Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure.
ABSTRACT The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Cinaciguat (BAY-58-2667), currently in development by Bayer AG, preferentially activates sGC in its oxidized or heme-free state, when the enzyme is insensitive to both NO and nitrovasodilators. Cinaciguat exhibits potent vasodilator and antiplatelet activity, a long-lasting antihypertensive effect and a hemodynamic profile similar to that of nitrates. In clinical trials in patients with acute decompensated heart failure, cinaciguat potently unloaded the heart, increased cardiac output and renal blood flow, and preserved renal function and sodium and water excretion without further neurohumoral activation. The pharmacokinetics of cinaciguat demonstrated dose-proportionality with low individual variability and a low incidence of adverse events. The phase I and II clinical trials performed with cinaciguat so far, however, are insufficient to provide convincing evidence on the efficacy and safety of the drug. Thus, caution should be exerted before extrapolating the present preliminary data to the clinical practice.
- SourceAvailable from: Pal PacherCirculation 05/2011; 123(20):2263-73. · 15.20 Impact Factor
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ABSTRACT: BACKGROUND: Although evidence now suggests cGMP is a negative regulator of cardiac hypertrophy, the direct consequences of the soluble guanylyl cyclase (sGC) activator BAY 58-2667 on cardiac remodeling, independent of changes in hemodynamic load, has not been investigated. In the present study, we tested the hypothesis that the NO(•)-independent sGC activator BAY 58-2667 inhibits cardiomyocyte hypertrophy in vitro. Concomitant impact of BAY 58-2667 on cardiac fibroblast proliferation, and insights into potential mechanisms of action, were also sought. Results were compared to the sGC stimulator BAY 41-2272. METHODS: Neonatal rat cardiomyocytes were incubated with endothelin-1 (ET(1), 60nmol/L) in the presence and absence of BAY 41-2272 and BAY 58-2667 (0.01-0.3 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. The impact of both sGC ligands on basal and stimulated cardiac fibroblast proliferation in vitro was also determined. RESULTS: We now demonstrate that BAY 58-2667 (0.01-0.3 µmol/L) elicited concentration-dependent antihypertrophic actions, inhibiting ET(1)-mediated increases in cardiomyocyte 2D area and de novo protein synthesis, as well as suppressing ET(1)-induced cardiomyocyte superoxide generation. This was accompanied by potent increases in cardiomyocyte cGMP accumulation and activity of its downstream signal, vasodilator-stimulated phosphoprotein (VASP), without elevating cardiomyocyte cAMP. In contrast, submicromolar concentrations of BAY 58-2667 had no effect on basal or stimulated cardiac fibroblast proliferation. Indeed, only at concentrations ≥10 µmol/L was inhibition of cardiac fibrosis seen in vitro. The effects of BAY 58-2667 in both cell types were mimicked by BAY 41-2272. CONCLUSIONS: Our results demonstrate that BAY 58-2667 elicits protective, cardiomyocyte-selective effects in vitro. These actions are associated with sGC activation and are evident in the absence of confounding hemodynamic factors, at low (submicromolar) concentrations. Thus this distinctive sGC ligand may potentially represent an alternative therapeutic approach for limiting myocardial hypertrophy.PLoS ONE 01/2012; 7(11):e44481. · 3.73 Impact Factor
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ABSTRACT: Nitric oxide (NO) stimulates cGMP synthesis by activating its intracellular receptor, soluble guanylyl cyclase (sGC). It is a currently prevailing concept that No and cGMP inhibits platelet function. However, the data supporting the inhibitory role of NO/sGC/cGMP in platelets have been obtained either in vitro or using whole body gene deletion that affects vessel wall function. Here we have generated mice with sGC gene deleted only in megakaryocytes and platelets. Using the megakaryocyte- and platelet-specific sGC-deficient mice, we identify a stimulatory role of sGC in platelet activation and in thrombosis in vivo. Deletion of sGC in platelets abolished cGMP production induced by either NO donors or platelet agonists, caused a marked defect in aggregation and attenuated secretion in response to low doses of collagen or thrombin. Importantly, megakaryocyte- and platelet-specific sGC deficient mice showed prolonged tail-bleeding times and impaired FeCl₃-induced carotid artery thrombosis in vivo. Interestingly, the inhibitory effect of the NO donor SNP on platelet activation was sGC-dependent only at micromolar concentrations, but sGC-independent at millimolar concentrations. Together, our data demonstrate important roles of sGC in stimulating platelet activation and in vivo thrombosis and hemostasis, and sGC-dependent and -independent inhibition of platelets by NO donors.Blood 07/2011; 118(13):3670-9. · 9.06 Impact Factor