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

Increased Na+/Ca2+-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 β1AR 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 β2AR blockade, suggesting a β2AR-mediated inhibition of β1AR signalling. Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that β2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to β2AR–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.