Antihypertensive action and blockade of alpha1-adrenoceptors by DL-017, a quinazoline derivative.

Abstract

3-[[4-(2-Methoxyphenyl)piperazin-1-yl]methyl]-5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (DL-017), a quinazoline derivative, exhibits alpha 1 -adrenoceptor antagonistic and type I antiarrhythmic effects on mammalian cardiac tissues. In the current study, the effects of DL-017 on the hemodynamic profile in anesthetized, spontaneously hypertensive rats were evaluated. Intravenous administration of DL-017 induced dose-dependent reductions of heart rate and blood pressure, which persisted over 2 h. DL-017 exerted a maximal antihypertensive effect at 0.1 mg/kg, which was similar to that of 0.1 mg/kg of prazosin. DL-017 was able to block the pressor response to phenylephrine but not to angiotensin II. Regional cerebral blood flow of the right parietal cortex decreased by 14 +/- 4% 10 min after bolus injection and then rapidly returned to control levels while the arterial pressure was still low. These results indicate that blockade of the alpha 1 -adrenoceptor by DL-017 contributes to reduction of arterial pressure. The antihypertensive effect without reflex tachycardia and loss of autoregulation of cerebral blood flow makes DL-017 suitable for chronic long-term treatment of hypertension.