© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
L-type calcium current and contractility in ventricular myocytes from mice overexpressing the cardiac β2-adrenoceptor1
aInstitut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany
bInstitut für Pharmakologie und Toxikologie, Universitätsklinikum der TU Dresden, Dresden, Germany
cAbteilung für Nieren und Hochdruckkranke, Zentrum Innere Medizin, Universitätsklinikum Essen, Essen, Germany
dBabraham Institute, Cambridge, UK
eDepartment of Surgery, Duke University, Durham, NC, USA
fCardiac Medicine, National Heart and Lung Institute at Imperial College, Dovehouse Street, London, UK
* Corresponding author. Institut für Pharmakologie und Toxikologie, Universitätsklinikum der TU Dresden, Karl-Marx-Strasse 3, D-01109 Dresden, Germany. Tel.: +49-351-8832 830; fax: +49-351-8832 832. E-mail address: ravens@rcs.urz.tu-dresden.de (U. Ravens)
Objectives: The reported increase in basal activity of hearts from transgenic mice (TG4) overexpressing the human β2-adrenoceptor (β2-AR) was explained by spontaneously active β2-ARs that stimulate the β-adrenergic cascade in the absence of an agonist. In order to examine altered myocardial function on a cellular level, we have investigated L-type calcium current (ICa,L) and cell shortening in ventricular myocytes from TG4 hearts. Myocytes from littermates (LM) and wild type animals (WT) served as controls. Methods: Cardiac β-AR density was measured by [125I]-iodocyanopindolol binding to ventricular membranes. ICa,L was assessed by standard whole-cell voltage clamp technique. Contractility was measured as cell shortening in ventricular myocytes and as force of contraction in electrically stimulated left atria. Results: Overexpression of β2-ARs was confirmed by an almost 400-fold increase in β-AR density. The β1:β2-AR ratio in WT mice was 71:29. Myocytes from TG4 and LM mice were similar in size as judged by membrane capacitance and two dimensional cell area. ICa,L amplitude was significantly lower in TG4 than in LM myocytes (with 2 mM [Ca2+]o –4.82±0.48 vs. –6.56±0.38 pA/pF, respectively). In TG4 myocytes, the ICa,L response to isoproterenol (1 µM) was almost abolished. Cell shortening was not different in physiological [Ca2+]o, but smaller in maximum [Ca2+]o when comparing TG4 to control myocytes. Basal force of contraction in left atria did not differ between TG4 and LM at any age investigated. In TG4 left atria the inotropic response to isoproterenol was also absent, whereas responses to high [Ca2+]o or dibutyryl-cAMP (1 mM) were present but reduced. The rate of spontaneous beating of right atria was elevated in TG4 mice. Conclusions: Since only spontaneous beating rate but neither basal ICa,L amplitude nor basal contractile activity were elevated, our data fail to reveal evidence for spontaneously active, stimulating β2-ARs in left atrium and ventricle. A contractile deficit unrelated to the β-adrenoceptor pathway is evident in TG4 myocytes and left atria.
KEYWORDS Transgenic mice; Myocardium; β2-Adrenoceptor overexpression; L-Type Ca2+ current; Myocyte shortening
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