A 5‐hydroxytryptamine receptor in human atrium

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Abstract
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, 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. 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 pKB of 6.7. 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. 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.