A 5-hydroxytryptamine receptor in human atrium.
1. The effects of 5-hydroxytryptamine (5-HT) were investigated on right atrial appendages obtained from patients treated with beta-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 microM (+/-)-propranolol, 1 microM (-)-pindolol, 0.4 microM methiothepin, 4 microM yohimbine, 0.4 microM ketanserin, 10 microM phenoxybenzamine, 1 microM methysergide, 2 microM MDL 72222 and 20 microM granisetron. 4. Cocaine 6 microM 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 pKB of 6.7. 6. In the presence of 0.4 microM (+/-)-propranolol, 10 microM 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 microM (-)-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.
Kaumann
A J
AJ
Smith Kline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire.
Sanders
L
L
Brown
A M
AM
Murray
K J
KJ
Brown
M J
MJ
D003042:Cocaine / Q000494:pharmacology; D003327:Coronary Disease / Q000378:metabolism / Q000601:surgery; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D000077526:Tropisetron
D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D000077526:Tropisetron; D000242:Cyclic AMP; D011494:Protein Kinases; D003042:Cocaine; D007545:Isoproterenol