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)

Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings with ET-1 or L-NMMA restores NTG-mediated relaxation.
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PMID:Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl L-arginine, and endothelin-1. 887 89

Accumulating evidence indicates that protein kinase C (PKC)-dependent, Ca2+-independent smooth muscle contraction plays the central role in the occurrence of chronic vasospasm following aneurysmal subarachnoid hemorrhage. As far as we know, the nitric oxide/ cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) system comprises the most efficacious inhibitory mechanism against the PKC-dependent contractile mechanism, and the myogenic tonus of normal cerebral arteries is thought to be maintained on the balance between these systems. Recent studies indicate that in spastic cerebral arteries, the rise in the intracellular diacylglycerol level causes PKC activation presumably owing to the overexpression of endothelin (ET)-1 as well as the generation of free radicals, whereas the cGMP level is inversely reduced owing to the inactivation of soluble guanylate cyclase through some as yet unknown mechanism. The resultant loss of balance between the two systems is considered to culminate in the occurrence of chronic vasospasm lasting for nearly 2 weeks. Based on the above concept, recent papers concerning the effects of reactive oxygen species on the arterial smooth muscle, alterations of various membrane ion channels, particularly of adenosine triphospate (ATP)-activated potassium channels in spastic arteries, the preventive effects of ET antagonists on vasospasm, and the causative role of ET-1 were reviewed in the present article. The roles of the above spasmogenic factors or mechanisms may be more clearly understood on the basis of the antagonistic interrelation between the PKC and the PKG systems, which exert diverse influences on the force-generating system as well as on its multifarious regulatory mechanisms in smooth muscle cells.
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PMID:Various pathogenetic factors revolving around the central role of protein kinase C activation in the occurrence of cerebral vasospasm 957 13

We studied the developmental mechanism of low myopia and the possibility of its drug treatment. I. Prevalence of myopia. According to surveys by the Japanese Ministry of Education, Science, Sports and Culture, the frequency of myopia in school children has gradually increased. We examined office workers from 20 to 60 years of age over a 3-year period. Myopia progression was observed in the thirties and fourties. Late-onset myopia is an important problem around the world. II. Developmental mechanism of low myopia. 1. Reduction of refraction after cycloplegia was statistically significant in adults after their twenties. We measured accommodative hysteresis after a close visual task. Accommodative hysteresis persisted for a long time in late-onset and adult-onset myopia. Continuous ciliary contraction seems to be related to late-onset myopia. 2. Bovine ciliary muscle strips were suspended in a Magnus double tube. The changes in isometric tension of the strips, when chemicals were added, were measured with a force-displacement transducer. After the addition of the cholinergic agonist carbachol, the strips of ciliary muscle produced a tonic contraction. When the muscarinic receptor antagonist cyclopentolate was added, relaxation was produced. After the addition of ET-1, a dual response occurred which consisted of a moderate relaxation and a long-lasting contraction. The mean contraction caused by ET-1 was weak but continuous compared to carbachol. The contractile response was inhibited by an ETA receptor antagonist. Also, when takusha, one component of gorei-san, a Chinese drug, was added to the ciliary muscle strips, contraction with ET-1 was attenuated. Contraction of the ciliary muscle with ET-1 was attenuated after addition of sodium nitroprusside (SNP), an NO donor. This reaction suggests that NO causes relaxation of the bovine ciliary muscle through the activation of guanylyl cyclase and an increase in cyclic GMP. Currently, at least 5 muscarinic receptor subtypes are recognized; they are named M1 to M5. The effects of M1, M2, and M3 on the contractile response to transmural electrical stimulation of the bovine ciliary muscle were studied. The contractions produced by transmural electrical stimulation were greatly attenuated by 4-DAMP as an M3 antagonist. 3. We measured autofluorescence of the lens by fluorophotometry. A statistically significant relation was found between autofluorescence of the lens and refraction. 4. Possibility of axial elongation: The anterior and posterior suprachoroidal spaces are different anatomically and physiologically. When the choroid is stretched forward by accommodation, the intraocular pressure may exert more influence on the posterior part of the sclera, than on the anterior part. Using a fluorophotometer, fluorescence leakage at a site 3 mm in front of the retina was examined. Intensity of fluorescence 3 mm in front of the retina was strong in late-onset myopia. This may indicate disturbance of the barrier of the retinal pigment epithelium. When cultured fibroblasts of the sclera of the chick embryo was stretched by a stretching apparatus, proliferation of the cultured cells was inhibited. Therefore, some influence may involve the posterior part of the eyeball. III. Possibility of drug treatment of low myopia: From these results, muscarinic receptor antagonists (especially M3), ET receptor agtagonists, and NO donors are possible drugs for low myopia treatment. As there are many causative factors of low myopia, there are several treatment methods to be evaluated.
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PMID:[Developmental mechanism of low myopia and therapeutic possibilities. A review]. 1002 13

