Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig

Abstract

1 It has recently been shown that the tachycardic response to 5-hydroxytryptamine (5-HT) in the anaesthetized pig, being mimicked by 5-methoxytryptamine and renzapride and blocked by high doses of ICS 205-930, is mediated by the putative 5-HT4 receptor. In the present investigation we have further characterized this receptor. 2 Intravenous bolus injections of the tryptamine derivatives, 5-HT (3, 10 and 30 μg kg-1), 5-methoxytryptamine (3, 10 and 30 μg kg-1) and α-methyl-5-hydroxytryptamine (α-methyl-5-HT; 3, 10, 30 and 100 μg kg-1), resulted in dose-dependent increases in heart rate of, respectively, 25 ± 2, 48 ± 3 and 68 ± 3 beats min-1 (5-HT; n = 35); 15 ± 1, 32 ± 2 and 57 ± 3 beats min-1 (5-methoxytryptamine; n = 30); 6 ± 4, 18 ± 6, 34 ± 6 and 64 ± 11 beats min-1 (α-methyl-5-HT; n = 3). 3 The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were generally less marked and not dose-dependent: 1 ± 5, 11 ± 3 and 10 ± 5 beats min-1 after 300, 1000 and 3000 μg kg-1 of metoclopramide, respectively, (n = 8); 21 ± 4, 19 ± 2 and 2 ± 2 beats min-1 after 100, 300 and 1000 μg kg-1 of cisapride, respectively, (n = 5); 6 ± 2, 14 ± 2, 37 ± 6, 43 ± 8 and 34 ± 10 beats min-1 after 10, 30, 100, 300 and 1000 μg kg-1 of zacopride, respectively, (n = 6); and 1 ± 1, 2 ± 1 and 5 ± 2 beats min-1 after 300, 1000 and 3000 μg kg-1 of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5-HT and 5-methoxytryptamine dose-dependently. 4 The 5-HT3 receptor agonist 1-phenyl-biguanide (100, 300 and 1000 μg kg-1) induced only slight increases in heart rate of 1 ± 1, 6 ± 2 and 11 ± 1 beats min-1, respectively, (n = 3). These effects were not antagonized by the selective 5-HT3 receptor antagonist granisetron (3 mg kg-1). In addition, 1-phenyl-biguanide (1000 μg kg-1) did not modify the tachycardia induced by either 5-HT- or 5-methoxytryptamine. 5 High doses (3 mg kg-1) of ICS 205-930, a 5-HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5-HT, 5-methoxytryptamine, α-Me-5-HT, metoclopramide, cisapride, zacopride, dazopride and 1-phenyl-biguanide. However, the 5-HT2 receptor antagonist ketanserin (0.5 mg kg-1), the 5-HT3 receptor antagonists granisetron (3 mg kg-1) and MDL 72222 (3 mg kg-1) and the dopamine D2 receptor antagonist domperidone (3 mg kg-1) had no antagonist activity. 6 The above results support our contention that 5-HT, 5-methoxytryptamine, α-Me-5-HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5-HT4 receptor. The pharmacological profile of this novel 5-HT receptor is similar (neurones from mouse brain colliculi and human heart), or, perhaps, even identical (guinea-pig cholinergic neurones) to other putative 5-HT4 receptors.