In
cardiovascular diseases, reduced responsiveness of
soluble guanylate cyclase (sGC) to
nitric oxide (NO) upon long-term application has led to the development of NO-independent sGC stimulators (
heme-dependent) and sGC activators (
heme-independent). Any direct inotropic or lusitropic effects of these compounds on isolated cardiac myocytes, however, remain to be elucidated. Here, we analyzed the dose-dependent effects of clinical relevant concentrations (10(-10)-10(-5) M) of the sGC activator
cinaciguat and the sGC stimulator
riociguat on the contraction, relaxation, and
calcium transients of isolated field-stimulated cardiac myocytes from healthy rats. For comparison, we used
isoproterenol, which induced a dose-dependent significant increase in cell contractility, relaxation, and
calcium transients,
verapamil that significantly decreased these parameters (both at 10(-9)-10(-5) M) and 8-(4-Chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (8-pCPT-cGMP) that induced a negative inotropic effect
at 10(-5) M accompanied by a slight increase in relaxation. In contrast, neither
cinaciguat nor
riociguat significantly influenced any measured parameters. Furthermore,
isoproterenol significantly increased intracellular cAMP levels that were not influenced by
cinaciguat or
riociguat (all
at 10(-6) M). Otherwise,
riociguat and
cinaciguat (both
at 10(-6) M) significantly enhanced intracellular cGMP generation. This accumulation was significantly augmented by
cinaciguat in the presence of the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 25 µM), whereas ODQ blocked cGMP generation by
riociguat. However, blocking of sGC did not influence cell contractility. Our results demonstrate that, in isolated cardiac myocytes from healthy rats, the increase in cGMP levels induced by
cinaciguat and
riociguat at clinical relevant concentrations is not associated with acute direct effects on cell contraction and relaxation.