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

Abstract

Abstract Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on α 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 α 2D -ARs and hypoxia. Arterioles from rat cremaster muscle that possess both α 1D (α 1A/D )- and α 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 α 2D - and α 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 α 2D stimulation but unaffected during α 1D stimulation. Activation of the K ATP channel by cromakalim inhibited α 2D constriction with greater potency than α 1D (EC 50 , 7.0±0.2 versus 6.3±0.1). Finally, GLB (0.5 μmol/L) abolished dose-dependent α 2D constriction, whereas α 1D was unaffected. These data suggest that α 2D but not α 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 (P o 2 , 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 α 2D stimulation, was completely restored by simultaneous activation of K ATP channels with hypoxia. These findings suggest that the sensitivity of α 2D -AR constriction to inhibition by hypoxia arises through “antagonistic coupling” between these two stimuli, by which the α 2D -AR inhibits and hypoxia activates K ATP channels.