Influence of forskolin on the force-frequency behavior in nonfailing and end-stage failing human myocardium.
End-stage failing human myocardium is characterized by a negative force-frequency relationship (FFR), possibly as a result of reduced SR Ca2+ uptake capacity. We investigated the effects of the direct adenylate cyclase stimulator, forskolin, on force of contraction and FFR in isolated human myocardium from 7 nonfailing hearts (NF) and end-stage failing hearts (NYHA IV) due to either ischemic (ICM; n = 13) or dilated cardiomyopathy (DCM; n = 16).


METHODS
Isolated left ventricular muscle strips, isometric contraction, electrical stimulation at a basal stimulation rate of 1 Hz (37 degrees C). Inotropic responses: Cumulative concentration-response curves for forskolin (0.01-10 microM) and for Ca2+ (2.5-15 mM). Force-frequency experiments: stepwise increase in stimulation rate from 0.5 to 3.0 Hz without and in the presence of 0.3, 1.0 or 3.0 microM forskolin.


RESULTS
Forskolin concentration-dependently increased force of contraction to 386 +/- 28% (n = 5) in NF, to 256 +/- 48% (n = 7) in ICM, and to 212 +/- 13% (n = 14) in DCM. The effectiveness of forskolin was significantly reduced in failing myocardium. Ca2+ increased force of contraction to maximally 438 +/- 108% in NF, to 267 +/- 15% in ICM, and to 292 +/- 20% in DCM. Again, the effectiveness of Ca2+ was significantly reduced in failing myocardium. Forskolin activated contractile reserve to similar extents in all types of myocardium (90%, 95%, and 82%, respectively). Force of contraction continuously increased with increasing stimulation rates in nonfailing myocardium (positive FFR), but was blunted or inversed in ICM and DCM. Prestimulation with forskolin (0.3 microM) further enhanced frequency-potentiation in nonfailing, and normalized the slope and optimum stimulation frequency in ICM and DCM. However, at higher concentrations of forskolin, FFR was blunted or inversed in non-failing myocardium, and further impaired in failing myocardium.


CONCLUSIONS
Low concentrations of forskolin with only marginal inotropic effects may partially normalize the inverse force-frequency relation in end-stage failing human myocardium. Reduced cAMP levels in conjunction with reduced expression of SR Ca2+ ATPase may be the underlying cause for altered excitation-contraction coupling in diseased human hearts.
Pieske
B
B
Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Germany.
Trost
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S
Schütt
K
K
Minami
K
K
Just
H
H
Hasenfuss
G
G
D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012016:Reference Values
D002316:Cardiotonic Agents; D005576:Colforsin; D002118:Calcium