Effects of DL-017, a novel, potent and specific α1-Adrenoceptor antagonist on hypertension and hyperlipidemia in spontaneously hypertensive rats

The hypotensive effect of DL-017, a newly synthesized quinazoline derivative, was investigated in spontaneously hypertensive rats (SHR). DL-017 (0.1, 1.0 and 3.0 fig/kg, p.o.) induced a dose-dependent reduction of mean arterial pressure (MAP) which reached a maximal effect at 30 min after oral administration and persisted over 5 hr in SHR. Furthermore, at the lower dose (0.1 ug/kg), the heart rate (HR) was significantly increased. In contrast, at the higher doses (1.0 and 3.0 mg/kg), the HR decreased instead of increased, but rapidly returned to control level at around 2 hr later. This change of HR seems to parallel the time course of the hypotensive response in SHR. DL-017 attenuated pressor responses to phenylephrine (PE, 10 /ug/kg, i.v.), but failed to inhibit the presser response to angiotensin II (Ang II, 0.5 ug/kg, i.v.) even at the maximal hypotensive dose (3.0 mg/kg, i. V.). This observation indicates that the hypotensive effect of DL-OI7 was achieved via (X/-adrenoceptor blockade. On the other hand, in SHR fed a high fat-high cholesterol (HF-HC) diet, DL-017 (1.0 mg/kg, p.o., bid for 4 weeks) caused significant reductions in total plasma cholesterol (CE), low-density lipoprotein (LDL)-CE and total plasma triglyceride (TG). DL-o17 therapy HDL-CE was improved. It is concluded that DL-017 possesses the antihypertensive effect via the (X)-adrenoceptor blockade and the lipid-lowering effect. This demonstrates that DL-017 may be potential as a potent antihypertensive drug holding the advantage of reduction of plasma lipid for cardiovascular diseases.