Increase in force of contraction by activation of the Na+/Ca(2+)-exchanger in human myocardium.
OBJECTIVE
The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP-independently, remain effective in failing human myocardium.


METHODS
Cumulative concentration-response curves with (+/-)BDF 9148 (0.01-10 mumol l-1), a Na(+)-channel activator, and ouabain (0.01-0.1 mumol l-1), a Na+/K(+)-ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilative cardiomyopathy, NYHA IV, heart transplantation, n = 16; nonfailing, donor hearts, n = 5). The beta-adrenoceptor agonist isoprenaline (0.001-1 mumol l-1) and Ca2+ (1.8-15 mmol l-1) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n = 7) in the presence of BDF 9148 (1 mumol l-1) or a high Na+ concentration (50 mmol l-1) to investigate a possible direct or indirect interaction of (+/-)BDF 9148 with the myofilaments.


RESULTS
While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P < 0.01), in NYHA IV, (+/-)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (+/-)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca2+. However, the potency for (+/-)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P < 0.05). Neither (+/-)BDF 9148 (1 mumol l-1) nor an increased concentration of Na+ (50 mmol l-1) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres.


CONCLUSIONS
The enhanced sensitivity of the failing human myocardium towards Na(+)-channel modulation is not due to a direct or indirect interaction of (+/-)BDF 9148 with cardiac myofilaments but may be due to an altered Na(+)-homeostasis in human heart failure.
Müller-Ehmsen
J
J
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Frank
K
K
Brixius
K
K
Schwinger
R H
RH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D017920:Antiporters / Q000187:drug effects / Q000378:metabolism*; D001384:Azetidines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006333:Heart Failure / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D000318:Adrenergic beta-Agonists; D017920:Antiporters; D001384:Azetidines; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D019831:Sodium-Calcium Exchanger; C071117:BDF 9148; D010042:Ouabain; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol; D002118:Calcium