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Hypertrophic cardiomyopathy: A desensitized cardiac \-adrenergic system in the presence of normal plasma catecholamine concentrations

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Abstract

Only few data are available concerning the biochemical and functional state of the \-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial \-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM).

Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of \-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the \-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC50-values were about 10 fold higher than the respective EC50-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the \-adrenoceptors, \-adrenoceptor density and \1:\2-adrenoceptor subtype distribution were determined in the same myocardium using 125I-Iodocyanopindolol saturation binding.

Myocardial \-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 ± 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of \1-adrenoceptors (24.9 ± 3.7 fmol/mg protein vs NF: 46.4 ± 6.8 fmol/mg protein, P < 0.05), whereas \2-adrenoceptor density was unchanged (19.0 ± 1.9 fmol/mg protein vs NF: 18.4 ± 3.3 fmol/mg protein, n.s.). In MR both \-adrenoceptor subtypes were reduced (\1: 26.9 ± 1.4 fmol/mg protein, \2: 9.6 ± 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM.

In summary, myocardial \-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the \-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the \-adrenergic desensitization previously described to occur in congestive heart failure.

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Authors and Affiliations

  1. Medizinische Klinik I, Rheinisch-Westfdlische Technische Hochschule Aachen, Pauwelsstrasse 30, D-52057, Aachen, Germany

    Carlos Schumacher, Helga Becker, Ralf Conrads, Ulrich Schotten, Susanne Pott, Melanie Kellinghaus, Martin Sigmund & Peter Hanrath

  2. Klinik für Thorax-Herz-und Gefasschirurgie, RheinischWestfälische Technische Hochschule Aachen, Pauwelsstrasse 30, D-52057, Aachen, Germany

    Friedrich Schöndube

  3. Abteilung für Thorax-, Herz- und Gefässchirurgie, Universität Düsseldorf, Moorenstrasse 5, D-40225, Düsseldorf, Germany

    Claus Preusse & Hagen D. Schulte

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Schumacher, C., Becker, H., Conrads, R. et al. Hypertrophic cardiomyopathy: A desensitized cardiac \-adrenergic system in the presence of normal plasma catecholamine concentrations. Naunyn-Schmiedeberg's Arch Pharmacol 351, 398–407 (1995). https://doi.org/10.1007/BF00169081

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