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

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Bobby Nossaman ◽  
Edward Pankey ◽  
Philip Kadowitz
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Soluble Guanylyl Cyclase ◽  
Smooth Muscle Relaxation ◽  
No Donors ◽  
No Formation ◽  
Continuous Use ◽  
Physiologic Responses ◽  
Cgmp Formation ◽  
Review Current

The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme withαandβsubunits 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.

scholarly journals A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation

2004 ◽  
Vol 286 (3) ◽  
pp. H1043-H1056 ◽  
Author(s):  
Nikolaos M. Tsoukias ◽  
Mahendra Kavdia ◽  
Aleksander S. Popel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Cgmp Formation

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency-rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of Ca2+ oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for Ca2+ oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo.

Peroxynitrite has potent pulmonary vasodilator activity in the rat

2012 ◽  
Vol 90 (4) ◽  
pp. 485-500 ◽  
Author(s):  
David B. Casey ◽  
Edward A. Pankey ◽  
Adeleke M. Badejo ◽  
Franklin R. Bueno ◽  
Manish Bhartiya ◽  
...  
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Muscle Relaxation ◽  
Inhibitory Effect ◽  
Smooth Muscle Relaxation ◽  
Experimental Conditions ◽  
No Donors ◽  
Major Mechanism ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity

Peroxynitrite (PN) worsens pathological conditions associated with oxidative stress. However, beneficial effects have also been reported. PN has been shown to demonstrate vasodilator as well as vasoconstrictor properties that are dependent upon the experimental conditions and the vascular bed studied. PN-induced vascular smooth muscle relaxation may involve the formation of nitric oxide (NO) donors. The present results show that PN has significant vasodilator activity in the pulmonary and systemic vascular beds, and that responses to PN were not attenuated by L-penicillamine (L-PEN), a PN scavenger, whereas responses to sodium nitroprusside (SNP) were decreased. PN had a small inhibitory effect on decreases in arterial pressure in response to the NO donors diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) and S-nitrosoglutathione (GSNO). PN partially reversed hypoxic pulmonary vasoconstriction. PN responses were attenuated by the soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and responses to PN and the PN precursor, 3-morpholinosydnonimine (SIN-1), were different. These data show that PN has potent pulmonary vasodilator activity in the rat, and provide evidence that a PN interaction with S-nitrosothiols is not the major mechanism mediating the response. These data suggest that responses to PN are mediated by the activation of sGC, and that PN has a small inhibitory effect on NO responses.

Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

2019 ◽  
Vol 19 (18) ◽  
pp. 1544-1557 ◽  
Author(s):  
Sijia Xiao ◽  
Qianbin Li ◽  
Liqing Hu ◽  
Zutao Yu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Smooth Muscle Relaxation ◽  
Secondary Messenger ◽  
Physiological Processes ◽  
Cgmp Pathway ◽  
Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine

1996 ◽  
Vol 271 (4) ◽  
pp. R990-R1001 ◽  
Author(s):  
C. Iadecola ◽  
F. Zhang
Keyword(s):  
Basal Forebrain ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Doppler Flowmetry ◽  
No Donors ◽  
Nos Inhibitors ◽  
Fusion Site ◽  
Nos Inhibitor ◽  
Hypercapnic Response ◽  
Major Mediator