We investigated the effects of endothelins (ETs) on cGMP production in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. ET-3 increased cGMP formation in a concentration-dependent manner (EC50 = 98nM), which was 2.5 times higher than that of ET-1. The ET(B)receptor agonists sarafotoxin-S6c and IRL 1620 also increased cGMP production, mimicking the effects of the ETs. The ET(B) receptor antagonist BQ 788, but not the ET(A) receptor antagonist BQ610, dose-dependently blocked ET-3-stimulated cGMP formation (IC50=10nM). The phorbol ester, Phorbol 12, 13-dibutyrate (PDBu), which inhibits particulate guanylyl cyclase in smooth muscle, dose-dependently inhibited ET-3-stimulated cGMP accumulation (IC50=66nM). LY83583 and ODQ, inhibitors of soluble guanylyl cyclases, as well as inhibitors of the nitric oxide cascade and of intracellular Ca2+ elevation had no appreciable effect on ET-3-induced cGMP production. ET-3 markedly inhibited carbachol-induced intracellular Ca2+ mobilization. We conclude that ET-3 increases intracellular cGMP levels in SV-CISM-2 cells through activation of the ET(B) receptor subtype and subsequent stimulation of the membrane-bound guanylyl cyclase. Elevation of cGMP by ET and the subsequent inhibition of muscarinic stimulation of intracellular Ca2+ mobilization by the cyclic nucleotide could serve to modulate the contractile effects of Ca2+-mobilizing agonists in the iris sphincter smooth muscle.
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PMID:Activation of particulate guanylyl cyclase by endothelins in cultured SV-40 transformed cat iris sphincter smooth muscle cells. 1002 47

A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-1-stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-1 interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1-mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO-ET-1 interactions may contribute to regulation of microvascular function.
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PMID:Nitric oxide modulates endothelin 1-induced Ca2+ mobilization and cytoskeletal F-actin filaments in human cerebromicrovascular endothelial cells. 1002 67

The presence of receptor subtypes for natriuretic peptides (NPs) and endothelin (ET) in the epididymis of the freshwater turtle, Amyda japonica, was examined by quantitative in vitro autoradiography using iodinated mammalian-type atrial NP ((125)I-ANP((1-28))), phylogenically conserved C-type NP ((125)I-[Tyr(0)]-CNP((1-22))), and ET-1 ((125)I-ET-1) as radiolabeled ligands. To characterize NP receptor (NPR) subtypes, we also performed an activation of particulate guanylyl cyclase (GC) in membranes of the epididymis by NPs. Specific (125)I-ANP((1-28)) and (125)I-[Tyr(0)]-CNP((1-22)) bindings were localized in surrounding smooth muscle cell layer of the duct of the epididymis with an apparent dissociation constant (K(d)) of 0.84+/-0.15 and 1.74+/-0.39 nM and a maximal binding capacity (B(max)) of 0.47+/-0.11 and 0.08+/-0.01 fmol/mm(2), respectively. Bindings of (125)I-ANP((1-28)) and (125)I-[Tyr(0)]-CNP((1-22)) to these sites were also displaced by des[Gln(18),Ser(19),Gly(20), Leu(21),Gly(22)]ANF((4-23)), a specific ligand of the NP clearance receptor. Production of 3',5'-cyclic guanosine monophosphate by particulate GC in membranes of the epididymis was stimulated by ANP((1-28)), BNP((1-26)), and CNP((1-22)). Receptor subtypes for ET in the epididymis were characterized by competition with BQ 123 and BQ 788 as specific antagonists for ET receptors, type A (ET(A)) and type B (ET(B)) subtypes, respectively. Specific (125)I-ET-1 bindings were localized in the smooth muscle cell layer of the duct of the epididymis with K(d) and B(max) of 0.21+/-0.03 nM and 0.52+/-0.05 fmol/mm(2), respectively. These specific bindings were potently inhibited in a dose-dependent manner by BQ 123, whereas BQ 788 (10 microM) was not in competing for specific (125)I-ET-1 bindings in this structure. Therefore, these results indicate that specific NP and ET receptors are localized in surrounding smooth muscle cells of the duct of the epididymis of the freshwater turtle. It is also suggested that biological and clearance NPR-like subtypes coexist in these cells, and the predominant ET receptor subtype in this tissue is the ET(A)-like receptor. The localization of specific receptors for NPs and ET in the epididymis may be involved in the control of the transport of sperm in the freshwater turtle.
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PMID:Localization of receptors for natriuretic peptide and endothelin in the duct of the epididymis of the freshwater turtle. 1075 64

