Exploring New Cardiovascular Pathways
Are Soluble Guanylate Cyclase Stimulators the Right Direction?
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See Article by Nakamura et al
Acting is very start and stop.
Despite major therapeutic advances in the treatment of heart failure (HF), this syndrome continues to extract an oppressive clinical penalty of morbidity and mortality. Moreover, the increased prevalence of HF also imposes a major health system economic burden. Hence, this rising cascade of unmet health needs has generated intense interest in discovering novel therapeutic solutions.
In this context, NO occupies central stage given its fundamental role in activating soluble guanylate cyclase (sGC).1 In turn, sGC generates cyclic GMP (cGMP)—a potent activator of the PKG1α (protein kinase G1α), which plays an essential and pleiotropic role in normal cardiovascular function by inhibiting vasoconstriction, inflammation, hypertrophy, and fibrosis.2 Hence, reduced sGC activity is an important contributor to coronary microvascular impairment, cardiomyocyte stiffness, and interstitial fibrosis.3 It is now recognized that oxidative stress is a key feature of the HF syndrome as reflected by excess production of reactive oxygen species (ROS) which reduce NO bioavailability.4 In cardiovascular disease, the most important sources of ROS are the mitochondrial respiratory chain, various oxidases, uncoupled NO synthase, and MPO (myeloperoxidase) from infiltrating monocytes and neutrophils.5 Clinically, there are several ways to enhance NO availability. These include inhalation of NO and the addition of nitrate therapy, but both have significant limitations.6 Reducing degradation of cGMP offers an additional therapeutic option. A variety of cyclic nucleotide PDEs (phosphodiesterases) break down cGMP into GMP, a process sensitive to inhibitors currently in clinical use, such as milrinone and theophylline. This alternative approach also led to rediscovery of the PDE5 inhibitor sildenafil for applications in cardiovascular medicine. Retarding catabolism of cGMP through PDE5 inhibition with sildenafil appeared a potentially attractive way to mitigate the …