Inhibition of nitric oxide (NO) synthesis attenuates the hypercapnic cerebrovasodilation or the increases in cerebral blood flow (CBF) produced by acetylcholine (ACh), either topically applied or endogenously released in neocortex by stimulation of the basal forebrain cholinergic system. We investigated whether exogenous administration of NO, using NO donors, can reverse the attenuation of these responses by NO synthase (NOS) inhibitors. In halothane-anesthetized, ventilated rats the frontoparietal cortex was exposed and superfused with Ringer. CBF was monitored at the super fusion site by laser-Doppler flowmetry. The basal forebrain was stimulated (100 microA; 50 Hz) with microelectrodes stereotaxically implanted. Superfusion with the NOS inhibitor NG-nitro-L-arginine (L-NNA; 1 mM) reduced resting CBF (-38 +/- 2%; mean +/- SE) and attenuated the vasodilation elicited by hypercapnia (Pco2, 50-60 mmHg; -79 +/- 3%), ACh (10 microM; -83 +/- 7%), or basal forebrain stimulation (-44 +/- 2%) (P < 0.05, analysis of variance and Tukey's test). After L-NNA, topical application of 3-morpholinosydnonimine (SIN-1) (n = 7), S-nitroso-N-acetylpenicillamine (SNAP) (n = 6), or 8-bromoguanosine 3',5'-monophosphate (8-BrcGMP, n = 4) reestablished resting CBF (P > 0.05 from Ringer) and reversed the attenuation of the response to hypercapnia (P > 0.05 from Ringer). However, SIN-1 or SNAP failed to reverse the attenuation of the response to basal forebrain stimulation or topical ACh (P > 0.05 from L-NNA). After L-NNA, the NO-independent vasodilator papaverine (n = 4) reestablished resting CBF (P > 0.05 from Ringer) but failed to restore the hypercapnic vasodilation (P > 0.05 from L-NNA). The attenuation of hypercapnic response by the neuronal NOS inhibitor 7-nitroindazole was counteracted only partially by SIN-1 (n = 4) or 8-BrcGMP (n = 4). The data support the hypothesis that the vasodilation elicited by hypercapnia requires resting levels of NO for its expression, whereas the response to endogenous or exogenous ACh depends on agonist-induced NOS activation. In hypercapnia NO may act as a permissive factor by facilitating the action of other vasodilators, whereas in the vascular response initiated by ACh NO is likely to be the major mediator of smooth muscle relaxation.

scholarly journals Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation

Reproduction ◽  
2021 ◽  
Vol 161 (1) ◽  
pp. 31-41
Author(s):  
Deepak S Hiremath ◽  
Fernanda B M Priviero ◽  
R Clinton Webb ◽  
CheMyong Ko ◽  
Prema Narayan
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Erectile Dysfunction ◽  
Sodium Nitroprusside ◽  
Signaling Pathway ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Activating Mutations

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

Influence of sildenafil on gastric sensorimotor function in humans

2004 ◽  
Vol 287 (5) ◽  
pp. G988-G992 ◽  
Author(s):  
Giovanni Sarnelli ◽  
Daniel Sifrim ◽  
Jozef Janssens ◽  
Jan Tack
Keyword(s):  
Gastric Emptying ◽  
Healthy Subjects ◽  
Soluble Guanylate Cyclase ◽  
Therapeutic Potential ◽  
Muscle Relaxation ◽  
Gastric Wall ◽  
Gastric Volume ◽  
Gastric Fundus ◽  
Smooth Muscle Relaxation ◽  
Gastric Accommodation

After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo ( n = 13) or sildenafil, 50 mg ( n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 ± 15 vs. 163 ± 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 ± 38 vs. 253 ± 42 ml, P < 0.05) or 60 min (348 ± 49 vs. 247 ± 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 ± 4 vs. 56 ± 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation.

l-Glutamine in vitro regulates rat aortic glutamate content and modulates nitric oxide formation and contractility responses

2007 ◽  
Vol 293 (1) ◽  
pp. C142-C151 ◽  
Author(s):  
David Schachter
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Plasma Concentrations ◽  
Smooth Muscle Relaxation ◽  
No Formation ◽  
Ketoacid Dehydrogenase ◽  
Glutamate Synthesis

These studies test the hypothesis that l-glutamine at its physiological plasma concentration, ∼0.5 mM, can increase tissue content and net synthesis of glutamate in rat aortic segments in vitro, thereby mediating relaxation of the underlying smooth muscle in the elastic reservoir region of the thoracic aorta. Aortic segments were incubated in an isotonic medium with and without 21 amino acids at their normal plasma concentrations. Of these amino acids only l-glutamine and l-leucine at their plasma concentrations increased glutamate synthesis and content. Tissue glutamate content resulting from increasing concentrations of each precursor reached an upper level of ∼1.3–1.6 μmol/g wet wt. Regulation of the tissue glutamate content involves an interaction of the synthetic pathways in which l-glutamine inhibits the endothelial leucine-to-glutamate pathway. l-Glutamine increases nitric oxide (NO) formation, and NO inhibits the controlling enzyme of the endothelial leucine-to-glutamate pathway, the branched-chain α-ketoacid dehydrogenase complex. Treatment of precontracted aortic rings with 0.5 mM l-glutamine elicits smooth muscle relaxation, a response that requires endothelial nitric oxide synthase activity and an intact endothelium. The results demonstrate that in vitro l-glutamine at its normal concentration in plasma can regulate rat aortic glutamate content and modulate NO formation and contractility responses of the thoracic aortic wall.

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