REDUCED ALPHA-1-ADRENOCEPTOR-MEDIATED AND BETA-2-ADRENOCEPTOR-MEDIATED POSITIVE INOTROPIC EFFECTS IN HUMAN END-STAGE HEART-FAILURE

1 Alpha(1)-Adrenoceptor (phenylephrine in the presence of propranolol) and beta(2)-adrenoceptor (fenoterol)-mediated positive inotropic effects were investigated in human ventricular preparations isolated from five nonfailing (prospective organ donors) and from eight explanted failing hearts with end-stage idiopathic dilative cardiomyopathy (NYHA IV). 2 For comparison, the nonselective beta-adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3 Furthermore, the influence of IBMX on adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE activity as well as total beta-adrenoceptor density, beta(1)- and beta(2)-adrenoceptor subtype distribution, and alpha(1)-adrenoceptor density were compared in nonfailing and human heart preparations. The radioligands (-)-[I-125]-iodocyanopindolol for beta-adrenoceptor binding and [H-3]-prazosin for alpha(1)-adrenoceptor binding were used. 4 The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal alpha(1)- and beta(2)-adrenoceptor-mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4-10. 5 The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6 The total beta-adrenoceptor density in nonfailing hearts was about 70 fmol mg-1 protein. In failing hearts the total number of beta-adrenoceptors was markedly reduced by about 60%. The beta1/beta2-adrenoceptor ratio was shifted from about 80/20% in nonfailing to approximately 60/40% in failing hearts which was due to a selective reduction of beta(1)-adrenoceptors. The beta(2)-adrenoceptor population remaining unchanged. Alpha(1)-Adrenoceptor density was increased from about 4 fmol mg-1 protein in nonfailing to 10 fmol mg-1 protein in failing hearts. 7 Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of alpha(1)- and beta(2)-adrenoceptor agonists in failing human hearts. This supports the hypothesis that impairment of other processes such as the coupling between receptor and effector system, i.e. the respective G-proteins, are equally important in end-stage heart failure.