慢性U50488H处理对大鼠心脏k－结合特性和生理特性的影响

Effects of chronic U50488H treatment on kappa-binding and physiological properties of the rat heart

受体结合分析研究表明，慢性Ｕ５０４８８Ｈ处理后，Ｂｍａｘ无明显改变，而Ｋｄ显著增大，表明ｋ－受体结合位点数量无改变而亲和力降低。在离体灌流心脏，Ｕ５０４８８Ｈ（１０－６ｍｏｌ·Ｌ－１）引起对照组心率、心肌收缩力降低和室性早搏增多；而在慢性Ｕ５０４８８Ｈ处理组，这种效应消失，表明心脏已对Ｕ５０４８８Ｈ产生耐受。以上结果表明，慢性Ｕ５０４８８Ｈ处理导致心脏对该激动剂耐受性的产生，但不伴有相应受体的下调现象。Ｐ＜０．０１但Ｋｄ值比对照组明显增加。２．２Ｕ５０４８８Ｈ对大鼠心脏的作用主要观察心率、心肌收缩力和心脏节律的改变。１０－７ｍｏｌ·Ｌ－１的Ｕ５０４８８Ｈ对这三种参数无明显影响。在３×１０－７ｍｏｌ·Ｌ－１，Ｕ５０４８８Ｈ明显降低心率。１０－６ｍｏｌ·Ｌ－１的Ｕ５０４８８Ｈ降低心率、心肌收缩力并诱发室性早搏。在慢性处理研究中，Ｕ５０４８８Ｈ（１０－６ｍｏｌ·Ｌ－１）对生理盐水处理组与上相似；但其对慢性Ｕ５０４８８Ｈ处理组几乎无任何作用（附表）。３讨论在本研究中，大鼠经慢性注射Ｕ５０４８８Ｈ４ｄ，产生了对Ｕ５０４８８Ｈ的低温效应耐受性，且能取消１０－６ｍｏｌ·Ｌ－１Ｕ５０４８８Ｈ对心率、心肌收缩力和心律的效应，?

Receptorbinding assay on the crude membrane homogenates of the heart revealed that there was no change in Bmax,but a significant increase of Kd in rats received chronically injection with U50488H for 4 d,indicating that the number of kappa binding sites remained unchanged whereas the affinity of the binding sites to kappa-agonist decreased.The study on the isolated perfused rat heart showed that although U50488H caused reductions of heart rate and force of ventricular contraction as well as ventricular ectopic beat in the heart of rats in the control group,its effects were absent in the chronically U50488H-treated group,indicating the development of tolerance in the heart to U50488H.The results indicate that the development of tolerance to the effects of a kappa-agonist after chronic treatment with it was not accompanied by down-regulation, but only a slight and significant reduction in affinity of kappa bindiug sites in the rat heart.