title: Pharmacologic characterization of FR172516: a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent.
abstract: The pharmacologic characterization of FR172516, a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent, was studied and compared with amlodipine in receptor-binding assay and in vivo studies. In the binding assay, Ki values of FR172516 for calcium channel and beta-receptor were 29.3 nM and 44.1 nM, respectively. In the in vivo studies with pithed rats, FR172516 shifted the dose-response curves of isoproterenol in heart rate to the right, suggesting that this compound has a antiadrenoceptor effect in vivo. The hypotensive effect of FR172516, which could be mainly attributed to its calcium channel-blocking action, was compared with that of amlodipine in normotensive Wistar rats (NTRs), spontaneously hypertensive rats (SHRs), and renal hypertensive dogs (RHDs). FR172516 showed more potent hypotensive action than amlodipine when administered intravenously to NTRs, and apparent bradycardia was seen only with FR172516. In SHRs, FR172516 showed a long-lasting hypotensive action and dose-dependently decreased heart rate, whereas amlodipine scarcely affected heart rate. In RHDs, oral administration of FR172516 once daily for 5 days decreased blood pressure without reflex tachycardia or an increase of plasma renin activity. On the other hand, amlodipine, in the dose at which hypotensive effects equipotent to those of FR172516 were observed, produced apparent reflex tachycardia and concomitant increase of plasma renin. These results indicate that FR172516 has a potent long-lasting antihypertensive effect without activating sympathetic tone by calcium channel-blocking and beta-adrenoceptor-blocking actions.
authors.affiliation: Medicinal Biology Research Laboratory, Fujisawa Pharmaceutical Co., Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Okubo
authors.forename: K
authors.initials: K
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Goto
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C119282:FR 172516