Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis, the canine heartworm, depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine, endothelium-dependent dilators (acetylcholine, histamine, and A23187), and nitroglycerin were done. In some experiments, inhibitors of cyclooxygenase (indomethacin and aspirin), guanylate cyclase (methylene blue), and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast, endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG, acetylcholine relaxation in control abdominal aorta was completely abolished; however, in abdominal aorta of Brugia-infected rats, acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however, relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control, suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.
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PMID:Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis. 190 79

The present study examined the effect of atrial natriuretic factor (ANF) on cGMP generation by dispersed chief cells from guinea pig stomach. ANF caused a rapid dose-dependent increase in cGMP, a 7-fold increase in cGMP caused by 1 microM ANF, with or without 3-isobutyl-1-methylxanthine present. Methylene blue reduced cGMP in response to nitroprusside but not ANF. Guanylate cyclase activity of a chief cell membrane fraction doubled in response to ANF, but was not affected by nitroprusside. ANF had no effect on guanylate cyclase activity of the soluble fraction of lysed chief cells. Dose-response curves for whole cell cGMP production and membrane guanylate cyclase activity in response to ANF were closely related. These data indicate that ANF increases chief cell cGMP production by activating particulate guanylate cyclase, providing functional evidence that chief cells possess surface membrane receptors for ANF.
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PMID:Atrial natriuretic factor activates membrane-bound guanylate cyclase of chief cells. 197 96

In superfusion experiments on isolated porcine coronary arterial and venous ring preparations precontracted by prostaglandin F2 alpha repeated bolus application of carbon monoxide induced a reproducible relaxation. The vessels were rubbed to remove the endothelium, 30 min superfusion with 10(-5) M of 8-bromocyclic-GMP decreased the tension in coronary artery and vein and reduced the carbon monoxide response in the latter. Methylene blue increased the tone and inhibited the carbon monoxide effect in both vessels. The results show that carbon monoxide relaxing action on vascular smooth muscle might be due to activation of guanylate cyclase similar to the action on nitric oxide and/or endothelium-derived relaxing factor.
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PMID:Study on the mechanism of carbon monoxide induced endothelium-independent relaxation in porcine coronary artery and vein. 197 2

The production of endothelium-derived relaxing factor(s) in response to kinins was investigated in cultured porcine aortic endothelial cells. The production was estimated by the measurement of the accumulation of cyclic GMP, a response which can be attributed to activation of the soluble guanylate cyclase of the endothelial cells by endothelium-derived relaxing factor(s). Bradykinin increased markedly the levels of cyclic GMP in endothelial cells without affecting those of cyclic AMP. The bradykinin-stimulated production of cyclic GMP was transient and concentration-dependent. Kallidin (an agonist at B2-kinin receptors) but not des-Arg9 bradykinin and des-Arg10 kallidin (agonists at B1 kinin receptors) also increased, in a concentration-dependent manner, the content of cyclic GMP. The B2 kinin receptor antagonist, D-Arg0 [Hyp3, D-Phe7]bradykinin but not the B1 kinin receptor antagonists Leu8-des-Arg9 bradykinin and Leu9-des-Arg10 kallidin inhibited the production of cyclic GMP upon stimulation of the endothelial cells with either bradykinin or kallidin. Both the basal and kinin (bradykinin and kallidin)-stimulated productions of cyclic GMP were reduced by hemoglobin and potentiated by superoxide dismutase. Methylene blue also reduced kinin-stimulated production of cyclic GMP. These findings suggest that cultured porcine aortic endothelial cells possess B2 kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor(s). The endothelium-derived relaxing factor(s) produced in turn enhances the activity of soluble guanylate cyclase and induces the accumulation of cyclic GMP.
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PMID:Bradykinin stimulates the production of cyclic GMP via activation of B2 kinin receptors in cultured porcine aortic endothelial cells. 215 53

Sodium nitroprusside (SNP), a nonreceptor mediated stimulant of soluble guanylate cyclase, and atrial natriuretic factor, a receptor-dependent stimulator of particulate guanylate cyclase, mediate relaxation responses by increasing intracellular cGMP. This in vitro study was designed to compare the ontogeny of relaxation responses to SNP and atrial natriuretic factor in the guinea pig thoracic aorta. Aortic rings from fetuses at 55-60 d gestation (term = 68 d), 1- to 3-d-old newborn, and 12-wk-old adult Hartley guinea pigs were mounted in an organ bath, bathed in Kreb's solution, and connected to a force-displacement transducer to measure isometric tension. Relaxation responses to SNP and atriopeptin III were studied with the vessels at optimal resting tension and after preconstriction with an EC85 concentration of norepinephrine. SNP-mediated relaxation showed a significant increase in sensitivity with development among the three age groups (p less than 0.05). Methylene blue, an inhibitor of soluble guanylate cyclase, produced no inhibition of relaxation to SNP in fetal aortae, significantly decreased responses along the straight portion of the concentration-response curve in newborn aortae (p less than 0.05), and significantly shifted the concentration-response curve to the right (p less than 0.05) in adult aortae; but did not prevent vessels from relaxing almost 100% in any age group. However, atriopeptin III-mediated responses were similar in the three age groups and were unaffected by methylene blue. These results suggest that 1) sensitivity to SNP increases with age from fetal through adult life; 2) relaxation mediated by atriopeptin III is similar during development; 3) methylene blue does not affect SNP mediated relaxation in fetuses but progressively decreases sensitivity to SNP in newborns and adults; and 4) methylene blue does not affect atriopeptin III-mediated relaxation in any age group.
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PMID:Developmental changes in sodium nitroprusside and atrial natriuretic factor mediated relaxation in the guinea pig aorta. 216 Jun 37

