OPC-28326, a selective femoral vasodilator, is an alpha(2C)-adrenoceptor-selective antagonist

OPC-28326 has been reported to selectively increase femoral blood flow in o pen-chest dogs and autoperfused canine femoral artery preparations. Prelimi nary data indicated that OPC-28326 has a high affinity at the alpha (2)-adr enoceptor. In the present study, we tested OPC-28326 in isoflurane anesthet ized rats at a dose of 3 mg/kg of body weight, given intraduodenally. OPC-2 8326 significantly increased femoral blood flow, by 447 +/- 13.8%, 45 min a fter drug administration, whereas carotid blood flow increased by only 3.6 +/- 5.5% (n = 6). Chinese hamster ovary cell lines overexpressing rat alpha (-)(2D)(,) alpha (2B)-, or alpha (2C)-adrenoceptor were established. These cells also coexpress luciferase, driven by CAMP elevation. In radioligand binding assays using cell membrane preparations, OPC-28326 dose dependently competed with [H-3]RX821002 binding, with calculated K-i values of 3840 +/ - 887, 633 +/- 46, and 13.7 +/- 1.9 nM on alpha (2D)-, alpha (2B)-, and alp ha (2C)-adrenoceptor, respectively. A similar affinity and rank order of po tency were also found for OPC-28326 on the alpha (2)-subtypes using epineph rine as agonist in luciferase assays. No agonistic effect of OPC-28326 was detected on any of the alpha (2)-adrenoceptors. Finally, in situ hybridizat ion performed on skeletal muscle tissue sections collected from rat hind li mb (musculus gastrocnemius) demonstrated a high level expression of alpha ( 2C) in the vascular tissues. Thus, the abundance of alpha (2C) in the skele tal muscle may account for the selective effect of OPC-28326 in increasing femoral blood flow.