Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We explored whether endothelium-derived nitric oxide (EDNO) acts in an autocrine or paracrine fashion to activate the soluble guanylate cyclase by measuring the elevations of cGMP levels. Comparisons were made between two culture models in which EDNO can stimulate cGMP synthesis within the same cells (endothelial cells) where it is formed, or in the neighboring cells (smooth muscle cells). The basal amount of EDNO showed no difference in cGMP levels when the endothelial cells (EC) were cultured either alone (iso-culture) or together with the smooth muscle cells (SMC, co-culture). However, cGMP levels were synergistically increased by the BK-stimulated EDNO when EC were co-cultured with SMC. The synergistical increase was significantly inhibited by 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), an extracellular radical scavenger. These findings suggest that the tonic formed basal EDNO has an autocrine effect on cGMP levels of EC themselves. In contrast, BK-stimulated phasic formed EDNO has not only an autocrine effect, but also a paracrine effect on cGMP levels of EC themselves and the adjacent SMC.
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PMID:Paracrine function of endothelium-derived nitric oxide. 900 41

Nitric oxide (NO), delivered by a single addition of S-nitrosoglutathione (GSNO, IC(50) = 60-75 microM), causes the prolonged, multi-day suppression of proliferation of asynchronous, logarithmically growing human (hCASMC, two cell strains), and porcine (porCASMC) coronary artery smooth muscle cells. The inhibition is not cytotoxic, but cytostatic and reversible. Transient exposure (>4-12 h) to GSNO is sufficient to elicit prolonged suppression, but a less than 4 h exposure produces little or no inhibition. Unlike porCASMC and rat and rabbit aortic SMC, hCASMC synthesize little cGMP in response to GSNO stimulation, suggesting loss of NO responsive guanylate cyclase in vitro. The guanylate cyclase inhibitor, ODQ, blocks the slight cGMP synthesis induced by GSNO in hCASMC, but does not prevent GSNO suppression of proliferation. These data support a cGMP independent mechanism for NO induced suppression of hCASMC proliferation which may be significant in the treatment of proliferative coronary artery diseases.
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PMID:Suppression of proliferation of human coronary artery smooth muscle cells by the nitric oxide donor, S-nitrosoglutathione, is cGMP-independent. 1115 25

Atrial natriuretic peptide (ANP) plays a key regulatory role in arterial blood pressure homeostasis. We recently generated mice with selective deletion of the ANP receptor, guanylyl cyclase-A (GC-A), in vascular smooth muscle (SMC GC-A knockout (KO) mice) and reported that resting arterial blood pressure was completely normal in spite of clear abolition of the direct vasodilating effects of ANP (Holtwick, R., Gotthardt, M., Skryabin, B., Steinmetz, M., Potthast, R., Zetsche, B., Hammer, R. E., Herz, J., and Kuhn M. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7142-7147). The purpose of this study was to clarify mechanisms compensating for the missing vasodilator responses to ANP. In particular, we analyzed the effect of the endothelial, cGMP-mediated vasodilators C-type natriuretic peptide and nitric oxide (NO). In isolated arteries from SMC GC-A KO mice, the vasorelaxing sensitivity to sodium nitroprusside and the endothelium-dependent vasodilator, acetylcholine, was significantly greater than in control mice. There was no difference in responses to C-type natriuretic peptide or to the activator of cGMP-dependent protein kinase I, 8-para-chlorophenylthio-cGMP. The aortic expression of soluble GC (sGC), but not of endothelial NO synthase or cGMP-dependent protein kinase I, was significantly increased in SMC GC-A KO mice. Chronic oral treatment with the NO synthase inhibitor N(w)-nitro-l-arginine methyl ester increased arterial blood pressure, the effect being significantly enhanced in SMC GC-A KO mice. We conclude that SMC GC-A KO mice exhibit a higher vasodilating sensitivity to NO. This can be attributed to an enhanced expression of sGC, whereas the expression and/or activity levels of downstream cGMP-effector pathways are not involved. Increased vasodilating responsiveness to endothelial NO contributes to compensate for the missing vasodilating effect of ANP in SMC GC-A KO mice.
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PMID:Increased sensitivity to endothelial nitric oxide (NO) contributes to arterial normotension in mice with vascular smooth muscle-selective deletion of the atrial natriuretic peptide (ANP) receptor. 1263 61

