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 cardiovascul ar metabolic syndrome (i.e., syndrome X), in rats. Hi,oh-fructose diet rats developed hypertension, hypertriglyceridemia, increased total cholesterol/ HDL (high-density lipoprotein)-cholesterol ratio, and hyperinsulinemia. KRN 4884 (0.3-3.0 mg/kg, twice a day for 14 days, p.o.) alleviated the risk fac tors in fructose-fed rats. Furthermore, fructose-fed rats exhibited impairm ent of glucose tolerance and excess insulin secretion when loaded with gluc ose 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, chol esterol, glucose, or insulin concentrations in normal rats. LPL (lipoprotei n lipase) activities in skeletal muscle and adipose tissue, and HTGL (hepat ic triglyceride lipase) activity in liver were measured after administratio n of KRN4884 or vehicle twice a day for 14 days in fructose-fed rats. KRN48 84 caused a significant increase in LPL activity in muscle and tended to in crease LPL activity in adipose tissue in fructose-fed rats. HTGL was decrea sed in fructose-fed rats as compared with normal controls and was unaffecte d by KRN4884. These findings suggested that KRN4884 enhances insulin sensit ivity and LPL activity, which are related to glucose and lipid metabolism a nd may be useful for the treatment of syndrome X.