Loss of β-adrenoceptor response in myocytes overexpressing the Na+/Ca2+-exchanger

Abstract Increased Na + /Ca 2+ -exchanger (NCX) and altered β-adrenoceptor (βAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to isoproterenol in adult rat ventricular myocytes. Responses to isoproterenol were largely mediated through the β 1 AR in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the isoproterenol concentration–response curve. Responses to isoproterenol could be restored to normal by β 2 AR blockade, suggesting a β 2 AR-mediated inhibition of β 1 AR signalling. Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that β 2 AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to β 2 AR–Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of βAR stimulation and that this may contribute to the alterations in βAR response seen in failing human heart.

[1]  W. Koch,et al.  Specific β2AR Blocker ICI 118,551 Actively Decreases Contraction Through a Gi-Coupled Form of the β2AR in Myocytes From Failing Human Heart , 2002 .

[2]  E. Lakatta,et al.  Inhibition of Spontaneous β2-Adrenergic Activation Rescues β1-Adrenergic Contractile Response in Cardiomyocytes Overexpressing β2-Adrenoceptor* , 2000, The Journal of Biological Chemistry.

[3]  Robert J. Lefkowitz,et al.  Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A , 1997, Nature.

[4]  K. Jakobs,et al.  Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. , 1990, Circulation.

[5]  W. Koch,et al.  The effect of Gi‐protein inactivation on basal, and β1‐ and β2AR‐stimulated contraction of myocytes from transgenic mice overexpressing the β2‐adrenoceptor , 2000 .

[6]  D. Bers,et al.  Upregulation of Na(+)/Ca(2+) exchanger expression and function in an arrhythmogenic rabbit model of heart failure. , 1999, Circulation research.

[7]  J. Black,et al.  Cardiac‐specific overexpression of human β2 adrenoceptors in mice exposes coupling to both Gs and Gi proteins , 2003, British journal of pharmacology.

[8]  T. Nagao,et al.  Determination β‐adrenoceptor subtype on rat isolated ventricular myocytes by use of highly selective β‐antagonists , 1995 .

[9]  R. Robinson,et al.  β2-Adrenergic Receptor Actions in Neonatal and Adult Rat Ventricular Myocytes , 1995 .

[10]  S. Vatner,et al.  Identification and Functional Role ofβ-adrenergic Receptor Subtypes in Primate and Rodent:In Vivoversus Isolated Myocytes , 1996 .

[11]  E. Lakatta,et al.  Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells. , 1993, Circulation research.

[12]  G. Hasenfuss,et al.  Impaired Contractile Performance of Cultured Rabbit Ventricular Myocytes After Adenoviral Gene Transfer of Na+-Ca2+ Exchanger , 2000, Circulation research.

[13]  R. Hajjar,et al.  Interaction between increased SERCA2a activity and beta -adrenoceptor stimulation in adult rabbit myocytes. , 2002, American journal of physiology. Heart and circulatory physiology.

[14]  J. Port,et al.  Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. , 1990, Circulation.

[15]  W. Koch,et al.  L-type calcium current and contractility in ventricular myocytes from mice overexpressing the cardiac β2-adrenoceptor , 1999 .

[16]  S. Harding,et al.  The effect of pertussis toxin on β‐adrenoceptor responses in isolated cardiac myocytes from noradrenaline‐treated guinea‐pigs and patients with cardiac failure , 1992, British journal of pharmacology.

[17]  M. Böhm,et al.  Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. , 1993, Circulation.

[18]  E. Lakatta,et al.  Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. , 1995, Molecular pharmacology.

[19]  H. Drexler,et al.  Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. , 1994, Circulation research.

[20]  S. Jamieson,et al.  Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. , 1986, Circulation research.

[21]  S. Robinson,et al.  Effects of Na+/Ca2+-exchanger Overexpression on Excitation–contraction Coupling in Adult Rabbit Ventricular Myocytes , 2002 .

[22]  S. Lotersztajn,et al.  Activation of Na+/Ca2+ exchange by adenosine in ewe heart sarcolemma is mediated by a pertussis toxin-sensitive G protein. , 1990, The Journal of biological chemistry.

[23]  E. Lakatta,et al.  Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. , 1999, Circulation research.

[24]  S. Harding,et al.  Cardiostimulant and cardiodepressant effects through overexpressed human β2-adrenoceptors in murine heart: regional differences and functional role of β1-adrenoceptors , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[25]  Heping Cheng,et al.  Cellular Mechanisms of p 38 MAPK – Induced Negative Inotropic Effect : Suppression of Myofilament Ca , 2002 .

[26]  P. Barnes,et al.  Gi-dependent suppression of β1-adrenoceptor effects in ventricular myocytes from NE-treated guinea pigs , 2000 .

[27]  J. Pepper,et al.  Coexistence of functioning beta 1- and beta 2-adrenoceptors in single myocytes from human ventricle. , 1993, Circulation.

[28]  M. Böhm,et al.  Role of guanine nucleotide-binding protein in the regulation by adenosine of cardiac potassium conductance and force of contraction. Evaluation with pertussis toxin , 1986, Naunyn-Schmiedeberg's Archives of Pharmacology.

[29]  J. Cheung,et al.  Overexpression of Na+/Ca2+ exchanger alters contractility and SR Ca2+ content in adult rat myocytes. , 2001, American journal of physiology. Heart and circulatory physiology.