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. METHODS AND 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.
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. METHODS AND 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.
Authors: J Mialet; I Berque-Bestel; P Eftekhari; M Gastineau; M Giner; Y Dahmoune; P Donzeau-Gouge; J Hoebeke; M Langlois; S Sicsic; R Fischmeister; F Lezoualc'h Journal: Br J Pharmacol Date: 2000-02 Impact factor: 8.739
Authors: Kurt A Krobert; Trond Brattelid; Finn Olav Levy; Alberto J Kaumann Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2005-07-13 Impact factor: 3.000