Abstract: Aim To investigate the effects of milrinone (a selective phosphodiesterase Ⅲ inhibitor PDE3) on insulin secretion, blood glucose, plasma free fatty acids (FFA) and dose-response relationship, and assess possible effects of milrinone on glucose metabolism and insulin sensitivity in conscious rats. Methods The catheterized nonstressed rats were administered various doses of milrinone (1, 5, 25 μmoL·kg^-1) and were compared with controls. A hyperinsulinaemic-euglycaemic clamp was established in counscious rats, and milrinone(25 μmoL·kg^-1) and 25 % dimethyl sulfoxide (DMSO, as a control) were given at 120 min during hyperinsulinaemic-euglycaemic clamping. Glucose turnover was determind with by gas chromatograph mass spectrometer (GC-MS). Results After dosing, plasma FFA levels in 3 milrinone groups significantly increased, compared with the controls and before dosing. The percentages of elevation of FFA by the different milrinone doses were very similar, 50%, and 52%, 55% for 1, 5, and 25 μmoL·kg^-1, repectively, at 2 min after dosing. Plasma insulin levels were significantly elevated in the 5 and 25 μmoL·kg^-1 groups, and the effect of milrione on glucose concentration was detectable only in 25 μ moL·kg^-1 group. During hyperinsulinaemic clamping, there were significant increase, in plasma FFA (from 173±15 to 634±87 μmoL·L^-1) and hepatic glucose production (HGP), and a significant decrease in glucose infusion rates (GIR) to about 21% and a slight increase in plasma insulin after milrinone treatment. Conclusion Milrinone impaires the ability of insulin to suppress lipolysis and HGP, and insulin-mediated glucose utilization in peripheral tissue. Therefore, milrinone administration may induce an acute insulin resistance in vivo.

Key words: milrinone, milrinone, insulin clamp, insulin clamp, insulin resistance, insulin resistance