Differential effects of cocaine on the positive inotropic effect of noradrenaline mediated by alpha(1)- and beta-adrenoceptors in failing human myocardium

Electrically driven (1 Hz) ventricular trabeculae from explanted failing hu man myocardium were indirectly examined for the localization of the alpha ( 1)-adrenoceptor population and the beta -adrenoceptor population in relatio n to sympathetic nerve endings. We examined the influence of neuronal uptak e blockade by cocaine upon the horizontal position of the concentration-res ponse curves for the inotropic effects exerted by noradrenaline in the pres ence and absence of appropriate adrenoceptor antagonists. Cocaine shifted t he concentration-response curve for alpha (1)-adrenoceptor stimulation, but not that for beta -adrenoceptor stimulation, to lower concentrations of no radrenaline in a parallel manner. The concentration-response curve for comb ined adrenoceptor stimulation was shifted by cocaine to lower concentration s of noradrenaline in a nonparallel manner. In explanted allograft heart, c ocaine had no effect upon the position of the concentration-response curve to alpha (1)-adrenoceptor stimulation. The data indicate that in the explan ted native hearts the alpha (1)-adrenoceptor population is located close to or within the synaptic cleft, while the beta -adrenoceptor population rema ining in the failing myocardium is located more distantly to the neuronal r elease sites. (C) 2001 Elsevier Science B.V. All rights reserved.