995 American Heart Association, Inc.

Articles

ATP-Sensitive K⁺ Channels Mediate _2D-Adrenergic Receptor Contraction of Arteriolar Smooth Muscle and Reversal of Contraction by Hypoxia

Jun Tateishi, James E. Faber

From the Department of Physiology, University of North Carolina, Chapel Hill.

Abstract Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on _2D-adrenergic receptors (ARs) for constriction of arterioles, together with the strong sensitivity of this constriction to inhibition by hypoxia. The present study examined the role of ATP-sensitive K⁺ (K_ATP) channels in the selective interaction between _2D-ARs and hypoxia. Arterioles from rat cremaster muscle that possess both _1D (_1A/D)- and _2D-AR subtypes were microcannulated, pressurized, and isolated in a tissue bath for measurement of changes in lumen diameter. Three studies first examined whether stimulation of _2D- and _1D-ARs involves inhibition of the K_ATP channel. Concentration-dependent constriction by the K_ATP antagonists glibenclamide (GLB, 0.01 to 10 µmol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during _2D stimulation but unaffected during _1D stimulation. Activation of the K_ATP channel by cromakalim inhibited _2D constriction with greater potency than _1D (EC₅₀, 7.0±0.2 versus 6.3±0.1). Finally, GLB (0.5 µmol/L) abolished dose-dependent _2D constriction, whereas _1D was unaffected. These data suggest that _2D but not _1D stimulation is "coupled" with closure of the K_ATP channel, leading to depolarization and contraction of vascular smooth muscle. In a second series, hypoxic (PO₂, 6 mm Hg) inhibition of intrinsic smooth muscle tone was completely reversed by 0.1 µmol/L GLB, concentration-dependent GLB constriction was enhanced during hypoxia, and hypoxia reversed GLB constriction. These data confirm reports by others that hypoxia potentiates the activation of K_ATP channels, leading to hyperpolarization and relaxation. Finally, GLB constriction, which was abolished by concomitant _2D stimulation, was completely restored by simultaneous activation of K_ATP channels with hypoxia. These findings suggest that the sensitivity of _2D-AR constriction to inhibition by hypoxia arises through "antagonistic coupling" between these two stimuli, by which the _2D-AR inhibits and hypoxia activates K_ATP channels.

Key Words: -adrenergic receptor • vascular smooth muscle • microcirculation • receptor coupling • hypoxia

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