EFFECT OF THE NA-CHANNEL MODULATOR BDF-9148 ON CA2+-SENSITIVITY AND FORCE OF CONTRACTION OF HYPERTROPHIC MYOCARDIUM FROM TRANSGENE RATS HARBORING THE MOUSE RENIN GENE (TG(MREN2)27)()

The present study aimed to investigate the inotropic effect of the Na-channel modulator BDF 9148 in hypertrophic myocardium compared to con trol tissue. Thus, TG(mREN2)27 rats (TGR), a model with hypertension i nduced cardiac hypertrophy, was compared with age matched Sprague-Dawl ey rats (SPDR). The effect of BDF 9148 (0.01-10 mu M) on force of cont raction (1 Hz, 37 degrees C), the force-frequency relationship (0.5-7 Hz) and the frequency-dependent diastolic tension (0.5-7 Hz) was studi ed on leftventricular papillary muscles from SPDR and TGR. Chemically skinned muscle fibers of the same hearts were used to examine the infl uence of BDF 9148 on the Ca2+-sensitivity of the contractile proteins. For control the Ca2+-sensitizer EMD 57033 was examined. In addition t he Na+/K+-ATPase activity was measured in both, SPDR and TGR. BDF 9148 showed a concentration dependent positive inotropic effect in SPDR an d TGR cardiac preparations. Comparing SPDR and TGR, a higher effective ness of BDF 9148 on TGR was found, while the potency was unchanged. Wi th increasing stimulation rates a significant higher decrease in force of contraction in TGR compared to SPDR was observed. In addition, a s ignificant higher increase in diastolic tension was found in TGR. Afte r exposure to 1 mu M BDF 9148 the decrease in force of contraction was significantly reduced in both SPDR and TGR, while only in TGR the inc rease in diastolic tension was reduced. BDF 9148 had no effect on the Ca2+-sensitivity or maximal developed tension of skinned fiber prepara tions from SPDR or TGR. In contrast, the Ca2+-sensitizer EMD 57033 inc reased the Ca2+-sensitivity. The activity of the Na+/K+-ATPase was sig nificantly reduced in TGR compared to controls. Conclusions: The Na+-c hannel modulator BDF 9148 was more effective in hypertrophic compared to control myocardium in increasing force of contraction, enhancing fr equency-dependent force generation and reducing diastolic tension. The se effects were not mediated via interaction with the contractile appa ratus. The enhanced effectiveness of Na+-channel modulation in hypertr ophic myocardium could result from alterations of the Na+ homeostasis, i.e. a reduced Na+/K+-ATPase activity.