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 for use in treating ischemic heart disease. We evaluated the effect of (+)-N-(6-amino-3-pyridil)-N'-[(1S,2R,4R)-bicyclo-[2.2.1]hept-2-yl] -N"- cyanoguanidine hydrochloride (AL0671), a newly synthesized cyanoguanidine-derivative potassium channel opener, on serum lipid and lipoprotein levels in obese Zucker rats, a genetically engineered model of type IV hyperlipidemia. AL0671 dose-dependently decreased systolic blood pressure in obese Zucker rats. Serial administration (for 1 or 2 weeks) of AL0671 (5 mg/kg/day) significantly decreased serum total triglyceride, chylomicron and very-low-density lipoprotein levels with increasing high-density lipoprotein cholesterol, 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 urea-derivative compound, AL0674, whose potassium channel-opening activity 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 channel-opening activity followed by decreasing triglyceride-rich lipoproteins in genetically obese hyperlipemic rats. Therefore, AL0671 might be beneficial in the treatment of hypertensive patients with hypertriglyceridemia (probably with insulin resistance).
Matzno
S
S
Basic Research Laboratory, Green Cross Corporation, Osaka, Japan.
Gohda
M
M
Eda
M
M
Ebisu
H
H
Uno
S
S
Ishida
N
N
Nakamura
N
N
Yamanouchi
K
K
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008049:Lipase / Q000097:blood; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000097:blood; D015221:Potassium Channels / Q000187:drug effects*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D011973:Receptors, LDL / Q000187:drug effects
C088267:AL 0670; D001643:Bridged Bicyclo Compounds; D006146:Guanidines; D000960:Hypolipidemic Agents; D015221:Potassium Channels; D011973:Receptors, LDL; C036053:VLDL receptor; D008049:Lipase; D008071:Lipoprotein Lipase; D011224:Prazosin