Sensitization of human atrial 5-HT4 receptors by chronic beta-blocker treatment.
BACKGROUND
Chronic treatment of patients with beta-blockers induces beta 2-adrenergic receptor hyperresponsiveness in atrium and sinoatrial node. To investigate whether other atrial Gs protein-coupled receptors also become hyperresponsive after chronic treatment with beta-blockers, we investigated 5-HT4 receptors in tissues and myocytes, which mediate serotonin-evoked increases of both contractile force and cAMP levels.


RESULTS
Isolated right atrial strips from patients who had been chronically treated or not treated with a beta-blocker were set up to contract. In tissues from beta-blocker-treated patients (n = 27), the maximum inotropic response to serotonin was 56 +/- 3% (mean +/- SEM) of the effect elicited by (-)-isoproterenol (200 mumol/L) compared with a response of 19 +/- 6% in tissues from non-beta-blocker-treated patients (n = 13) (P < .001). The responsiveness of the tissues to Ca2+ was unchanged by chronic beta-blocker treatment. Serotonin (1 and 10 mumol/L) increased tissue cAMP levels, the increase with 10 mumol/L being significantly greater (P < .05) in tissues from beta-blocker-treated (n = 9) than in non-beta-blocker-treated (n = 7) patients. In paced atrial myocytes, serotonin caused concentration-dependent increases in contraction. Myocytes obtained from atria of beta-blocker-treated patients were more sensitive (P < .01) to the effects of serotonin (-log EC50, 7.9 +/- 0.2 mol/L; n = 12) than myocytes obtained from non-beta-blocker-treated patients (-log EC50, 7.3 +/- 0.2 mol/L, n = 12). Chronic beta-blocker treatment had no effect on forskolin-evoked myocyte responses. Carbachol (1 mumol/L) suppressed the effects of both serotonin (n = 6) and (-)-isoproterenol (n = 6) in the same atrial myocyte.


CONCLUSIONS
Chronic treatment of patients with beta-blockers causes atrial 5-HT4 receptor inotropic hyperresponsiveness and enhanced serotonin-evoked increases in cAMP levels. This may be due to modified cross talk between 5-HT4 receptors, beta-adrenergic receptors, and muscarinic receptors.
Sanders
L
L
Human Pharmacology Laboratory, Babraham Institute, Cambridge, UK.
Lynham
J A
JA
Bond
B
B
del Monte
F
F
Harding
S E
SE
Kaumann
A J
AJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000368:Aged; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006325:Heart Atria / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D011940:Receptor Aggregation; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000242:Cyclic AMP