title: Chronic beta 1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: rôle of cyclic nucleotides.
abstract: We have reported that chronic treatment of patients with beta 1-adrenoceptor blockers sensitises isolated atrial preparations to adrenaline, noradrenaline and 5-Ht. We have now examined the effect of chronic treatment with beta-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 beta-adrenoceptor blockers. Histamine increased contractile force in paced preparations; the effects were blocked by the H2 receptor antagonist famotidine (0.1-30 mumol/l). The maximum inotropic response to histamine was doubled and the inotropic potency of histamine 0.4 log units greater in atria from beta-adrenoceptor blocker-treated compared to non beta-adrenoceptor blocker-treated patients. Histamine elicited frequency-dependent arrhythmias that were blocked by famotidine (30 mumol/l) but not by mepyramine (1 mumol/l). The incidence of arrhythmias was higher in atria from beta-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 beta-adrenoceptor blocker-treated compared to those from untreated patients. Mepyramine 1 mumol/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 beta blockers. Sodium nitroprusside 10 mumol/l caused smaller increase of cyclic GMP levels than histamine and restored the contracile force depressed by mepyramine to its original level in atria from beta-adrenoceptor blocker-treated patients. The evidence is consistent with sensitisation of both the histamine H1 and histamine H2 receptor systems by chronic beta 1-adrenoceptor blockade. H1 receptor-mediated increases in cyclic GMP, enhanced through an as yet unknown mechanism by chronic beta 1-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.
authors: Human Pharmacology Laboratory, Babraham Institute, Cambridge, UK.
authors: L
authors: L
authors: Sanders
authors: J A
authors: JA
authors: Lynham
authors: A J
authors: AJ
authors: Kaumann
mesh_terms: D000319:Adrenergic beta-Antagonists; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000737:chemistry / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects*; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013268:Stimulation, Chemical
chemical_list: D000319:Adrenergic beta-Antagonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D015738:Famotidine; D006632:Histamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D011738:Pyrilamine