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.