Reduced alpha 1- 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 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.
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Germany.
M
M
Steinfath
W
W
Danielsen
H
H
von der Leyen
U
U
Mende
W
W
Meyer
J
J
Neumann
M
M
Nose
T
T
Reich
W
W
Schmitz
H
H
Scholz
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D002118:Calcium / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013268:Stimulation, Chemical
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D009124:Muscle Proteins; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; C000977:dihydroouabain; D010042:Ouabain; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002118:Calcium