Krobert Kurt A, Brattelid Trond, Levy Finn Olav, Kaumann Alberto J
Department of Pharmacology, University of Oslo, P.O. Box 1057, Blindern, 0316 Oslo, Norway.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Jun;371(6):473-9. doi: 10.1007/s00210-005-1068-0. Epub 2005 Jul 13.
Prucalopride is a gastrointestinal prokinetic drug that acts through 5-HT4 receptors, but its potential effects on cardiac atrial function are unknown. We investigated the effects of prucalopride on human right atrium, piglet left atrium, and piglet sinoatrial node. The effects of prucalopride on 5-HT4 receptor splice variants a, b, g and i, known to be expressed in human atrium, were studied for comparison. Prucalopride was an inotropic partial agonist, compared with 5-HT, on paced human atrial trabeculae (-logEC50M=7.4) and porcine left atria (-logEC50M=7.2), with intrinsic activity of 0.77 and 0.63 respectively. Prucalopride (1 microM) surmountably antagonized the positive inotropic effects of 5-HT on human (pK(P)=7.2) and porcine (pK(P)=7.1) atrium. Prucalopride was also a chronotropic partial agonist (-logEC50M=7.4, intrinsic activity=0.72 with respect to 5-HT) on spontaneously beating piglet atria. The cardiostimulant effects of prucalopride were prevented by GR113808 (1 microM), consistent with mediation through 5-HT4 receptors. Prucalopride bound to recombinant 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, labeled by [3H]GR113808, with pKi values of 7.6, 7.5, 7.4, and 7.8 respectively. Prucalopride stimulated adenylyl cyclase as a partial agonist on 5-HT4(a), 5-HT4(b), and 5-HT4(i) receptors with intrinsic activities of 0.82, 0.86, and 0.78 and -logEC50 values of 7.2, 7.3, and 7.2 respectively. At the 5-HT4(g) receptor prucalopride acted as a full agonist (-logEC50M=8.0) compared with 5-HT in the cell line tested, which was probably due to high receptor expression levels. We conclude that prucalopride is a cardiostimulatory partial agonist through human and porcine 5-HT4 receptors. Since prucalopride acts similarly through 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, any of these variants could be involved in the mediation of cardiostimulation.
普芦卡必利是一种通过5-HT4受体发挥作用的胃肠促动力药物，但其对心脏心房功能的潜在影响尚不清楚。我们研究了普芦卡必利对人右心房、仔猪左心房和仔猪窦房结的影响。为作比较，还研究了普芦卡必利对已知在人心房中表达的5-HT4受体剪接变体a、b、g和i的影响。与5-羟色胺相比，普芦卡必利对起搏的人房小梁（-logEC50M=7.4）和猪左心房（-logEC50M=7.2）是一种变力性部分激动剂，内在活性分别为0.77和0.63。普芦卡必利（1微摩尔）可克服性拮抗5-羟色胺对人（pK(P)=7.2）和猪（pK(P)=7.1）心房的正性变力作用。普芦卡必利对自发搏动的仔猪心房也是一种变时性部分激动剂（-logEC50M=7.4，相对于5-羟色胺的内在活性=0.72）。GR113808（1微摩尔）可阻止普芦卡必利的心脏刺激作用，这与通过5-HT4受体介导一致。普芦卡必利与用[3H]GR113808标记的重组5-HT4(a)、5-HT4(b)、5-HT4(g)和5-HT4(i)受体结合，pKi值分别为7.6、7.5、7.4和7.8。普芦卡必利作为部分激动剂刺激5-HT4(a)、5-HT4(b)和5-HT4(i)受体上的腺苷酸环化酶，内在活性分别为0.82、0.86和0.78，-logEC50值分别为7.2、7.3和7.2。在5-HT4(g)受体上，与所测试细胞系中的5-羟色胺相比，普芦卡必利作为完全激动剂（-logEC50M=8.0），这可能是由于受体表达水平较高。我们得出结论，普芦卡必利通过人和猪的5-HT4受体是一种心脏刺激部分激动剂。由于普芦卡必利通过5-HT4(a)、5-HT4(b)、5-HT4(g)和5-HT4(i)受体的作用相似，这些变体中的任何一种都可能参与心脏刺激的介导。
