title: Altered inotropism in the failing human myocardium.
abstract: Beta-adrenoreceptor-cAMP-dependent inotropic interventions lose their effectiveness depending on the degree of myocardial failure. This blunted effect of beta-adrenoreceptor-dependent stimulation might be due to a downregulation of beta-adrenoreceptors and an increase of inhibitory G-proteins leading to decreased intracellular cAMP-concentrations. However, the maximal positive inotropic effect elicited by elevation of the extracellular [Ca2+] does not differ between failing and nonfailing human myocardium, indicating that terminally failing human myocardium is effective to increase force of contraction to the same degree as nonfailing tissue. Agents which increase force of contraction primarily via increasing the intracellular [Na+], e.g., cardiac glycosides and the Na(+)-channel activator BDF 9148, exert a higher potency in failing myocardium than in nonfailing tissue to increase force of contraction. This could result from an enhanced protein expression of the Na+/Ca(2+)-exchanger observed in diseased human hearts. Alterations in the intracellular Ca(2+)-homeostasis reported in failing myocardium lead to a negative force-frequency-relationship and a prolonged relaxation. As the protein expression of SERCA IIa and phospholamban seems to be similar in NYHAIV and nonfailing tissue, the reduced Ca(2+)- uptake may result from an altered regulation of these proteins, e.g., reduced phosphorylation of phospholamban or the SERCA IIa. After inhibition of the Ca(2+)-ATPase of the sarcoplasmic reticulum with the high specific inhibitor cyclopiazonic acid the former positive force-frequency-relationship became significantly less positive even in the nonfailing tissue and twitch course became similar to diseased hearts. These findings may be indicative for the importance of the Ca(2+)-reuptake mechanism into the sarcoplasmic reticulum in addition to the regulatory control at the site of the contractile apparatus for the regulation of contraction and relaxation in human myocardium.
authors.affiliation: Universität zu Köln Medizinische Klinik III, Köln, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Bavendiek
authors.forename: K
authors.initials: K
authors.lastname: Brixius
authors.forename: K
authors.initials: K
authors.lastname: Frank
authors.forename: H
authors.initials: H
authors.lastname: Reuter
authors.forename: M
authors.initials: M
authors.lastname: Pietsch
authors.forename: A
authors.initials: A
authors.lastname: Gross
authors.forename: J
authors.initials: J
authors.lastname: Müller-Ehmsen
authors.forename: E
authors.initials: E
authors.lastname: Erdmann
authors.forename: R H
authors.initials: RH
authors.lastname: Schwinger
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D001384:Azetidines / Q000008:administration & dosage; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D007545:Isoproterenol / Q000008:administration & dosage; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010042:Ouabain / Q000008:administration & dosage; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D001384:Azetidines; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007545:Isoproterenol; D010042:Ouabain; D012964:Sodium; D000099211:Phospholamban; C071117:BDF 9148; C000543:cyclopiazonic acid