ATP-Sensitive K + Channels Mediate α 2D -Adrenergic Receptor Contraction of Arteriolar Smooth Muscle and Reversal of Contraction by Hypoxia

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Abstract
Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on α2D-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+ (KATP) channels in the selective interaction between α2D-ARs and hypoxia. Arterioles from rat cremaster muscle that possess both α1D (α1A/D)- and α2D-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 α2D- and α1D-ARs involves inhibition of the KATP channel. Concentration-dependent constriction by the KATP antagonists glibenclamide (GLB, 0.01 to 10 μmol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during α2D stimulation but unaffected during α1D stimulation. Activation of the KATP channel by cromakalim inhibited α2D constriction with greater potency than α1D (EC50, 7.0±0.2 versus 6.3±0.1). Finally, GLB (0.5 μmol/L) abolished dose-dependent α2D constriction, whereas α1D was unaffected. These data suggest that α2D but not α1D stimulation is “coupled” with closure of the KATP 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 KATP channels, leading to hyperpolarization and relaxation. Finally, GLB constriction, which was abolished by concomitant α2D stimulation, was completely restored by simultaneous activation of KATP channels with hypoxia. These findings suggest that the sensitivity of α2D-AR constriction to inhibition by hypoxia arises through “antagonistic coupling” between these two stimuli, by which the α2D-AR inhibits and hypoxia activates KATP channels.