Article

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; 2012:290805. DOI: 10.1155/2012/290805
Source: PubMed

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.

Download full-text

Full-text

Available from: Edward A Pankey, Aug 10, 2015
1 Follower
 · 
398 Views
  • [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 · 7.65 Impact Factor
  • Source
    [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; 2012:240314. DOI:10.1155/2012/240314 · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) is a free radical, actively produced in human body. NO exerts crucial roles in vascular and neuronal signal transduction, smooth muscle contractility, bioenergetics, platelet adhesion and aggregation, immunity, and cell death regulation. The evidence accumulated over the last 25 years suggests that a defective control of the NO levels causes pathologies, such as hypertension, cardiovascular dysfunctions, neurodegeneration, arthritis, asthma and septic shock. Despite dealing with NO, the boundary between health and disease is still blurry, although the feeling is that pulses of NO in the low concentration range (piconanomolar) are by and large physiological, whereas cell persistence in the high concentration range (micromolar) may turn to pathological. Evidence is growing that the dark side of NO resides on its concentration levels and on the production of peroxynitrite and other reactive oxygen and nitrogen species; last but not least, the type of biomolecule reacting with NO and, when present, the cell bioenergetic changes induced strongly contribute to physiological or pathological outcomes. Key Concepts: Nitric oxide shares with O2 and towards biomolecules, high reactivity and duality of effects, both beneficial and detrimental.In the human body, a variety of metabolic effects are induced by NO, owing to the widespread nitrergic signalling and bioenergetic chemistry.It is time to verify whether the S-nitrosation of proteins and enzymes is as important as their phosphorylation.The NO chemistry in the human body appears tightly integrated with the chemistry of H2S and CO.The intracellular NO and O2−• concentration, both absolute and relative, are vital to cell redox homoeostasis: it is their imbalance that triggers pathological responses.Sometimes, the NO released by one isoform antagonises the effects of NO produced by another isoform. During cerebral ischaemia, for instance, the nNOS appears involved in tissue injury, whereas the eNOS preserves blood flow and tissue oxygenation.The mechanism of macromolecular damage by peroxynirite is still poorly understood.Feeling is growing that besides the oxidative stress, a reductive stress should be also considered.For how long should a cell Ca++ transient lasts to stimulate cNOS? Moreover, is amplitude and duration of such a stimulus different in physiology and pathology?Keywords:radical chemistry;nitrosative stress;bioenergetics;nitrergic transmission;neurodegeneration;mitochondria;haem proteins pathophysiology;warburg effect;melatonin;molecular mechanisms
    eLS, 04/2013; , ISBN: 0470016175
Show more