Reduced α1‐ and β2‐adrenoceptor‐mediated positive inotropic effects in human end‐stage heart failure

1 α1‐Adrenoceptor (phenylephrine in the presence of propranolol) and β2‐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 β‐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 β‐adrenoceptor density, β1‐ and β2‐adrenoceptor subtype distribution, and α1‐adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (−)‐[125I]‐iodocyanopindolol for β‐adrenoceptor binding and [3H]‐prazosin for α1‐adrenoceptor binding were used. 4 The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal α1‐ and β2‐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 β‐adrenoceptor density in nonfailing hearts was about 70 fmol mg−1 protein. In failing hearts the total number of β‐adrenoceptors was markedly reduced by about 60%. The β1/β2‐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 β1‐adrenoceptors. The β2‐adrenoceptor population remaining unchanged. α1‐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 α1‐ and β2‐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.