Parker S G, Taylor E M, Hamburger S A, Vimal M, Kaumann A J
Smith Kline Beechman Pharmaceuticals, Welwyn, UK.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):28-35. doi: 10.1007/BF00168912.
We investigated the blockade of the positive inotropic effects of 5-hydroxytryptamine (5-HT) by SB 203 186 (piperidinoethyl-indole-3-carboxylate hydrochloride) and its affinity for 5-HT4 receptors of human right atrium and piglet left atrium. We also compared the blocking effects of SB 203 186 against 5-HT-evoked tachycardia in anaesthetised adult Yucatan minipigs as well as new-born Camborough piglets. SB 203 186 caused competitive antagonism of the positive inotropic effects of 5-HT in electrically paced atrial preparations of man (pKB = 8.9) and piglet (pKB = 8.5) at concentrations (up to 0.3 micromol/l) which were devoid of depressant or stimulant effects. The affinity of SB 203 186 for atrial 5-HT4 receptors was 30-160 times higher than that of tropisetron. 5-HT caused tachycardia with similar potency and efficacy in Yucatan minipigs and new-born Camborough piglets. SB 203 186 (0.1-3 mg/kg, i.v.) surmountably antagonised 5-HT-evoked tachycardia in anaesthetised Yucatan minipigs or new-born Camborough piglets with similar potency. The blocking potency of SB 203 186 in Yucatan minipigs was 17 times higher than that of tropisetron. Intraduodenally administered SB 203 186 (0.3-3 mg/kg) to new-born Camborough piglets produced blockade of 5-HT-evoked tachycardia which was maximal after 20 min and lasted for more than 3 h with 0.3 mg/kg. The antagonism produced by the SB 203 186 administration in new-born Camborough piglets was dose-related and threefold greater through the intravenous route than through the intraduodenal route. We conclude that SB 203 186 is an antagonist with nanomolar affinity for both human and porcine atrial 5-HT4 receptor. The in vivo results demonstrate that the sinoatrial 5-HT4 receptors function is similar in new-born Camborough piglets and adult Yucatan minipigs. Both porcine breeds are valid models for human atrial 5-HT4 receptors as demonstrated with the antagonist SB 203 186.
我们研究了SB 203 186（盐酸哌啶基乙基吲哚-3-羧酸酯）对5-羟色胺（5-HT）正性肌力作用的阻断作用及其对人右心房和仔猪左心房5-HT4受体的亲和力。我们还比较了SB 203 186对麻醉的成年尤卡坦小型猪和新生坎伯罗仔猪中5-HT诱发心动过速的阻断作用。在浓度高达0.3微摩尔/升且无抑制或刺激作用的情况下，SB 203 186在人（pKB = 8.9）和仔猪（pKB = 8.5）的电起搏心房制剂中对5-HT的正性肌力作用产生竞争性拮抗。SB 203 186对心房5-HT4受体的亲和力比托烷司琼高30 - 160倍。5-HT在尤卡坦小型猪和新生坎伯罗仔猪中引起心动过速的效力和效果相似。SB 203 186（0.1 - 3毫克/千克，静脉注射）可克服性地拮抗麻醉的尤卡坦小型猪或新生坎伯罗仔猪中5-HT诱发的心动过速，效力相似。SB 203 186在尤卡坦小型猪中的阻断效力比托烷司琼高17倍。对新生坎伯罗仔猪十二指肠内给药SB 203 186（0.3 - 3毫克/千克）可产生对5-HT诱发心动过速的阻断作用，在20分钟后达到最大，0.3毫克/千克时持续超过3小时。SB 203 186给药对新生坎伯罗仔猪产生的拮抗作用与剂量相关，静脉途径产生的作用比十二指肠途径大3倍。我们得出结论，SB 203 186是一种对人和猪心房5-HT4受体具有纳摩尔亲和力的拮抗剂。体内结果表明，新生坎伯罗仔猪和成年尤卡坦小型猪的窦房结5-HT4受体功能相似。如拮抗剂SB 203 186所示，这两个猪品种都是人心房5-HT4受体的有效模型。
