ATP-sensitive K+ channels mediate alpha 2D-adrenergic receptor contraction of arteriolar smooth muscle and reversal of contraction by hypoxia.

Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on alpha 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+ (KATP) channels in the selective interaction between alpha 2D-ARs and hypoxia. Arterioles from rat cremaster muscle that possess both alpha 1D (alpha 1A/D)- and alpha 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 alpha 2D- and alpha 1D-ARs involves inhibition of the KATP channel. Concentration-dependent constriction by the KATP antagonists glibenclamide (GLB, 0.01 to 10 mumol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during alpha 2D stimulation but unaffected during alpha 1D stimulation. Activation of the KATP channel by cromakalim inhibited alpha 2D constriction with greater potency than alpha 1D (EC50, 7.0 +/- 0.2 versus 6.3 +/- 0.1). Finally, GLB (0.5 mumol/L) abolished dose-dependent alpha 2D constriction, whereas alpha 1D was unaffected. These data suggest that alpha 2D but not alpha 1D 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 mumol/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 alpha 2D stimulation, was completely restored by simultaneous activation of KATP channels with hypoxia. These findings suggest that the sensitivity of alpha 2D-AR constriction to inhibition by hypoxia arises through "antagonistic coupling" between these two stimuli, by which the alpha 2D-AR inhibits and hypoxia activates KATP channels.