title: Antihypertensive effect of the new dihydropyridine calcium antagonist (+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedica rbo xylate hydrochloride in dogs.
abstract: The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate hydrochloride, CAS 96515-74-1), a new calcium antagonist, was investigated in normotensive dogs (NTD) and renal hypertensive dogs (RHD). By oral administration, the antihypertensive activity of TC-81 (ED20% was 0.09 mg/kg p.o.) was about 18 times more potent in conscious RHD in comparison with nicardipine (ED20% was 1.65 mg/kg p.o.). Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at equipotent dose. Similar results were observed more clearly by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized dogs. Tolerance of the antihypertensive effect of TC-81 in daily dosing for 2 weeks and the rebound phenomena after discontinuance of the treatment were not observed in RHD. TC-81 at a concentration of 10(10)-3 x 10(-9) mol/l inhibited the KCl- or norepinephrine-induced contraction of isolated dog femoral artery. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.
authors.affiliation: Pharmacological Research Department, 2nd Bio-Medical Research Laboratories, Teijin Limited, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okamiya
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.forename: K
authors.initials: K
authors.lastname: Sunakawa
authors.forename: K
authors.initials: K
authors.lastname: Aoki
authors.forename: H
authors.initials: H
authors.lastname: Tanabe
authors.forename: T
authors.initials: T
authors.lastname: Takeshita
authors.forename: T
authors.initials: T
authors.lastname: Naruchi
mesh_terms: D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011189:Potassium Chloride; C074351:TC 81; D009529:Nicardipine; D009638:Norepinephrine