Abstract
The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysiologic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular disease.
Highlights
Guanylyl cyclase (GC) is an enzyme that catalyzes the formation of guanosine 3,5 -monophosphate from guanosine triphosphate (GTP) and is found in tissues throughout the animal kingdom [1, 2]
nitric oxide (NO) is endogenously generated by endothelial NO synthase from L-arginine and activates soluble guanylyl cyclase (sGC) in adjacent vascular smooth muscle cells to increase cGMP levels and induce relaxation (Figure 1)
When released from the endothelium in response to physiologic stimuli such as shear stress, NO binds to the normally reduced heme moiety of sGC and increases the formation of cGMP from GTP leading to a decrease in intracellular calcium and vasodilation [7,8,9,10]
Summary
Guanylyl cyclase (GC) is an enzyme that catalyzes the formation of guanosine 3 ,5 -monophosphate (cGMP) from guanosine triphosphate (GTP) and is found in tissues throughout the animal kingdom [1, 2]. Soluble GC (sGC) is the receptor for nitric oxide (NO) in vascular smooth muscle [3, 4]. NO is endogenously generated by endothelial NO synthase (eNOS) from L-arginine and activates sGC in adjacent vascular smooth muscle cells to increase cGMP levels and induce relaxation (Figure 1). When released from the endothelium in response to physiologic stimuli such as shear stress, NO binds to the normally reduced heme moiety of sGC and increases the formation of cGMP from GTP leading to a decrease in intracellular calcium and vasodilation [7,8,9,10]. The NO-sGC-cGMP pathway is essential for the control of a number of physiologic processes, including neuronal transmission, host defense, cell growth and proliferation, and vascular and platelet homeostasis [11,12,13,14,15,16,17,18]
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