Stimulators and Activators of Soluble Guanylate Cyclase: Review and Potential Therapeutic Indications

Critical Care Medicine Section, Department of Anesthesiology, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans, LA 70121, USA.
Critical care research and practice 02/2012; 2012(23):290805. DOI: 10.1155/2012/290805
Source: PubMed


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.

Download full-text


Available from: Edward A Pankey,
  • Source
    • "As a result, the cell is getting short of bioactive NO and responses with up-regulation of NOS and enzymes engaged in detoxification of ROS, such as catalase and superoxide dismutase6. Combined with ROS and degraded further to reactive nitrogen oxide species (RNOS), NO can damage the cell of its origin and thereby cause a variety of diseases17. However, the role of NO in the course of pancreatitis remains controversial. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of nitric oxide (NO) in the human pancreas and in pancreatitis still remains controversial. Furthermore, conflicting conclusions have been reached by different laboratories about the localization of the NO-generating enzyme (NO synthase, NOS) in the pancreas. Here, we investigated the co-expression of NOS with enzymes involved in regulation of NO signalling in the normal human pancreas and in pancreatitis. We found that the whole NO signalling machinery was up-regulated in pancreatitis, especially within the exocrine compartment. Furthermore, the exocrine parenchymal cells revealed higher levels of oxidative stress markers, nitrotyrosine and 8-hydroxyguanosine, in pancreatitis, which reflects the exceptional susceptibility of the exocrine parenchyma to oxidative stress. This study provides a direct link between oxidative stress and the enzymatic control of the NO bioavailability at the cellular level and endows with further insight into fundamental mechanisms underlying pancreatic disorders associated with disruptions in the L-arginine-NO-cGMP signalling enzyme cascade.
    Scientific Reports 05/2013; 3:1899. DOI:10.1038/srep01899 · 5.58 Impact Factor
  • Source
    • "Previous studies showed that FIR could increase generation of nitric oxide (NO) and calmodulin in cells [19, 20, 36]. Associated physiological roles of NO include immune regulation [37, 38], neurotransmission [39], and vascular smooth muscle relaxation [40, 41]. Previous reports have demonstrated that NO in endothelial cells plays an important role in regulating smooth muscle [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to assess the beneficial effects of using a far-infrared (FIR) belt on the management of patients with primary dysmenorrhea. This is the first study to determine the efficacy of somatothermal FIR using a parallel-arm randomized sham-controlled and double-blinded design with objective physical evidence and psychometric self-reports. Fifty-one Taiwanese women with primary dysmenorrhea were enrolled in the study. Results indicate that there was an increased abdominal temperature of 0.6°C and a 3.27% increase in abdominal blood flow in the FIR group (wearing FIR belt) compared to those in the control group (wearing sham belt). Verbal rating scale and numeric rating scale scores in the FIR group were both lower than those in the control group. Compared to the blank group (wearing no belt), the average dysmenorrhea pain duration of the FIR group was significantly reduced from 2.5 to 1.8 days, but there was no significant difference in the control group. These results demonstrate that the use of a belt made of far-infrared ceramic materials can reduce primary dysmenorrhea.
    Evidence-based Complementary and Alternative Medicine 12/2012; 2012(2):240314. DOI:10.1155/2012/240314 · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adenylyl cyclases (ACs) and guanylyl cyclases (GCs) produce the second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate, respectively. ACs and GCs are differentially regulated by intercellular signaling molecules and are implicated in various disease states, including cardiovascular diseases, aging, pain, and neuropsychiatric ailments. Hence, ACs and GCs constitute interesting drug targets. Because the catalytic sites of these enzymes are highly conserved, it is difficult to achieve isoform specificity. However, studies have provided evidence for the notion that regulatory allosteric domains in the vicinity of the catalytic site provide new opportunities for pharmacological intervention. Here, we summarize the current status of such research and discuss future directions in this exciting field.
    Science Signaling 09/2012; 5(240):pe37. DOI:10.1126/scisignal.2003466 · 6.28 Impact Factor
Show more