A POSSIBLE MECHANISM OF ACTION OF A NEW POTASSIUM CHANNEL OPENER, AL0671, ON LIPID-METABOLISM IN OBESE ZUCKER RATS

Antihypertensive drugs are expected to have a lipid-lowering effect fo r use in treating ischemic heart disease. We evaluated the effect of R ,4R)-bicyclo-[2.2.1]hept-2-yl]-N''-cyanoguanidine hydrochloride (AL067 1), a newly synthesized cyanoguanidine-derivative potassium channel op ener, on serum lipid and lipoprotein levels in obese Zucker rats, a ge netically engineered model of type IV hyperlipidemia. AL0671 dose-depe ndently decreased systolic blood pressure in obese Zucker rats. Serial administration (for 1 or 2 weeks) of AL0671 (5 mg/kg/day) significant ly decreased serum total triglyceride, chylomicron and very-low-densit y lipoprotein levels with increasing high-density lipoprotein choleste rol, whereas low-density lipoprotein levels did not change. AL0671 (5 mg/kg/day) increased lipoprotein lipase activities 4-fold and hepatic triglyceride lipase activities 3-fold in postheparin plasma. Another u rea-derivative compound, AL0674, whose potassium channel-opening activ ity is diminished, did not affect serum lipid and lipoprotein levels. These results suggested that AL0671 activates both lipoprotein lipase and hepatic triglyceride lipase activities through its potassium chann el-opening activity followed by decreasing triglyceride-rich lipoprote ins in genetically obese hyperlipemic rats. Therefore, AL0671 might be beneficial in the treatment of hypertensive patients with hypertrigly ceridemia (probably with insulin resistance).