Zhang W M, Wu S, Yu X C, Wang H X, Bian J S, Wong T M
Department of Physiology and Institute of Cardiovascular Science and Medicine, Faculty of Medicine, University of Hong Kong, Republic of China.
J Mol Cell Cardiol. 1999 Feb;31(2):355-62. doi: 10.1006/jmcc.1998.9998.
To explore the existence of multiplicity of kappa receptor in the heart, two series of experiments were performed. In the first we studied the antagonistic actions of nor-BNI, a selective kappa 1 antagonist, and quadazocine, a preferential kappa 2 antagonist, against the effects of U50488, a selective kappa 1 agonist, and bremazocine, a universal agonist preferentially binding to kappa 2 receptor, on the electrically stimulated [Ca2+]i transient and forskolin-stimulated cAMP accumulation in the rat ventricular myocyte. In the second series of experiments, we determined and compared the effects of above two kappa receptor agonists in the ventricular myocytes made insensitive to kappa 1 and kappa 2 agonists by prior exposure to the respective agonists. At the concentration range of 3 x 10(-6)-3 x 10(-5) M, both U50488 and bremazocine dose-dependently inhibited the [Ca2+]i transient induced by electrical stimulation. The inhibitory effects of U50488 and bremazocine were antagonized by nor-BNI and quadazocine. The antagonistic actions of nor-BNI were significantly greater against the effects of U50488, but smaller against the effects of bremazocine than those of quadazocine. At 1 x 10(-6)-5 x 10(-5) M, both U50488 and bremazocine dose-dependently and significantly inhibited the forskolin-induced cAMP accumulation. The inhibitory effect of 30 microM U50488 on cAMP accumulation was significantly attenuated by 5 microM nor-BNI, but not by quadazocine at the same concentration; whereas the effect of 30 microM bremazocine was significantly blocked by 5 microM quadazocine, but not by nor-BNI at the same concentration. The inhibitory effect of 30 microM U50488 on electrically stimulated [Ca2+]i was abolished by preincubation of myocytes with 10(-6) M U50488 for 24 h, but not with 10(-6) M bremazocine for h; whereas the inhibitory effect of 30 microM bremazocine on electrically stimulated [Ca2+]i transient was significantly attenuated after incubation of the myocyte with 10(-6) M bremazocine for 24 h, but not with 10(-6) M U50488 for 24 h. The observations indicate the existence of kappa receptor subtypes in the rat heart.
为探究心脏中κ受体亚型的存在情况，我们进行了两个系列的实验。在第一个实验中，我们研究了选择性κ1拮抗剂nor-BNI和优先性κ2拮抗剂夸达佐辛，对选择性κ1激动剂U50488和优先与κ2受体结合的通用激动剂布马佐辛，在大鼠心室肌细胞电刺激诱导的[Ca2+]i瞬变和福斯高林刺激的cAMP积累方面的拮抗作用。在第二个系列实验中，我们测定并比较了上述两种κ受体激动剂，对预先暴露于各自激动剂而对κ1和κ2激动剂不敏感的心室肌细胞的影响。在3×10(-6) - 3×10(-5) M的浓度范围内，U50488和布马佐辛均剂量依赖性地抑制电刺激诱导的[Ca2+]i瞬变。U50488和布马佐辛的抑制作用被nor-BNI和夸达佐辛拮抗。nor-BNI对U50488作用的拮抗作用显著大于对布马佐辛作用的拮抗作用，但小于夸达佐辛对布马佐辛作用的拮抗作用。在1×10(-6) - 5×10(-5) M时，U50488和布马佐辛均剂量依赖性且显著地抑制福斯高林诱导的cAMP积累。30μM U50488对cAMP积累的抑制作用被5μM nor-BNI显著减弱，但相同浓度的夸达佐辛则无此作用；而30μM布马佐辛的作用被5μM夸达佐辛显著阻断，但相同浓度的nor-BNI则无此作用。30μM U50488对电刺激[Ca2+]i的抑制作用，在心肌细胞与10(-6) M U50488预孵育24小时后被消除，但与10(-6) M布马佐辛预孵育24小时则无此作用；而30μM布马佐辛对电刺激[Ca2+]i瞬变的抑制作用，在心肌细胞与10(-6) M布马佐辛孵育24小时后显著减弱，但与10(-6) M U50488孵育24小时则无此作用。这些观察结果表明大鼠心脏中存在κ受体亚型。
