Differential Sensitivity of Venular and Arteriolar α-Adrenergic Receptor Constriction to Inhibition by Hypoxia

Abstract

Abstract Reflex adrenergic constriction of the venous circulation is considerably less sensitive than the arterial circulation to local metabolic inhibition, but the basis for this difference remains unclear. The purpose of the present study was to determine whether α-adrenergic receptor (AR) constriction of venular smooth muscle is in fact protected against inhibition by hypoxia, per se, and to examine possible mechanisms for this protection. An intermediate level of α 1 -AR (norepinephrine+rauwolscine) or α 2 -AR (UK 14,304+prazosin) tone was induced in rat cremaster skeletal muscle arterioles and venules (control lumen diameter, 134 and 194 μm, respectively), and tissue bath P o 2 was lowered from the control value (30 mm Hg). Arteriolar α 2 -AR tone was inhibited by 29% at 5 mm Hg P o 2 ( P <.05), whereas arteriolar α 1 -, venular α 1 -, and venular α 2 -AR constrictions were unaffected. Like these findings obtained for in situ vessels with normal blood flow, α 1 -AR tone induced in vascularly “isolated” venules and basal diameter were again unaffected by hypoxia, whereas α 2 -AR tone was actually enhanced by 19% ( P <.05). This constriction was prevented by indomethacin but not by endothelin or nitric oxide blockade; importantly, however, venular α 2 - and α 1 -AR tone still remained insensitive to inhibition by hypoxia. ATP-sensitive K + (K ATP ) channels, which are known to participate in hypoxic inhibition of arteriolar smooth muscle, were examined for a role in this differential arteriolar versus venular sensitivity to hypoxia. Use of the K ATP antagonists glibenclamide and U-37883A and the K ATP channel opener cromakalim suggested that venular, unlike arteriolar, smooth muscle had no detectable basal or inducible K ATP activity. Also, unlike arteriolar α 2 -AR constriction, venular α 2 -AR tone did not depend on K ATP activity. Finally, venular α 2 -AR tone was unaffected by nifedipine (0.06 to 3 μmol/L), whereas venular α 1 -AR tone was inhibited by 50% ( P <.05), findings opposite those found for arteriolar α 1 and α 2 tone. These data demonstrate that venular α 1 - and α 2 -AR constrictions are insensitive to inhibition by hypoxia and suggest that this may be due to a paucity of K ATP channels on venular smooth muscle. In addition, venular α 1 - but not α 2 -ARs appear to couple to dihydropyridine-sensitive voltage-operated Ca 2+ channels.