Kaumann A J, Sanders L, Brown A M, Murray K J, Brown M J
SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, UK.
Naunyn Schmiedebergs Arch Pharmacol. 1991 Aug;344(2):150-9. doi: 10.1007/BF00167212.
The effects of 5-carboxamidotryptamine (5-CT) and the gastrokinetic benzamides renzapride and cisapride on contractile force were investigated using isolated paced right atrial appendages from patients treated with beta-adrenoceptor blocking agents who were undergoing open heart surgery. These effects were compared to those of 5-hydroxytryptamine (5-HT). The effects of the drugs on atrial cyclic AMP levels and cyclic AMP-dependent protein kinase ratios were also investigated. The drugs all increased contractile force of rank order of potency was 5-HT greater than renzapride greater than cisapride greater than 5-CT. The maximum responses, expressed as a fraction of the response to 200 mumol/l (-)-isoprenaline, were 5-HT 0.6, 5-CT 0.6, renzapride 0.4 and cisapride greater than or equal to 0.2, suggesting that the latter two are partial agonists. 5-HT, 5-CT and renzapride but not cisapride caused significant shortening of time to peak force. The effects of the four drugs were blocked by mumolar concentrations of ICS 205-930, suggesting an involvement of 5-HT4 receptors. As expected of partial agonists both renzapride and cisapride caused simple competitive antagonism of the positive inotropic effects of 5-HT. The estimated equilibrium dissociation constants pKP (-log mol/l KP) were 6.7 for renzapride and 6.2 for cisapride. 5-CT at concentrations up to 10 mumol/l did not antagonise the effects of 5-HT. In the presence of (+/-)-propranolol 0.4 mumol/l, 5-HT 10 mumol/l, 5-CT 100 mumol/l, renzapride 10 mumol/l and cisapride 40 mumol/l significantly increased cyclic AMP levels. 5-HT and renzapride also significantly increased cyclic AMP-dependent protein kinase activity, whereas 5-CT caused only marginal stimulation and cisapride was ineffective. The results confirm the existence of a human right atrial 5-HT receptor that is similar in nature to, but not necessarily identical with, the 5-HT4 receptor of mouse embryonic colliculi neurones. The main difference is that in human right atrium the benzamides are less potent and efficacious than 5-HT and that cisapride is less potent and less efficacious than renzapride while in mouse embryonic colliculi these two benzamides are equipotent with and more efficacious agonists than 5-HT. We designate the human right atrial 5-HT receptor 5-HT4-like. The human right atrial 5-HT4-like receptor greatly resembles porcine sinoatrial and left atrial 5-HT4-like receptors and also appears to be similar to 5-HT4-like receptors of guinea-pig ileum and rat oesophagus.
使用接受心脏直视手术且正在接受β-肾上腺素能受体阻滞剂治疗的患者的离体起搏右心耳，研究了5-羧基酰胺色胺（5-CT）以及促胃肠动力苯甲酰胺类药物瑞扎普明和顺阿普唑仑对收缩力的影响。将这些影响与5-羟色胺（5-HT）的影响进行了比较。还研究了这些药物对心房环磷酸腺苷（cAMP）水平和环磷酸腺苷依赖性蛋白激酶比率的影响。这些药物均增加了收缩力，效力顺序为5-HT＞瑞扎普明＞顺阿普唑仑＞5-CT。以对200μmol/L（-）-异丙肾上腺素反应的分数表示的最大反应分别为：5-HT 0.6、5-CT 0.6、瑞扎普明0.4和顺阿普唑仑≥0.2，这表明后两者是部分激动剂。5-HT、5-CT和瑞扎普明，但不是顺阿普唑仑，导致达到峰值力的时间显著缩短。四种药物的作用被毫摩尔浓度的ICS 205-930阻断，提示涉及5-HT4受体。正如对部分激动剂所预期的那样，瑞扎普明和顺阿普唑仑均对5-HT的正性肌力作用产生简单的竞争性拮抗作用。估计的平衡解离常数pKP（-log mol/L KP），瑞扎普明为6.7，顺阿普唑仑为6.2。浓度高达10μmol/L的5-CT不拮抗5-HT的作用。在存在0.4μmol/L（±）-普萘洛尔的情况下，5-HT 10μmol/L、5-CT 100μmol/L、瑞扎普明10μmol/L和顺阿普唑仑40μmol/L显著增加了环磷酸腺苷水平。5-HT和瑞扎普明也显著增加了环磷酸腺苷依赖性蛋白激酶活性，而5-CT仅引起轻微刺激，顺阿普唑仑则无效。结果证实了人右心房存在一种5-HT受体，其性质与小鼠胚胎小丘神经元的5-HT4受体相似，但不一定相同。主要区别在于，在人右心房中，苯甲酰胺类药物的效力和效能低于5-HT，顺阿普唑仑的效力和效能低于瑞扎普明，而在小鼠胚胎小丘中这两种苯甲酰胺类药物与5-HT效力相当且是更有效的激动剂。我们将人右心房5-HT受体命名为5-HT4样受体。人右心房5-HT4样受体与猪窦房结和左心房5-HT4样受体非常相似，似乎也与豚鼠回肠和大鼠食管的5-HT4样受体相似。
