title: In vitro and in vivo vasodilating effects of KRN4884, Ki1769 and Ki3005, pyridinecarboxamidine derivatives.
abstract: The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 [5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ] were compared with those of Ki1769 [N-cyano-N'-(2-phenylethyl)-3-pyridinecarboxamidine] and Ki3005 [N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro. KRN4884 (10(-10)-10(-6) M). Ki1769 (10(-8)-10(-5) M) and Ki3005 (10(-10)-10(-6) M) produced concentration-dependent relaxations. KRN4884 was about 100- and 10-fold more potent than Ki1769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1-10 micrograms/kg, intravenously [i.v.]), Ki1769 (10-100 micrograms/kg, i.v.) and Ki3005 (3-30 micrograms/kg, i.v.) produced dose-dependent decreases in mean blood pressure with slight increases in heart rate. At 10 micrograms/kg, i.v., the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5-fold more pronounced than that of Ki1769. The hypotensive action remained for a longer period after KRN4884 administration. In rats pre-treated with glibenclamide (20 mg/kg, i.v.), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.
authors.affiliation: Pharmaceutical Research Laboratory, Kirin Brewery Co, Ltd, Gunma, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Izumi
authors.forename: J
authors.initials: J
authors.lastname: Kawahara
authors.forename: A
authors.initials: A
authors.lastname: Takeuchi
authors.forename: T
authors.initials: T
authors.lastname: Izawa
authors.forename: N
authors.initials: N
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005905:Glyburide; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; C096484:KRN 4884; C110731:Ki 3005; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C084622:Ki 1769; D005905:Glyburide