title: Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart.
abstract: BACKGROUND
  In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro. The present study was aimed to investigate whether inotropic stimulation influences the inverse force-frequency relationship in failing human myocardium.
  
  
  RESULTS
  The effects of the cAMP-independent positive inotropic agents ouabain (0.01 mumol/L) and BDF 9148 (0.1 mumol/L) as well as the beta-adrenoceptor agonist isoprenaline (0.01 mumol/L and 0.1 mumol/L) on the force-frequency relationship in electrically driven papillary muscle strips from nonfailing (brain death, n = 5) and terminally failing (NYHA class IV, heart transplants, dilated cardiomyopathy, n = 22) human myocardium were studied. For comparison, we examined the effect of elevation of the extracellular Ca2+ concentration (3.2 mmol/L and 6.2 mmol/L). In nonfailing myocardium, force of contraction, peak rate of tension rise, and peak rate of tension decay increased, whereas time to peak tension and time to half relaxation decreased following an increase of stimulation frequency. In NYHA class IV, force of contraction gradually declined followed by changes of other parameters of isometric contraction. Moderate stimulation of contractility by isoprenaline (0.01 mumol/L) partly reversed the negative force-frequency relationship in NYHA class IV and preserved the positive force-frequency relationship in nonfailing myocardium. The addition of ouabain and BDF 9148 together restored completely the force-frequency relationship in NYHA class IV. In contrast, high concentrations of isoprenaline (0.1 mumol/L) and an elevation of the extracellular Ca2+ concentration enhanced the decline in force of contraction in the presence of higher stimulation frequencies.
  
  
  CONCLUSIONS
  It is concluded that functionally important changes occur in the intracellular Ca2+ handling, leading to the negative force-frequency relationship in terminally failing human myocardium. Interestingly, the negative force-frequency relationship can be restored by agents producing positive inotropic effects by elevation of the intracellular Na+ concentration. These findings suggest that hitherto unknown changes in the intracellular ionic homeostasis occur in the failing human heart. Even though increasing [Ca2+]i in failing heart cells may be detrimental, increasing [Na+bdi may be beneficial through a mechanism independent of an increase in [Ca2+]i.
authors.affiliation: Klinik III für Innere Medizin, Universität zu Köln, Germany.
authors.forename: R H
authors.initials: RH
authors.lastname: Schwinger
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: J
authors.initials: J
authors.lastname: Müller-Ehmsen
authors.forename: R
authors.initials: R
authors.lastname: Uhlmann
authors.forename: U
authors.initials: U
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Stäblein
authors.forename: P
authors.initials: P
authors.lastname: Uberfuhr
authors.forename: E
authors.initials: E
authors.lastname: Kreuzer
authors.forename: B
authors.initials: B
authors.lastname: Reichart
authors.forename: H J
authors.initials: HJ
authors.lastname: Eissner
mesh_terms: D000328:Adult; D001384:Azetidines / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007537:Isometric Contraction; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D010042:Ouabain / Q000494:pharmacology
chemical_list: D001384:Azetidines; D002316:Cardiotonic Agents; C071117:BDF 9148; D010042:Ouabain; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium