and tKlinik fur Herz-, Thorax-und Gefdii3chirurgie, Medizinische Hochschule Hannover, Konstanty-Gutschow-Strape 8, 3000 Hannover 61, Germany 1 a1-Adrenoceptor (phenylephrine in the presence of propranolol) andf/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 fJ-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 #-adrenoceptor density, /J,-andfi2-adrenoceptor subtype distribution, and xl-adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (_)-j[j25I]-iodocyanopindolol for fJ-adrenoceptor binding and [3H]-prazosin for o1-adrenoceptor binding were used. 4 The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal cl-and /12-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 fJ-adrenoceptor density in nonfailing hearts was about 70 fmol mg-' protein. In failing hearts the total number of,-adrenoceptors was markedly reduced by about 60%. The l/2-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 /11-adrenoceptors. The 2-adrenoceptor population remaining unchanged. ac-Adrenoceptor density was increased from about 4 fmol mg-' protein in nonfailing to 10 fmol mgprotein in failing hearts. 7 Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of ax-and f12-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.

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