title: Blockade of alpha1-adrenoceptors and cardiac depressant effect by a newly synthetic antihypertensive drug, DL-017 of quinazoline derivative.
abstract: The electromechanical effects of 3-[[4-(2-methoxy phenyl)piperazin-1-yl]methyl]-5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (DL-017), a newly synthesized quinazoline-derived antihypertensive agent, on mammalian cardiac tissues were evaluated. In driven canine Purkinje fibers, DL-017 decreased twitch tension, the maximal rate of upstroke of the action potential (Vmax), and intracellular Na+ activity (a(i)Na) in a concentration-dependent manner. The action potential duration was decreased in canine Purkinje fibers but increased in guinea pig papillary muscles. In guinea pig ventricular papillary muscles, phenylephrine in the presence of 1 microM propranolol increased the twitch tension in a concentration-dependent manner. At 10 microM, phenylephrine significantly decreased a(i)Na and shortened the action potential duration. DL-017 at 0.01 microM inhibited these phenylephrine-induced effects and shifted the concentration-dependent curve to the right. In sinoatrial nodes, DL-017 inhibited pacemaker activity, involving decreases in the slope of diastolic depolarization and Vmax and an increase in a delay of repolarization. These results suggest that, in addition to blockade of alpha1-adrenoceptors and Na+ channels, DL-017 reduces cardiac excitability and contractility in association with inhibition of slow inward Ca2+ and outward K+ channels. Since two order higher concentrations are required, the contribution of DL-017 to cardiac depressant from blockade of ionic channels seems to be less important when this compound is clinically used as an antihypertensive drug.
authors.affiliation: Department of Internal Medicine, Armed Forces Taoyuan General Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: F C
authors.initials: FC
authors.lastname: Ke
authors.forename: S N
authors.initials: SN
authors.lastname: Yang
authors.forename: L M
authors.initials: LM
authors.lastname: Tsai
authors.forename: H L
authors.initials: HL
authors.lastname: Wu
authors.forename: J N
authors.initials: JN
authors.lastname: Wu
authors.forename: T C
authors.initials: TC
authors.lastname: Yuen
authors.forename: C I
authors.initials: CI
authors.lastname: Lin
authors.forename: J W
authors.initials: JW
authors.lastname: Chern
authors.forename: J M
authors.initials: JM
authors.lastname: Yang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001683:Biological Clocks / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D010210:Papillary Muscles / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; C108153:DL 017; D011799:Quinazolines