SENSITIZATION OF HUMAN ATRIAL 5-HT4 RECEPTORS BY CHRONIC BETA-BLOCKER TREATMENT

Background Chronic treatment of patients with P-blockers induces beta(2)-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 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 mu mol/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 mu mol/L) increased tissue cAMP levels, the increase with 10 mu mol/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 EC(50), 7.9+/-0.2 mol/L; n=12) than myocytes obtained from non-B-blocker-treated patients (-log EC(50), 7.3+/-0.2 mol/L, n=12). Chronic beta-blocker treatment had no effect on forskolin-evoked myocyte responses. Carbachol (1 mu mol/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.