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

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 alpha-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 alpha 1-AR (norepinephrine + rauwolscine) or alpha 2-AR (UK 14,304 + prazosin) tone was induced in rat cremaster skeletal muscle arterioles and venules (control lumen diameter, 134 and 194 micron respectively), and tissue bath PO2 was lowered from the control value (30 mm Hg). Arteriolar alpha 2-AR tone was inhibited by 29% at 5 mm Hg PO2 (P < .05), whereas arteriolar alpha 1-, venular alpha 1, and venular alpha 2-AR constrictions were unaffected. Like these findings obtained for in situ vessels with normal blood flow, alpha 1-AR tone induced in vascularly "isolated" venules and basal diameter were again unaffected by hypoxia, whereas alpha 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 alpha 2- and alpha 1-AR tone still remained insensitive to inhibition by hypoxia. ATP-sensitive K+ (KATP) 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 KATP antagonists glibenclamide and U-37883A and the KATP channel opener cromakalim suggested that venular, unlike arteriolar, smooth muscle had no detectable basal or inducible KATP activity. Also, unlike arteriolar alpha 2-AR constriction, venular alpha 2-AR tone did not depend on KATP activity. Finally, venular alpha 2-AR tone was unaffected by nifedipine (0.06 to 3 mumol/L), whereas venular alpha 1-AR tone was inhibited by 50% (P < .05), findings opposite those found for arteriolar alpha 1 and alpha 2 tone. These data demonstrate that venular alpha 1- and alpha 2-AR constrictions are insensitive to inhibition by hypoxia and suggest that this may be due to a paucity of KATP channels on venular smooth muscle. In addition, venular alpha 1- but not alpha 2-ARs appear to couple to dihydropyridine-sensitive voltage-operated Ca2+ channels.