EFFECTS OF DC-015, A NOVEL POTENT AND SELECTIVE ALPHA(1)-ADRENOCEPTORANTAGONIST ON PLASMA-LIPID AND VASCULAR REACTIVITY IN HYPERLIPIDEMIC RATS

1. The effects of DC-015, a newly synthesized quinazoline derivative, on plasma lipids, lipoprotein levels and vascular reactivity were inve stigated in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rat s (SHR). 2. The hypotensive effect of DC-015 was compared with prazosi n in SHR. Intravenous administration of DC-015 and prazosin (both at 0 .01, 0.05 and 0.1 mg/kg) induced dose-dependent reductions in mean art erial pressure (MAP) which reached a maximal effect 5 min after inject ion and persisted over 2 h in SHR. DC-015 decreased MAP with equal eff iciency compared with prazosin. 3. The plasma levels of total choleste rol (CE), low-density lipoprotein (LDL)-CE and total triglyceride (TG) were markedly increased and the levels of high-density lipoprotein (H DL)-CE were markedly decreased in both high fat-high cholesterol (HF-H C) diet fed WKY and SHR. 4. In HF-HC diet fed WKY and SHR, the total p lasma CE, LDL-CE and total plasma TG were significantly reduced after oral administration of DC-015 (1 mg/kg, twice a day) for 4 weeks. Furt hermore, DC-015 therapy was associated with increased HDL-CE levels an d thus the ratio of total CE to HDL-CE was improved. The antihyperlipi daemic effect of prazosin was less than that of DC-015. 5. Significant ly attenuated median effective concentration (EC(50)) values and augme nted maximal responses for phenylephrine-induced contraction of aortic rings were observed in HF-HC diet fed WKY and SHR. Endothelium-depend ent relaxation to acetylcholine was impaired while endothelium-indepen dent relaxation to nitroglycerin was well preserved. 6. Oral administr ation of DC-015 (1 mg/kg, twice a day) for 4 weeks significantly augme nted EC(50) values and attenuated maximal responses for phenylephrine- induced contraction of aortic rings in HF-HC diet fed WKY and SHR. Pra zosin (1 mg/kg, twice a day) showed a lesser extent of efficiency than DC-015 at normalization of vasorelaxation in HF-HC diet fed WKY and S HR. 7. It is concluded that DC-015, a potent antihypertensive agent, m ay have additional advantage in also reducing hyperlipidaemia.