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.
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[Show abstract][Hide abstract] ABSTRACT: The concept of sGC stimulation as a treatment for cardiopulmonary disease has developed rapidly since its inception in the mid-1990s, and preclinical studies continue to shed new light on the properties of this drug class in a wide range of cardiopulmonary diseases (Figure 3). Riociguat, the first sGC stimulator to enter clinical development, has shown promising phase II results in CTEPH, PAH, and PH associated with interstitial lung disease and chronic obstructive pulmonary disease, whereas a phase II study of BAY 60-4552 has suggested that sGC stimulation may also have potential as a treatment for PH associated with biventricular heart failure. The ongoing phase III randomized controlled trials of riociguat in CTEPH and PAH are the first of many clinical studies of sGC stimulators. If successful, these studies will herald a new generation of treatments for cardiopulmonary disease.
[Show abstract][Hide abstract] ABSTRACT: Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin-angiotensin-aldosterone system activation, defects in Ca(2+) cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials.
No preview · Article · Jun 2011 · Nature Reviews Drug Discovery
[Show abstract][Hide abstract] 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.