Electrical and mechanical effects of a novel antihypertensive quinazoline derivative, 3-[[4-(2-methoxyphenyl) piperazin-1-ly]methyl]-5-(methylthio)-2,3-dihydroimidazo [1,2-c]quinazoline, on guinea pig ventricular muscles.
Electrical and mechanical effects of 3-[[4-(2-methoxyphenyl)piperazin-1-ly]methyl]-5-(methylthio)-2,3-+ ++dihydroimidazo[1,2-c]quinazoline (DL-017), a new synthesized antihypertensive agent, were studied in guinea-pig ventricular papillary muscles. In muscle fibers driven at 1 Hz, DL-017 decreased the twitch force in a concentration-dependent manner and significantly increased the action-potential duration and decreased intracellular Na+ activity (ai(Na)) and maximal rate of upstroke of action-potential (Vmax) when concentrations were greater than 1 microM. Phenylephrine in the presence of 1 microM propranolol produced a concentration-dependent positive inotropy. DL-017 (0.01 microM) antagonized the positive inotropic effect of phenylephrine and shifted the concentration-response curve to the right. In K+-depolarized muscle fibers, 0.1 microM DL-017 significantly decreased the contractile force without changing the slow action potential. In low-[K+]o and high-[Ca2+]o solutions, a train of stimuli triggered a spontaneous rhythm that could be abolished by 3 microM DL-017. Our results suggest that DL-017 not only exhibits an alpha1-antagonistic effect but also induces negative inotropy by a decrease in myofibrillar calcium sensitivity and inhibits Na+ channels at higher concentrations, contributing to the drug's negative inotropic and type-I antiarrhythmic effects.
Yang
J M
JM
Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Yuen
T C
TC
Chang
C W
CW
Jin
J S
JS
Yen
M H
MH
Chern
J W
JW
D000200:Action Potentials / Q000187:drug effects; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; C108153:DL 017; D011799:Quinazolines; D015222:Sodium Channels; D002118:Calcium