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

Abstract

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.

Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

“…These results are similar to those of other groups who have reported a diminished response with PDE inhibition in isometrically contracting trabeculae from failing human heart as compared to those from non-failing hearts (Bohm et al, 1988d; von der Leyen et al, 1991;Steinfath et al, 1992). The same studies show no differences in the response to high calcium, or in the basal activity of the PDE enzymes, between failing and nonfailing human papillary muscle preparations.…”

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

“…Previous studies have demonstrated that, despite myocardial ␤-AR downregulation following chronic Iso administration, ␣-AR-induced inotropic upregulation may occur (6,24). These changes may be mediated by an increased density of myocardial ␣ 1 -ARs (17,18,29,33).…”

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

“…Furthermore, a 1 -AR expression levels in human heart determined by ligand binding are similar to mouse and most other species (human: mean of 6 studies, ;12 fmol/mg protein) (Bohm et al, 1988;Bristow et al, 1988;Vago et al, 1989;Steinfath et al, 1992b;Hwang et al, 1996;Jensen et al, 2009a). Human myocardium has the a 1 Aand a 1 B-subtypes, with the a 1 B predominant, similar to other species (Jensen et al, 2009a,b), and the a 1 A is functional in signaling (R. C. Thomas and P. C. Simpson, unpublished data).…”

“…In contrast, radioligand-binding studies indicate that myocardial a 1 -AR levels are slightly increased in human heart failure (mean of six studies, increased from ;12 to ;19 fmol/mg protein) (Bohm et al, 1988;Bristow et al, 1988;Vago et al, 1989;Steinfath et al, 1992b;Hwang et al, 1996;Jensen et al, 2009a). This means that a 1 -AR levels in the heart, which normally represent approximately 11% of the total AR population at baseline (range 2-23%, mean of six studies), are proportionately increased to approximately 25% of the total AR population in heart failure (range 9-41%) (Bohm et al., 1988;Bristow et al, 1988;Vago et al, 1989;Steinfath et al, 1992b;Hwang et al, 1996;Jensen et al, 2009a). Given that sympathetic drive and catecholamine levels are increased in heart failure (Cohn et al, 1984), this could imply that a 1 -ARs sustain adrenergic function when b 1 -ARs are downregulated.…”