Effects of doxazosin and other antihypertensives on serum lipid levels and lipoprotein lipase in the C57BR/cdJ mouse.
Doxazosin has been shown to lower serum cholesterol levels in the cholesterol-fed (0.75% in a synthetic diet that contains sucrose and cholic acid) C57BR/cdJ mouse. These studies show that the drug's main effect is to lower low-density lipoprotein (LDL) cholesterol and leave high-density lipoprotein (HDL) cholesterol levels unchanged. The drug had cholesterol-lowering effects in this model at doses down to 3 mg/kg. In order to determine if these effects are unique to selective alpha 1-inhibitors, other antihypertensives including hydralazine, papaverine, and captopril were investigated. None of the drugs has any effects on the plasma lipid metabolite levels. The effects of propranolol and polythiazide on plasma lipid levels were also examined in these mice. Propranolol had no effect, whereas the diuretic increased plasma cholesterol levels. Both propranolol and polythiazide increased plasma triglycerides. Doxazosin has been shown to inhibit cGMP phosphodiesterase in the laboratory. The effects of zaprinast, a cGMP phosphodiesterase inhibitor, were tested in order to determine if this property of the drug could be responsible for its lipid-lowering activity. The data show that there are no effects on plasma lipids in zaprinast-treated animals. Doxazosin treatment increased heparin-releasable lipoprotein lipase in fasted chow-fed mice. The drug was without effect on the activity of hepatic lipase present in the plasma after heparin release. No effects were observed on the tissue levels of either hepatic or lipoprotein lipases (heart or adipose tissue).
Krupp
M N
MN
Central Research Division, Pfizer Inc., Groton, Connecticut.
Hoover
K W
KW
Valentine
J J
JJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D017292:Doxazosin; D008049:Lipase / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood*
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011688:Purinones; D014280:Triglycerides; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C011145:zaprinast; D017292:Doxazosin; D011224:Prazosin