Blockade of α ₁ -adrenoceptors and cardiac depressant effect by a newly synthetic antihypertensive drug, DL-017 of quinazoline derivative

The electromechanical effects of 3-[]4-(2-methoxyphenyl)piperazin-1-yl]methyl]-5-(methylthio) 2,3-dihydroimidazol 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 μM propranolol increased the twitch tension in a concentration-dependent manner. At 10 μM, phenylephrine significantly decreased a ⁱ _Na and shortened the action potential duration. DL-017 at 0.01 μM 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 V max and an increase in a delay of repolarization. These results suggest that, in addition to blockade of α ₁ -adrenoceptors and Na ⁺ channels, DL-017 reduces cardiac excitability and contractility in association with inhibition of slow inward Ca ²⁺ 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.