ELECTRICAL AND MECHANICAL EFFECTS OF A NOVEL ANTIHYPERTENSIVE QUINAZOLINE DERIVATIVE, (METHYLTHIO)-2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE, ONGUINEA-PIG VENTRICULAR MUSCLES

Electrical and mechanical effects of -(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 fi bers driven at 1 Hz, DL-017 decreased the twitch force in a concentrat ion-dependent manner and significantly increased the action-potential duration and decreased intracellular Na+ activity (a(Na)(i)) and maxim al rate of upstroke of action-potential ((V) over dot(max)) when conce ntrations were greater than 1 mu M. Phenylephrine in the presence of 1 mu M propranolol produced a concentration-dependent positive inotropy . DL-017 (0.01 mu M) antagonized the positive inotropic effect of phen ylephrine and shifted the concentration-response curve to the right. I n K+-depolarized muscle fibers, 0.1 mu M DL-017 significantly decrease d the contractile force without changing the slow action potential. In low-[K+](0) and high-[Ca2+](0) solutions, a train of stimuli triggere d a spontaneous rhythm that could be abolished by 3 mu M DL-017. Our r esults suggest that DL-017 not only exhibits an alpha(1)-antagonistic effect but also induces negative inotropy by a decrease in myofibrilla r calcium sensitivity and inhibits Na+ channels at higher concentratio ns, contributing to the drug's negative inotropic and type-I antiarrhy thmic effects.