Reduced α1- and β2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure
| Autor: | Hasso Scholz, Ulrike Mende, Volker Döring, Axel Haverich, Wiebke Danielsen, Markus Steinfath, Peter Kalmár, Torsten Reich, Wilfried Meyer, Jutta Starbatty, Monika Nose, Wilhelm Schmitz, Joachim Neumann, Heiko von der Leyen, Birgitt Stein |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Adult
Male Inotrope medicine.medical_specialty IBMX Population Muscle Proteins Propranolol In Vitro Techniques Radioligand Assay chemistry.chemical_compound 3' 5'-Cyclic-GMP Phosphodiesterases Internal medicine Isoprenaline Receptors Adrenergic beta Idiopathic dilated cardiomyopathy medicine Humans Ouabain education Phenylephrine Heart Failure Pharmacology education.field_of_study Phosphoric Diester Hydrolases Phosphodiesterase Adrenergic beta-Agonists Middle Aged Receptors Adrenergic alpha Myocardial Contraction Stimulation Chemical Endocrinology chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Papers Calcium Female Adrenergic alpha-Agonists medicine.drug |
| Zdroj: | British Journal of Pharmacology. 105:463-469 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/j.1476-5381.1992.tb14276.x |
| Popis: | 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%. The betal/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 beta1-adrenoceptors. The beta2-adrenoceptor population remaining unchanged. alpha-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 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. |
| Databáze: | OpenAIRE |
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