A 5-HYDROXYTRYPTAMINE RECEPTOR IN HUMAN ATRIUM

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. 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. The effects of 5-HT were resistant to blockade by 0.4 μM (±)-propranolol, 1 μM (-)-pindolol, 0.4 μM methiothepin, 4 μM yohimbine, 0.4 μM ketanserin, 10 μM phenoxybenzamine, 1 μM methysergide, 2 μM MDL 72222 and 20 μM granisetron. 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. ICS 205930 antagonized competitively the effects of 5-HT with a pK(B) of 6.7. In the presence of 0.4 μM (±)-propranolol, 10 μM 5-HT increased both adenosine 3':5' cyclic-monophosphate (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. 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. 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.