Mechanisms of action of OPC-28326, a selective hindlimb vasodilator.
The unique cardiovascular profile of OPC-28326 [4-(N-methyl-2-phenylethylamino)-1-(3, 5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monohydrate] provides insight into basic mechanisms of this new drug as determined by experiments in dogs and rats. In anesthetized open-chest dogs, an i.v. administration of a low dose (0.3 and 1.0 microg/kg) of OPC-28326 selectively increased femoral artery blood flow with only minimal action on systemic blood pressure, heart rate and coronary, carotid, vertebral, renal, and mesenteric blood flows. Biochemical study suggests that OPC-28326 had no effect on phosphodiesterase-3 and -5. OPC-28326 dose-dependently inhibited phenylephrine-induced increases in blood pressure in spinally anesthetized dogs. The potency of OPC-28326 was, however, about 180 times lower than that of prazosin. Although binding studies have revealed an affinity of OPC-28326 to serotonin 5-HT(2) receptors, the drug is without effect, except at very high concentrations, on serotonin-induced contraction in an isolated canine femoral artery preparation. The potency of OPC-28326 on the increase in femoral artery blood flow was about 14 times higher than that of prazosin but was at about the same level as that obtained with yohimbine in canine autoperfused femoral artery preparations. In perfused rat hindlimb preparations, OPC-28326 inhibited the decrease in perfusion flow induced by brimonidine, a selective alpha(2)-adrenoceptor agonist. The potency of OPC-28326 was at least 10 times less than that of yohimbine. Taken together, the results show that at low doses, OPC-28326 selectively exerts a potent vasodilating effect on the femoral arterial bed, in part due to an alpha(2)-adrenoceptor-blocking activity.
Orito
K
K
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Imaizumi
T
T
Yoshida
K
K
Fujiki
H
H
Kishi
M
M
Teramoto
S
S
Tanaka
M
M
Shimizu
H
H
Tominaga
M
M
Kimura
Y
Y
Kambayashi
J
J
Mori
T
T
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000758:Anesthesia; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000068438:Brimonidine Tartrate; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D018674:Adrenergic Antagonists; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D010880:Piperidines; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D014665:Vasodilator Agents; D010656:Phenylephrine; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C400276:OPC 28326; D011224:Prazosin