Interaction between autoantibodies against the β₁-adrenoceptor and isoprenaline in enhancing L-type Ca²⁺ current in rat ventricular myocytes

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• 作者：Torsten Christ ; Stefan Schindelhauer ; Erich Wettwer ; Gerd Wallukat and Ursula Ravens
• 关键词：Autoantibodies ; β ; -adrenoceptors ; Cardiomyocytes ; L-type Ca²⁺ current
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2006
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：October 2006
• 卷：41
• 期：4
• 页码：716-723
• 文件大小：498 K

摘要

Autoantibodies against the β₁-adrenoceptor (β₁-AAB) in the serum of patients with dilated cardiomyopathy (DCM) are associated with stimulatory effects at cardiac β₁-adrenoceptors. They enhance cardiomyocyte shortening and increase the amplitude of L-type Ca²⁺ current, I_Ca. However, in contrast to the unselective β-adrenoceptor agonist (–)-isoprenaline, β₁-AAB produce positive responses in a fraction of myocytes (responder cells) only and fail to do so in the remaining ones (non-responder cells). To understand this peculiar behaviour, the electrophysiological characteristics of I_Ca in response to β₁-AAB and (–)-isoprenaline were investigated in responder and non-responder cells. The immunoglobulin G (IgG) fractions containing β₁-AAB (β₁-IgG) were obtained from patients with DCM undergoing immunoabsorption therapy. Only antibody preparations that tested positive in the neonatal rat cardiomyocyte bio-assay by enhancing beating rate were used for further experimentation. Calcium currents were measured with the standard patch clamp technique in adult rat ventricular myocytes. Less than half of all cells exposed to β₁-IgG or purified β₁-AAB were responder cells in which I_Ca amplitude increased. I_Ca increase by β₁-IgG or (–)-isoprenaline was reversed by addition of carbachol. Exposure to subtype-selective β-adrenoceptor blockers indicated that the effects of IgG were mediated via β₁-adrenoceptors. In responder cells, there were no differences between β₁-IgG- and (–)-isoprenaline-induced changes in current-voltage relationship of I_Ca, in the time constants of fast inactivation, and in steady-state activation and steady-state inactivation curves. (–)-Isoprenaline (1 μM) effectively increased I_Ca after wash-out of antibody in all cells including non-responder cells. However, when non-responder cells were challenged with (–)-isoprenaline in the presence of β₁-IgG, any further increase in I_Ca was completely suppressed. Conversely, in responder cells, the cumulative concentration-response curves for (–)-isoprenaline on top of the autoantibodies reached the same maximum I_Ca amplitude as in control cells. From these interactions we conclude that β₁-AAB not only may enhance I_Ca via stimulation of β₁-adrenoceptors but also may inhibit β₁-adrenoceptor-mediated increase upon stimulation with catecholamines suggesting a receptor interaction distinct from that with (–)-isoprenaline.