A 5‐hydroxytryptamine receptor in human atrium

Abstract

1 The effects of 5-hydroxytryptamine (5-HT) were investigated on right atrial appendages obtained from patients treated with β-adrenoceptor blocking agents who were undergoing open heart surgery. Atrial strips were paced under isometric conditions. 2 5-HT increased contractile force to approximately one half of the force produced by a saturating concentration of (−)−isoprenaline. Both 5-HT and (−)−isoprenaline accelerated the onset of relaxation, as indicated by an abbreviation of time to peak force. 3 The effects of 5-HT were resistant to blockade by 0.4 μm (±)-propranolol, 1μm (−)−pindolol, 0.4 μm methiothepin, 4 μm yohimbine, 0.4 μm ketanserin, 10 μm phenoxybenzamine, 1μm methysergide, 2 μm MDL 72222 and 20 μm granisetron. 4 Cocaine 6 μm potentiated the effects of 5-HT, increasing the pEC₅₀ from 6.6 to 7.4. The inotropic potency of 5-HT is five times greater than that of (−)−noradrenaline. 5 ICS 205930 antagonized competitively the effects of 5-HT with a pK_B of 6.7. 6 In the presence of 0.4 μm (±)-propranolol, 10 μm 5-HT increased both adenosine 3′:5′ cyclicmonophosphate (cyclic AMP) levels and cyclic AMP-dependent protein kinase activity by approximately one half and two thirds respectively, of the corresponding effects of 200 μm (−)−isoprenaline. 7 Both the increase in cyclic AMP levels and the stimulation of protein kinase activity are consistent with the inotropic effects of 5-HT being mediated by cyclic AMP-dependent phosphorylation of Ca²⁺ channels and of proteins involved in contraction and relaxation. 8 The human atrial 5-HT receptor resembles the neuronal ‘so called’ 5-HT₄ receptor of rodents both in increasing cyclic AMP levels and in its affinity for ICS 205930.