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 forc e-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 iso lated human myocardium from 7 nonfailing hearts (NE) and end-stage fai ling hearts (NYHA IV) due to either ischemic (ICM; n = 13) or dilated cardiomyopathy (DCM; n = 16). Methods: Isolated left ventricular muscl e strips, isometric contraction, electrical stimulation at a basal sti mulation rate of 1 Hz (37 degrees C). Inotropic responses: Cumulative concentration-response curves for forskolin (0.01-10 mu M) and for Ca2 + (2.5-15 mM). Force-frequency experiments: stepwise increase in stimu lation rate from 0.5 to 3.0 Hz without and in the presence of 0.3, 1.0 or 3.0 mu M forskolin. Results: Forskolin concentration dependently i ncreased force of contraction to 386 +/- 28 % (n = 5) in NE to 256 +/- 48 % (n = 7) in ICM, and to 212 +/- 13 % (n = 14) in DCM. The effecti veness of forskolin was significantly reduced in failing myocardium. C a2+ increased force of contraction to maximally 438 +/- 108 % in NE to 267 +/- 15 % in ICM, and to 292 +/- 20 % in DCM. Again, the effective ness of Ca2+ was significantly reduced in failing myocardium. Forskoli n activated contractile reserve to similar extents in all types of myo cardium (90 %, 95 %, and 82 %, respectively). Force of contraction con tinuously increased with increasing stimulation rates in nonfailing my ocardium (positive FFR), but was blunted or inversed in ICM and DCM. P restimulation with forskolin (0.3 mu M) further enhanced frequency-pot entiation in nonfailing, and normalized the slope and optimum stimulat ion frequency in ICM and DCM. However, at higher concentrations of for skolin, FFR was blunted or inversed in nonfailing myocardium, and furt her impaired in failing myocardium. Conclusion: Low concentrations of forskolin with only marginal inotropic effects may partially normalize the inverse force-frequency relation in endstage failing human myocar dium. Reduced cAMP levels in conjunction with reduced expression of SR Ca2+ ATPase map be the underlying cause for altered excitation-contra ction coupling in diseased human hearts.