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Chronic β1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: role of cyclic nucleotides

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Abstract

We have reported that chronic treatment of patients with β1-adrenoceptor blockers sensitises isolated atrial preparations to adrenaline, noradrenaline and 5-HT. We have now examined the effect of chronic treatment with β-adrenoceptor blockers on responses to histamine of human right atrial appendages. We compared the effects of histamine on contractile force, cyclic AMP and cyclic GMP levels as well as cyclic AMP-dependent protein kinase (PKA) activity and explored the arrhythmogenic effects of histamine in preparations obtained from patients chronically treated or not treated with β-adrenoceptor blockers.

Histamine increased contractile force in paced preparations; the effects were blocked by the H2 receptor antagonist famotidine (0.1–30 μmol/1). The maximum inotropic response to histamine was doubled and the inotropic potency of histamine 0.4 log units greater in atria from β-adrenoceptor blocker-treated compared to non β-adrenoceptor blocker-treated patients. Histamine elicited frequency-dependent arrhythmias that were blocked by famotidine (30 μmol/1) but not by mepyramine (1 μmol/1). The incidence of arrhythmias was higher in atria from β-adrenoceptor blocker-treated compared to untreated patients. Histamine increased both cyclic AMP and cyclic GMP levels, as well as PKA activity, significantly more in atria from β-adrenoceptor blocker-treated compared to those from untreated patients. Mepyramine 1 μmol/l prevented the histamine-evoked increase in cyclic GMP levels, reduced the inotropic hyperresponsiveness and abolished the hyperresponsiveness in cyclic AMP levels and PKA activity observed in patients chronically treated with β blockers. Sodium nitroprusside 10 μmol/l caused smaller increases of cyclic GMP levels than histamine and restored the contracile force depressed by mepyramine to its original level in atria from β-adrenoceptor blocker-treated patients.

The evidence is consistent with sensitisation of both the histamine H1 and histamine H2 receptor systems by chronic β1-adrenoceptor blockade. H1 receptor-mediated increases in cyclic GMP, enhanced through an as yet unknown mechanism by chronic β1-adrenoceptor blockade, may inhibit phosphodiesterase 3 activity, thereby causing enhanced histamine-evoked increases in cyclic AMP levels and PKA activity, and accounting partially for the increased inotropic responses to histamine through H2 receptors.

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Authors and Affiliations

  1. Human Pharmacology Laboratory, The Babraham Institute, CB2 4AT, Babraham, Cambridge, UK

    Louise Sanders, James A. Lynham & Alberto J. Kaumann

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  1. Louise Sanders
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  2. James A. Lynham
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  3. Alberto J. Kaumann
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Sanders, L., Lynham, J.A. & Kaumann, A.J. Chronic β1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: role of cyclic nucleotides. Naunyn-Schmiedeberg's Arch Pharmacol 353, 661–670 (1996). https://doi.org/10.1007/BF00167185

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