Insofar as neutral endopeptidase inhibition has afforded evidence for a tubular luminal action of atrial natriuretic peptide (ANP), the present study was undertaken to investigate a possible effect of the peptide on chloride reabsorption (JCl) in thick ascending limb (TAL). Luminal addition of ANP to in vitro microperfused cortical TAL (CTAL) significantly decreased JCl with a threshold and a maximum concentration of 10(-12) M and 10(-9) M, respectively. A similar effect of 10(-9) M ANP was observed in medullary TAL (MTAL). The effect of luminal ANP was significantly reduced by HS-142-1, a specific inhibitor of guanylyl cyclase receptor, and by H-8, a protein kinase G inhibitor, but was not affected by the protein kinase C inhibitor bisindolylmaleimide I. Unexpectedly, the effect of ANP was not additive with that of endothelin (ET), a peptide that was previously shown to decrease JCl in TAL through a calcium-independent, protein kinase C-mediated pathway. Indeed, ET-1 (10(-8) M in the lumen) significantly decreased JCl and prevented a further effect of ANP on the same tubule. Similarly, the decrease of JCl induced by simultaneous addition of ET and ANP was not higher than that obtained with each agent alone. Conversely, the inhibitory effect of ANP was enhanced in the presence of cyclic guanosine monophosphate (cGMP; 10(-6) M in the lumen). ET-1 significantly attenuated the ANP-stimulated generation of cGMP in microdissected CTAL and failed to prevent a further decrease of JCl promoted by a permeant cGMP analogue. It is concluded that luminal ANP decreased Cl reabsorption in mouse CTAL and MTAL. This effect was abrogated by ET-1 as a result of the inhibition of ANP-stimulated cGMP generation.
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PMID:Effect of luminal atrial natriuretic peptide on chloride reabsorption in mouse cortical thick ascending limb: inhibition by endothelin. 1100 8

The effect of the nitric oxide (NO) donor sodium nitroprusside (SNP) on both [Ca(2+)](i)and mechanical activity was studied in the rat isolated pulmonary artery (RPA). In freshly isolated myocytes loaded with 1 microM indo-lacetoxymethyl ester for 30 min, short (40-60 s) application of ATP (100 microM) or ET-1 (0.1 microM) induced 3-6 cyclic rises in [Ca(2+)](i)(Ca-oscillations) of decreasing amplitude. Preincubation of cells with SNP (10-250 microM) for 10 min had no effect on the resting [Ca(2+)](i)value, but progressively abolished the oscillations. A similar effect was obtained with 8-bromo-cGMP (100-500 microM). SNP (0.001-100 microM) concentration-dependently relaxed ATP (10 mM, n = 4) and ET-1 (0.1 microM, n = 4)-precontracted RPA. 1H-[1,2,4]oxadiazolol [4,3,-a]quinoxalin-1-one (ODQ, 10 microM), a potent inhibitor of the cytosolic guanylyl cyclase, fully reversed the effect of SNP on ATP-induced [Ca(2+)](i)oscillations as well as on ATP-precontracted RPA. In contrast, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H8, 10 microM), a potent inhibitor of cGMP-dependent protein kinase (PKG), did not alter the effect of SNP. Caffeine (5 mM) induced only one transient [Ca(2+)](i)-increase (n = 24), the amplitude of which was altered neither by SNP nor by 8-bromo-cGMP. Our results show that the relaxing effect of NO in RPA is related, at least in part, to its action on the Ca-signalling pathway. NO interacts with inositol trisphosphate pathway without interacting with the ryanodine-sensitive receptor. Finally, the effect of NO involves an increase in cGMP but appears independent of activation of PKG.
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PMID:NO-induced modulation of calcium-oscillations in pulmonary vascular smooth muscle. 1101 63

The secretagogue effect of endothelins (ETs) on the rat adrenal cortex is mediated by the ETB receptor. ETB receptors are coupled with nitric oxide (NO) synthase (NOS), and NO is known to inhibit steroid-hormone secretion from adrenal cortex. We investigated whether ETB-mediated NO production interferes with the stimulatory action of ETs on rat adrenal cortex. The selective agonist of ETB receptor BQ-3020 concentration-dependently increased aldosterone secretion from dispersed zona glomerulosa (ZG) cells and corticosterone secretion from dispersed zona fasciculata-reticularis (ZF/R) cells, and the NOS inhibitor NG-nitro-L-arginine methylester (L-NAME) potentiated the effect of BQ-3020 in a concentration-dependent manner. The guanylate cyclase inhibitor Ly-83583, at a concentration suppressing guanylin- and L-arginine-induced cyclic-GMP release from dispersed adrenocortical cells, did not affect the secretory response of ZG and ZF/R cells to BQ-3020. ET-1, an agonist of both ETA and ETB receptors, stimulated the release of both aldosterone and corticosterone by in situ perfused rat adrenal gland. This effect was potentiated by L-NAME and unaffected by Ly-83583. Collectively, our findings allow us to suggest that endogenous NO exerts in vivo and in vitro a cyclic-GMP-independent buffering action on the ETB receptor-mediated adrenocortical secretagogue action of ETs.
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PMID:Buffering action of endogenous nitric oxide on the adrenocortical secretagogue effect of endothelins in the rat. 1111 9

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.
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PMID:Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery. 1139 74


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