Antihypertensive action and blockade of alpha1-adrenoceptors by DL-017, a quinazoline derivative.
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.
Tsai
L M
LM
Department of Physiology and Biophysics, National Defense Medical Center, National Defense University, Taipei, Taiwan, R.O.C.
Yang
S N
SN
Lee
S F
SF
Ding
Y A
YA
Chern
J W
JW
Yang
J M
JM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007700:Kinetics; D017078:Laser-Doppler Flowmetry; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D011224:Prazosin / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; C108153:DL 017; D011799:Quinazolines; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D011224:Prazosin