Abstract
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 μg/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-HT2receptors, 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 α2-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 α2-adrenoceptor-blocking activity.
Footnotes
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Send reprint requests to: Kensuke Orito, D.V.M., Ph.D., Thrombosis & Vascular Research Laboratory, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho Tokushima 771-0192, Japan. E-mail: k_orito{at}research.otsuka.co.jp
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↵1 Current address: Thrombosis & Vascular Research Laboratory, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho Tokushima 771-0192, Japan.
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↵2 Current address: Maryland Research Laboratories, Otsuka America Pharmaceutical Inc., 9900 Medical Center Dr. Rockville, MD 20850.
- Abbreviations:
- FBF
- femoral artery blood flow
- BP
- blood pressure
- SR
- sinoatrial rate
- ASA
- anterior septal artery
- OPC-28326
- 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionylaminobenzoyl)piperidine hydrochloride monohydrate
- CF
- contractile force
- POAD
- peripheral occlusive arterial disease
- CBF
- coronary artery blood flow
- HR
- heart rate
- VBF
- vertebral artery blood flow
- CaBF
- carotid artery blood flow
- RBF
- renal artery blood flow
- MBF
- mesenteric artery blood flow
- 5-HT
- 5-hydroxytryptamine (serotonin)
- Received April 16, 1999.
- Accepted July 16, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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