Influence of Na+,K+,2Cl(-)-cotransport and chloride permeability of the cell membrane on electrically-induced action potential and contraction of smooth muscle cells from guinea pig ureter was examined with the methods of the double sucrose gap junction. Mesatone (10 microM) and histamine (10 microM) induced prolongation of the action potential and elevation of smooth muscle cell contraction, whereas hyperosmic medium (+150 mM sucrose), and recovery of solution osmolality in hyposmic condition (70 mM NaCl) after a single contraction. Inhibitor Na+,K+,2Cl(-)-cotransport bumetanide (10 microM) and chloride permeability blockers niflumic acid (10-100 microM) and SITS (10-500 microM) attenuated stimulating effects of mesatone, histamine and hyperosmic medium. In opposite to adenylate cyclase activation with forskolin (1 microM), guanylate cyclase activation with sodium nitroprusside (SN, 100 microM) decreased both inhibitory action of bumetanide, niflumic acid and activating effects of mesatone, histamine on action potential and elevation contraction of smooth muscle cells. Influence of forskolin rather and not SN on AP and SMC C was inhibited with tetraethylammonium (5 mM). These results suggest that influence of Na+,K+,2Cl(-)-cotransport on electrical and contractil properties of ureter smooth muscle cells is mediated by stimulation of Ca(2+)-activated chloride permeability of the cell membrane and modulated by intracellular cGMP, but not triggered by Ca2+ release from sarcoplasmic reticulum.
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PMID:[Na+,K+,2Cl(-)-cotransport and chloride permeability of the cell membrane in mezaton and histamine regulation of electrical and contractile activity in smooth muscle cells from the guinea pig ureter]. 1759 74

Oesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO-sensitive guanylyl cyclase (NO-GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO-GC in LES relaxation, we used cell-specific knockout (KO) mouse lines for NO-GC. These include mice lacking NO-GC in smooth muscle cells (SMC-GCKO), in interstitial cells of Cajal (ICC-GCKO) and in both SMC/ICC (SMC/ICC-GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell-specific expression/deletion of NO-GC was monitored by immunohistochemistry. Swallowing-induced LES relaxation is strongly reduced by deletion of NO-GC in ICC. Basal LES tone is affected by NO-GC deletion in either SMC or ICC. Lack of NO-GC in both cells leads to a complete interruption of NO-induced relaxation and, therefore, to an achalasia-like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO-GC in SMC and ICC whereas swallow-induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.
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PMID:Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter. 2563 Feb 61

Phosphodiesterase 3 (PDE3) exists in two isoforms (PDE3A and PDE3B) and is known to act as cGMP-inhibited cAMP-degrading PDE. Therefore, PDE3 may likely be involved in the interaction between the two second messenger pathways. NO-sensitive guanylyl cyclase (NO-GC) is the most important cytosolic generator of cGMP. Here, we investigated the effect of NO-GC deletion on PDE3A-mediated signaling in animals lacking NO-GC either globally (GCKO) or specifically in smooth muscle cells (SMC-GCKO). PDE3A expression is detected in murine aortic smooth muscle, platelets, and heart tissue. Expression and activity of PDE3A in aortae from GCKO and SMC-GCKO mice was reduced by approx. 50% compared to that in control animals. PDE3A downregulation can be linked to the reduction in NO-GC and is not an effect of the increased blood pressure levels resulting from NO-GC deletion. Despite the different PDE3A expression levels, smooth muscle relaxation induced by forskolin to stimulate cAMP signaling was similar in all genotypes. Basal and forskolin-stimulated cAMP levels in aortic tissue were not different between KO and control strains. However, the potency of milrinone, a selective inhibitor of PDE3A, to induce relaxation was higher in aortae from GCKO and SMC-GCKO than that in aorta from control animals. These data were corroborated by the effect of milrinone in vivo, which led to an increase in systolic blood pressure in both KO strains but not in control mice. We conclude that NO-GC modulates PDE3A expression and activity in SMC in vivo conceivably to preserve functional cAMP signaling.
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PMID:Phosphodiesterase 3A expression and activity in the murine vasculature is influenced by NO-sensitive guanylyl cyclase. 2929 49