Na(+)-channel activators increase cardiac glycoside sensitivity in failing human myocardium.
Na(+)-channel activators increase intracellular Na+ and thereby enhance the transport rate of sarcolemmal Na+,K(+)-ATPase. We investigated the interaction of the new Na(+)-channel activator BDF 9148 (BDF) with the cardiac glycoside ouabain (OUA) in human myocardium. The influence of OUA (0.01-0.1 microM) and of OUA after prestimulation with BDF (0.1 microM, 1 microM; BDF+OUA) on isometric force of contraction (FOC, force of contraction; +T/-T, peak rate of tension increase/decay) of electrically driven (1 Hz, 37 degrees C) papillary muscle strips from terminally failing [New York Heart Association classification IV (NYHA IV) heart transplants, n = 19] human myocardium was studied. We also examined the effects of BDF and OUA on nonfailing human myocardium (brain death resulting from traumatic injury, n = 5). 0.01 microM OUA enhanced FOC only after prestimulation with BDF (NYHA IV+2.9 +/- 0.4 mN; p less than 0.01). The time until maximal (Tmax: BDF+OUA 117 min, OUA 166 min), half-maximal (T1/2max: BDF+OUA 47 min, OUA 85 min) inotropic effects and time until toxic signs (contracture, extrasystoles) occurred were significantly shorter with BDF+OUA as compared with OUA alone. BDF influenced Tmax, T1/2max, and time until toxic side effects occurred (Ttox) of the OUA-mediated inotropism in a concentration-dependent manner. Both OUA and BDF enhanced +T and -T. The effectiveness of OUA and BDF in increasing FOC was similar to that of Ca2+ (1.8-15 mM) but significantly (p less than 0.01) higher as compared with the beta-adrenoceptor-agonist isoprenaline in NYHA IV. In myocardial membranes, [3H]ouabain binding (Bmax, Kd) was not affected by BDF.(ABSTRACT TRUNCATED AT 250 WORDS)
Schwinger
R H
RH
Medizinische Klinik I, Universität München, Klinikum Grosshadern, Germany.
Böhm
M
M
La Rosée
K
K
Schmidt
U
U
Schulz
C
C
Erdmann
E
E
D000328:Adult; D001384:Azetidines / Q000494:pharmacology*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000378:metabolism / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects
D001384:Azetidines; D002316:Cardiotonic Agents; D015222:Sodium Channels; C071117:BDF 9148; D010042:Ouabain