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(Circulation. 1995;92:2526-2539.)
© 1995 American Heart Association, Inc.

Articles

Sensitization of Human Atrial 5-HT₄ Receptors by Chronic ß-Blocker Treatment

Louise Sanders, MA; James A. Lynham, BSC; Brian Bond, MSC; Federica del Monte, MD; Sian E. Harding, PhD; Alberto J. Kaumann, MD, PhD

From the Human Pharmacology Laboratory, The Babraham Institute (L.S., J.A.L., A.J.K.), Babraham, Cambridge; the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital (L.S., A.J.K.), Cambridge; SmithKline Beecham Pharmaceuticals (B.B.), Welwyn; and the Department of Cardiac Medicine, National Heart and Lung Institute (F.d.M., S.E.H.), London, UK.

Correspondence to Dr A.J. Kaumann, Human Pharmacology Laboratory, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.

Background Chronic treatment of patients with ß-blockers induces ß₂-adrenergic receptor hyperresponsiveness in atrium and sinoatrial node. To investigate whether other atrial G_s protein–coupled receptors also become hyperresponsive after chronic treatment with ß-blockers, we investigated 5-HT₄ receptors in tissues and myocytes, which mediate serotonin-evoked increases of both contractile force and cAMP levels.

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

Conclusions Chronic treatment of patients with ß-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, ß-adrenergic receptors, and muscarinic receptors.

Key Words: atrium • receptors, serotonin₄ • receptors, adrenergic, beta • contractility • cAMP • receptors, serotonergic

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