Effects of DC-015, a novel potent and selective alpha 1-adrenoceptor antagonist on plasma lipid and vascular reactivity in hyperlipidaemic rats.
1. The effects of DC-015, a newly synthesized quinazoline derivative, on plasma lipids, lipoprotein levels and vascular reactivity were investigated in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). 2. The hypotensive effect of DC-015 was compared with prazosin 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 arterial pressure (MAP) which reached a maximal effect 5 min after injection and persisted over 2 h in SHR. DC-015 decreased MAP with equal efficiency compared with prazosin. 3. The plasma levels of total cholesterol (CE), low-density lipoprotein (LDL)-CE and total triglyceride (TG) were markedly increased and the levels of high-density lipoprotein (HDL)-CE were markedly decreased in both high fat-high cholesterol (HF-HC) diet fed WKY and SHR. 4. In HF-HC diet fed WKY and SHR, the total plasma 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. Furthermore, DC-015 therapy was associated with increased HDL-CE levels and thus the ratio of total CE to HDL-CE was improved. The antihyperlipidaemic effect of prazosin was less than that of DC-015. 5. Significantly attenuated median effective concentration (EC50) values and augmented maximal responses for phenylephrine-induced contraction of aortic rings were observed in HF-HC diet fed WKY and SHR. Endothelium-dependent relaxation to acetylcholine was impaired while endothelium-independent relaxation to nitroglycerin was well preserved. 6. Oral administration of DC-015 (1 mg/kg, twice a day) for 4 weeks significantly augmented EC50 values and attenuated maximal responses for phenylephrine-induced contraction of aortic rings in HF-HC diet fed WKY and SHR. Prazosin (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 SHR. 7. It is concluded that DC-015, a potent antihypertensive agent, may have additional advantage in also reducing hyperlipidaemia.
Sheu
J R
JR
Graduate Institute of Medical Science, Taipei Medical College, Taiwan.
Peng
I H
IH
Lee
Y M
YM
Yen
M H
MH
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006949:Hyperlipidemias / Q000097:blood / Q000503:physiopathology*; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008055:Lipids; D008074:Lipoproteins; D011799:Quinazolines; C100699:DC 015; D011224:Prazosin