title: Hypertrophic cardiomyopathy: a desensitized cardiac beta-adrenergic system in the presence of normal plasma catecholamine concentrations.
abstract: Only few data are available concerning the biochemical and functional state of the beta-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial beta-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 beta-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the beta-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-1-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 beta-adrenoceptors, beta-adrenoceptor density and beta 1: beta 2-adrenoceptor subtype distribution were determined in the same myocardium using 125I-Iodocyanopindolol saturation binding. Myocardial beta-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 beta 1-adrenoceptors (24.9 +/- 3.7 fmol/mg protein vs NF: 46.4 +/- 6.8 fmol/mg protein, P < 0.05), whereas beta 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 beta-adrenoceptor subtypes were reduced (beta 1: 26.9 +/- 1.4 fmol/mg protein, beta 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 beta-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 beta-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the beta-adrenergic desensitization previously described to occur in congestive heart failure.
authors.affiliation: Medizinische Klinik I, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schumacher
authors.forename: H
authors.initials: H
authors.lastname: Becker
authors.forename: R
authors.initials: R
authors.lastname: Conrads
authors.forename: U
authors.initials: U
authors.lastname: Schotten
authors.forename: S
authors.initials: S
authors.lastname: Pott
authors.forename: M
authors.initials: M
authors.lastname: Kellinghaus
authors.forename: M
authors.initials: M
authors.lastname: Sigmund
authors.forename: F
authors.initials: F
authors.lastname: Schöndube
authors.forename: C
authors.initials: C
authors.lastname: Preusse
authors.forename: H D
authors.initials: HD
authors.lastname: Schulte
mesh_terms: D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D002395:Catecholamines / Q000097:blood*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D008297:Male; D008875:Middle Aged; D008944:Mitral Valve Insufficiency / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; C000977:dihydroouabain; D010042:Ouabain; D020120:Iodocyanopindolol; D010869:Pindolol; D000254:Sodium-Potassium-Exchanging ATPase