title: OPC-28326, a selective femoral vasodilator, is an alpha2C-adrenoceptor-selective antagonist.
abstract: OPC-28326 has been reported to selectively increase femoral blood flow in open-chest dogs and autoperfused canine femoral artery preparations. Preliminary data indicated that OPC-28326 has a high affinity at the alpha2-adrenoceptor. In the present study, we tested OPC-28326 in isoflurane anesthetized rats at a dose of 3 mg/kg of body weight, given intraduodenally. OPC-28326 significantly increased femoral blood flow, by 44.7 +/- 13.8%, 45 min after drug administration, whereas carotid blood flow increased by only 3.6 +/- 5.5% (n = 6). Chinese hamster ovary cell lines overexpressing rat alpha2D-, alpha2B-, or alpha2C-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 [3H]RX821002 binding, with calculated K(i) values of 3840 +/- 887, 633 +/- 46, and 13.7 +/- 1.9 nM on alpha2D-, alpha2B-, and alpha2C-adrenoceptor, respectively. A similar affinity and rank order of potency were also found for OPC-28326 on the alpha2-subtypes using epinephrine as agonist in luciferase assays. No agonistic effect of OPC-28326 was detected on any of the alpha2-adrenoceptors. Finally, in situ hybridization performed on skeletal muscle tissue sections collected from rat hind limb (musculus gastrocnemius) demonstrated a high level expression of alpha2C in the vascular tissues. Thus, the abundance of alpha2C in the skeletal muscle may account for the selective effect of OPC-28326 in increasing femoral blood flow.
authors.affiliation: Vascular Biology and Circulation, Maryland Research Laboratories, Otsuka Maryland Research Institute, Rockville, MD 20850, USA. bings@otsuka.com
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.forename: S
authors.initials: S
authors.lastname: Lockyer
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Yoshitake
authors.forename: J I
authors.initials: JI
authors.lastname: Kambayashi
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000527:Alprostadil / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D005268:Femoral Vein / Q000187:drug effects*; D006614:Hindlimb / Q000187:drug effects; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008156:Luciferases / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000814:Aniline Compounds; D010880:Piperidines; D014665:Vasodilator Agents; D015016:Yohimbine; D008156:Luciferases; D000527:Alprostadil; C400276:OPC 28326