The present studies were conducted to examine the role of cerebrovascular guanylate cyclase in hypoxic cerebral vasodilatation. In arteries mounted in vitro for measurements of isometric tension, 20 min of hypoxia (bath oxygen partial pressure, approximately 15 Torr) significantly increased cyclic GMP levels from 16 to 32, from 15 to 25 and from 20 to 38 pmol/g in rabbit common carotid, internal carotid and basilar arteries. These increases were blocked either by pretreatment with 3 microM methylene blue, or by removal of the vascular endothelium. Methylene blue also significantly delayed hypoxic relaxation in the basilar and internal carotid arteries, and blocked transient hypoxic vasoconstriction in the common carotid. Together, these in vitro results demonstrate that vascular cytosolic guanylate cyclase participates in an endothelium-dependent manner in the direct effects of hypoxia on cerebral arteries, and that the nature of this participation varies significantly between arteries. When methylene blue (20 mg/kg) was administered in vivo, however, it had no effect on the magnitude of hypoxic cerebral vasodilatation as determined by both local (mass spectrometry) and global (venous outflow) methods of blood flow measurement. This latter finding suggests that: 1) large and small cerebral arteries may differ significantly in terms of either endothelial function or sensitivity to methylene blue; or 2) feedback regulation of other mechanisms of hypoxic cerebral vasodilatation compensate for the effects of guanylate cyclase inhibition. Additional experiments using other inhibitors of cytosolic guanylate cyclase and/or vessels isolated from the cerebral microcirculation will be necessary to distinguish between these possibilities.
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PMID:Effects of methylene blue on hypoxic cerebral vasodilatation in the rabbit. 216 99

Treatment of mesangial cells with recombinant human interleukin 1 beta (IL-1 beta) or recombinant human tumor necrosis factor alpha (TNF alpha) dose-dependently increased cGMP formation. Both IL-1 beta and TNF alpha-stimulated formation of cGMP occurred after a initial lag period of 4 to 8 hours. Treatment of cells with actinomycin D, cycloheximide or dexamethason completely abolished cytokine-induced cGMP formation. Furthermore, the guanylate cyclase inhibitor Methylene blue completely blocked IL-1 beta- and TNF alpha-stimulated cGMP generation. NG-mono-methyl-L-arginine attenuated IL-1 beta- and TNF alpha-induced cGMP production, an effect that was reversed by L-arginine.
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PMID:Interleukin 1 and tumor necrosis factor stimulate cGMP formation in rat renal mesangial cells. 217 27

Endothelium-dependent relaxation mediated by the formation of nitric oxide (NO) from L-arginine, is prevented by the arginine analog NG-monomethyl L-arginine (L-NMMA) (Palmer et al., Biochem. Biophys. Res. Comm. 153:1251-1256 (1988)). In the rat mesenteric arterial bed, incubation with L-NMMA did not prevent acetylcholine-induced relaxation, which, however, was reversed when L-NMMA was added during its maximum effect. A similar profile of action was observed with methylene blue, an inhibitor of guanylate cyclase. Methylene blue, but not L-NMMA, increased basal perfusion pressure. These data indicate that in the mesenteric arterial bed, NO formation via the L-NMMA-sensitive pathway occurs during stimulation with acetylcholine, but not under basal conditions.
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PMID:Influence of NG-monomethyl-L-arginine on endothelium-dependent relaxations in the perfused mesenteric vascular bed of the rat. 236 29

Transmural electrical stimulation was used to elicit frequency-dependent adrenergic neurogenic contractions in isolated carotid arteries from cholesterol-fed and control rabbits. In rings with endothelium, responses to adrenergic nerve stimulation were significantly greater in arteries from cholesterol-fed as compared with those from control rabbits. Responses to adrenergic nerve stimulation of rings without endothelium were not different between the two groups. Methylene blue, a guanylate cyclase inhibitor, increased contractions of rings with endothelium and abolished the difference between the responses of arteries from cholesterol-fed and control rabbits. Methylene blue had no significant effect on arteries without endothelium. The overflow of endogenous norepinephrine (NE) caused by transmural electrical stimulation was not different between segments of arteries from cholesterol-fed and control rabbits. In control rabbits, exogenously applied NE contracted arteries with endothelium less than arteries without endothelium, whereas in cholesterol-fed rabbits the contractions caused by NE were not different between arteries with and without endothelium. Acetylcholine-induced relaxations were not different between rings with endothelium from cholesterol-fed and control rabbits. These results suggest that hypercholesterolemia selectively impairs the inhibitory influence of the endothelium on adrenergic contractions.
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PMID:Augmented adrenergic contractions of carotid arteries from cholesterol-fed rabbits due to endothelial cell dysfunction. 248 75

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta. 253 55


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