Effects of the K+ channel opener KRN4884 on the cardiovascular metabolic syndrome model in rats.
We examined the effects of the potassium channel opener KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ) on cardiovascular metabolic syndrome (i.e., syndrome X), in rats. High-fructose diet rats developed hypertension, hypertriglyceridemia, increased total cholesterol/HDL (high-density lipoprotein)-cholesterol ratio, and hyperinsulinemia, KRN4884 (0.3-3.0 mg/kg, twice a day for 14 days, p.o.) alleviated the risk factors in fructose-fed rats. Furthermore, fructose-fed rats exhibited impairment of glucose tolerance and excess insulin secretion when loaded with glucose orally. Treatment with KRN4884 (1.0 mg/kg, twice a day for 14 days, p.o.) improved the glucose intolerance and inhibited hypersecretion of insulin in the glucose-loaded, fructose-fed rats. In contrast, KRN4884 (0.3-1.0 mg/kg, twice a day for 10 days, p.o.) did not affect serum triglyceride, cholesterol, glucose, or insulin concentrations in normal rats. LPL (lipoprotein lipase) activities in skeletal muscle and adipose tissue, and HTGL (hepatic triglyceride lipase) activity in liver were measured after administration of KRN4884 or vehicle twice a day for 14 days in fructose-fed rats. KRN4884 caused a significant increase in LPL activity in muscle and tended to increase LPL activity in adipose tissue in fructose-fed rats. HTGL was decreased in fructose-fed rats as compared with normal controls and was unaffected by KRN4884. These findings suggested that KRN4884 enhances insulin sensitivity and LPL activity, which are related to glucose and lipid metabolism and may be useful for the treatment of syndrome X.
Okada
Y
Y
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Takasaki, Gunma, Japan. y-okada@kirin.co.jp
Yoshino
T
T
Takeuchi
A
A
Endoh
M
M
Ohta
H
H
Jinno
Y
Y
Yokoyama
T
T
Izawa
T
T
Kobayshi
E
E
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D005632:Fructose; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017566:Microvascular Angina / Q000188:drug therapy*; D018482:Muscle, Skeletal / Q000378:metabolism; D015221:Potassium Channels; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D014280:Triglycerides / Q000032:analysis; D014665:Vasodilator Agents / Q000627:therapeutic use*
D001786:Blood Glucose; D007328:Insulin; C096484:KRN 4884; D015221:Potassium Channels; D011725:Pyridines; D014280:Triglycerides; D014665:Vasodilator Agents; D005632:Fructose; D002784:Cholesterol; D008071:Lipoprotein Lipase; D005947:Glucose