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)-adrenegic 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 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 K-ATP channel. Concentration-dependent constriction by the K-ATP antagonists glibenclamide (GLB, 0.01 to 10 mu mol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during alpha(2D) stimulation but unaffected during alpha(1D) stimulation. Activation of the K-ATP channel by cromakalim inhibited alpha(2D) constriction with greater potency than alpha(1D) (EC(50), 7.0+/-0.2 versus 6.3+/-0.1). Finally, GLB (0.5 mu mol/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 K-ATP channel, leading to depolarization and contraction of vascular smooth muscle. In a second series, hypoxic (Po-2, 6 mm Hg) inhibition of intrinsic smooth muscle tone was completely reversed by 0.1 mu mol/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 alpha(2D) stimulation, was completely restored by simultaneous activation of K-ATP 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 K-ATP channels.