Reduced α1- and β2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure |
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Authors: | Markus Steinfath Wiebke Danielsen Heiko von der Leyen Ulrike Mende Wilfried Meyer Joachim Neumann Monika Nose Torsten Reich Wilhelm Schmitz Hasso Scholz Jutta Starbatty Birgitt Stein Volker Dring Peter Kalmar and Axel Haverich |
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Institution: | Abteilung Allgemeine Pharmakologie, Universit?ts-Krankenhaus Eppendorf, Universit?t Hamburg, Germany. |
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Abstract: | 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 non-failing (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 failing human heart preparations. The radioligands (-)-125I]-iodocyanopindolol for beta-adrenoceptor binding and 3H]-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%.(ABSTRACT TRUNCATED AT 250 WORDS) |
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