Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.
Horm Metab Res. 2010 Apr;42(4):261-7. doi: 10.1055/s-0029-1246190. Epub 2010 Feb 8.
Racecadotril is known as an inhibitor of enkephalinase. Increase of plasma insulin by racecadotril has been observed in rats while the mechanism of the action remains obscure. In the present study, intravenous injection of male Wistar rats with racecadotril significantly decreased blood glucose levels. However, this effect of racecadotril was not modified by naloxone at the dose sufficient to block opioid receptors. Thus, the blood glucose-lowering action of racecadotril might be through an endogenous opioid independent mechanism. Otherwise, we found that C-peptide content was also raised by racecadotril in parallel with the increase of insulin in Wistar rats. Thus, the blood glucose-lowering action of racecadotril was related to insulin secretion, but not through the inhibition of plasma insulin degradation. In addition, racecadotril showed no direct effect on insulin secretion in isolated islets or cultured HIT-T15 beta cells. The increase of plasma insulin and blood glucose-lowering action induced by racecadotril were reduced by pretreatment with atropine and enhanced by physotigmine. Direct inhibition of cholinesterase was not observed in brain homogenates treated with racecadotril. Moreover, actions of racecadotril were significantly reduced in rats receiving hemicholinium-3 at a sufficient dose to decrease endogenous acetylcholine. Activation of cholinergic tone is possibly involved in the blood glucose-lowering effect of racecadotril. Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats.
瑞卡曲肽是一种脑啡肽酶抑制剂。在大鼠体内观察到瑞卡曲肽会增加血浆胰岛素，但其作用机制尚不清楚。在本研究中，瑞卡曲肽静脉注射雄性 Wistar 大鼠显著降低血糖水平。然而，这种瑞卡曲肽的作用不会被纳洛酮改变，因为纳洛酮的剂量足以阻断阿片受体。因此，瑞卡曲肽的降血糖作用可能是通过内源性阿片肽独立的机制。此外，我们发现瑞卡曲肽还可使 C 肽含量平行升高，同时增加 Wistar 大鼠胰岛素水平。因此，瑞卡曲肽的降血糖作用与胰岛素分泌有关，但不是通过抑制血浆胰岛素降解。此外，瑞卡曲肽对分离的胰岛或培养的 HIT-T15β细胞的胰岛素分泌没有直接作用。瑞卡曲肽预处理可降低其引起的血浆胰岛素增加和降血糖作用，并增强其作用。瑞卡曲肽处理的脑匀浆中未观察到直接抑制胆碱酯酶的作用。此外，在给予足够剂量的 hemicholinium-3 以减少内源性乙酰胆碱的大鼠中，瑞卡曲肽的作用明显降低。胆碱能张力的激活可能参与了瑞卡曲肽的降血糖作用。我们的结果表明，瑞卡曲肽通过调节 Wistar 大鼠的副交感神经张力来增加胰岛素分泌以降低血糖。
