Influence of the new antihypertensive drug, SM-2470 (a quinazoline derivative), on cholesterol metabolism in rats.
The influence of SM-2470 (4-amino-2-(4-[bicyclo(2,2,2)oct-2-ene-5-carbonyl]-1-piperazinyl)- 6,7-dimethoxyquinazoline), a new antihypertensive agent, on cholesterol metabolism was investigated in hypercholesterolaemic rats, using the dual isotope method (cholesterol absorption) and the intestinal ligated loop method (cholesterol uptake). In the hypercholesterolaemic model, 1-30 mg kg-1 doses of SM-2470 significantly inhibited the elevation of the total serum cholesterol and very low and low density lipoproteins (VLDL + LDL)-cholesterol, without causing any change in the hepatic cholesterol level. In a dual isotope model experiment, SM-2470 (10, 30 mg kg-1) inhibited the intestinal absorption of cholesterol, but did not affect biliary excretion of sterol and/or bile acids, nor did it affect cholesterol movement from the liver to blood. In the intestinal ligated loop method, SM-2470 remarkably inhibited the mucosal uptake of cholesterol in a dose-dependent manner in 0.5-2.0 mg mL-1 of micellar solution. In addition, SM-2470 inhibited micellar formation in-vitro, which increased the distribution of large sized micelles as well as cholesterol absorption inhibitors. From these results, it can be assumed that a possible mechanism behind the hypocholesterolaemic effect of SM-2470 is the inhibition of cholesterol absorption related to the reduction of cholesterol solubilization, occurring in the gut micelles, similar to the action of plant sterol.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002784:Cholesterol / Q000493:pharmacokinetics*; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D002784:Cholesterol; C047165:SM 2470; D011224:Prazosin