Interaction between autoantibodies against the beta(1)-adrenoceptor and isoprenaline in enhancing L-type Ca(2+) current in rat ventricular myocytes

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Item Type:	Article
Title:	Interaction between autoantibodies against the beta(1)-adrenoceptor and isoprenaline in enhancing L-type Ca(2+) current in rat ventricular myocytes
Creators Name:	Christ, T., Schindelhauer, S., Wettwer, E., Wallukat, G. and Ravens, U.
Abstract:	Autoantibodies against the beta(1)-adrenoceptor (beta(1)-AAB) in the serum of patients with dilated cardiomyopathy (DCM) are associated with stimulatory effects at cardiac beta(1)-adrenoceptors. They enhance cardiomyocyte shortening and increase the amplitude of L-type Ca(2+) current, I(Ca). However, in contrast to the unselective beta-adrenoceptor agonist (-)-isoprenaline, beta(1)-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 beta(1)-AAB and (-)-isoprenaline were investigated in responder and non-responder cells. The immunoglobulin G (IgG) fractions containing beta(1)-AAB (beta(1)-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 beta(1)-IgG or purified beta(1)-AAB were responder cells in which I(Ca) amplitude increased. I(Ca) increase by beta(1)-IgG or (-)-isoprenaline was reversed by addition of carbachol. Exposure to subtype-selective beta-adrenoceptor blockers indicated that the effects of IgG were mediated via beta(1)-adrenoceptors. In responder cells, there were no differences between beta(1)-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 muM) 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 beta(1)-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 beta(1)-AAB not only may enhance I(Ca) via stimulation of beta(1)-adrenoceptors but also may inhibit beta(1)-adrenoceptor-mediated increase upon stimulation with catecholamines suggesting a receptor interaction distinct from that with (-)-isoprenaline.
Keywords:	Autoantibodies, beta-adrenoceptors, Cardiomyocytes, L-type Ca2+ current, Animals, Rats
Source:	Journal of Molecular and Cellular Cardiology
ISSN:	0022-2828
Publisher:	Elsevier
Volume:	41
Number:	4
Page Range:	716-723
Date:	October 2006
Official Publication:	https://doi.org/10.1016/j.yjmcc.2006.06.011
PubMed:	View item in PubMed

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