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Sensitization of human atrial 5-HT4 receptors by chronic beta-blocker treatment
L Sanders1, J A Lynham, B Bond
1Human Pharmacology Laboratory, Babraham Institute, Cambridge, UK.
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.
Insights
Beta-blocker treatment causes atrial 5-HT4 receptor hyperresponsiveness, enhancing serotonin
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Chronic beta-blocker therapy is known to induce beta 2-adrenergic receptor hyperresponsiveness in the atrium and sinoatrial node.
- This study investigates potential hyperresponsiveness in other atrial Gs protein-coupled receptors, specifically 5-HT4 receptors, following chronic beta-blocker treatment.
Purpose of the Study:
- To determine if chronic beta-blocker treatment leads to hyperresponsiveness of atrial 5-HT4 receptors.
- To assess the impact on serotonin-evoked increases in contractile force and cAMP levels in atrial tissues and myocytes.
Main Methods:
- Isolated right atrial strips and atrial myocytes from patients with and without chronic beta-blocker treatment were used.
- Inotropic responses to serotonin and calcium, as well as serotonin- and forskolin-evoked cAMP levels, were measured.
- Myocyte sensitivity to serotonin was determined by concentration-response curves.
Main Results:
- Atrial tissues from beta-blocker-treated patients showed significantly greater inotropic responses to serotonin compared to non-treated patients.
- Serotonin-induced increases in cAMP levels were significantly greater in tissues from beta-blocker-treated patients.
- Atrial myocytes from beta-blocker-treated patients exhibited increased sensitivity to serotonin's contractile effects.
Conclusions:
- Chronic beta-blocker treatment induces atrial 5-HT4 receptor inotropic hyperresponsiveness and enhanced cAMP signaling.
- This phenomenon may involve altered cross-talk between 5-HT4, beta-adrenergic, and muscarinic receptors.