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)

1. There is currently considerable interest in the role of locally produced vasodilators such as nitric oxide and adenosine in the pathogenesis of the peripheral vasodilatation of cirrhosis. However, the signal transduction pathways involving guanylate cyclase and adenylate cyclase have not been clearly delineated in the isolated blood vessel. 2. We therefore aimed to examine the in vitro vasorelaxant effects of the endothelium-dependent dilator bethanechol, the endothelium-independent dilator sodium nitroprusside and adenosine, as drugs that work via activation of guanylate and adenylate cyclases, in isolated aortic and superior mesenteric arterial rings from cirrhotic and control rats. 3. Cirrhosis was induced by chronic bile duct ligation and section of 24-28 days' duration, while controls underwent sham operation. The vessels were precontracted with the alpha 1-adrenoceptor agonist phenylephrine, then relaxed by incremental doses of the three drugs. 4. Marked attenuation of vasoconstriction induced by phenylephrine in isolated aortic and mesenteric arterial rings from cirrhotic rats compared with the control vessels was observed. 5. There were no significant differences in relaxation between the cirrhotic and control vessels to the three drugs. We conclude that in vitro vasodilatory responses mediated through signal transduction pathways involving guanylate cyclase and adenylate cyclase remain unchanged in a rat model of biliary cirrhosis.
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PMID:Vasodilatory responses of isolated arteries of cirrhotic rats. 749 16

Adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) mediate penile erection. We have previously established that adenylate and guanylate cyclase activity is elevated in the diabetic rat penis and aorta. This study investigates the action of papaverine and vasoactive intestinal polypeptide (VIP) on these cyclases. The aortae and penes of Sprague Dawley rats (n = 7) were stimulated with VIP and papaverine. Diabetes mellitus (DM) was induced in Sprague Dawley rats (n = 7) with streptozotocin and the penile and aortic tissues were treated with VIP. The penes, aortae and carotid arteries of New Zealand White rabbits were similarly processed. cAMP and cGMP generation was measured by radioimmunoassay. In all tissues: VIP stimulated cAMP synthesis; VIP did not increase cGMP levels; papaverine was without effect on either cAMP or cGMP synthesis. VIP-stimulated cAMP was significantly enhanced in the diabetic rat penis and aorta; there was also a significant elevation in the basal levels of cGMP in these tissues. These data: (1) consolidate that cAMP is a mediator of penile erection, (2) indicate that papaverine and VIP elicit erection by different mechanisms, (3) suggest that an enhanced penile capacity to generate cAMP in DM may constitute an adaptive response to counteract the previously reported reduction in VIP content and VIP receptors, and (4) indicate that the penile and vascular tissues of the rabbit respond in a similar manner to VIP and papaverine.
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PMID:Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study. 749 46

Human foreskins were examined for enzyme-histochemical staining of microvessels using guanylate cyclase, an enzyme similar to adenylate cyclase. Like 5'-nucleotidase (which hydrolyzes 5'-adenosine monophosphate to adenosine), and adenylate cyclase (which converts adenosine triphosphate to cyclic AMP), guanylate cyclase selectively stains positive for lymphatic capillaries and therefore may be another useful histochemical marker to differentiate dermal lymph from blood capillaries.
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PMID:Enzyme-histochemical staining of dermal lymphatic capillaries by guanylate cyclase. 751 10

Amphiphiles are known to modulate the activity of ATPase, phospholipase A2, adenylate and guanylate cyclase amongst others and relax vascular smooth muscle. The effect of two amphiphiles, lysophosphatidylcholine (LPC) and digitonin on the activity of nitric oxide synthase (NOS), as measured by conversion of radiolabeled L-arginine to L-citrulline, has been studied. Neither digitonin (0.01 mmol/l) nor LPC (0.01 mmol/l) influenced NOS activity in endothelial cell homogenates. Digitonin but not LPC stimulated NOS in intact endothelial cells. NOS activity was markedly inhibited by L- but not by D-omega-nitroarginine (D-NNA, 0.1 mmol/l). L-NNA or D-NNA data demonstrate no effect of amphiphiles on isolated NOS. NOS activation may occur as a result of detergent action on the membrane.
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PMID:Effect of amphiphiles on nitric oxide synthase in endothelial cells. 751 49

Na+/Ca2+ exchange contributes to the control of cytosolic free Ca2+ levels ([Ca2+]i) in resting and activated cultured human mesangial cells. We have previously shown that activation of phospholipase C by vasoconstrictors enhances Ca2+ influx upon extracellular Na+ withdrawal. This effect is not mediated by concurrent activation of protein kinase (PK) C, since it occurs even after PKC inhibition, and phorbol esters actually blunt both basal and stimulated Na+/Ca2+ exchange. We now studied the effects of PKA and PKG activation by adenylate/guanylate cyclase stimuli or by permeant analogues of cyclic nucleotides in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe, fura-2. The exchanger was inhibited by the stable prostaglandin I2 analogue, iloprost, which is transduced by cAMP (peak [Ca2+]i inhibition by 1 microM iloprost 35 +/- 3%). Similarly, non-receptor activation of adenylate cyclase by 10 microM forskolin inhibited basal and agonist-stimulated Na+/Ca2+ exchange by 52 +/- 4 and 66 +/- 4%, respectively. Dibutyryl-cAMP (0.1 mM) also inhibited stimulated Na(+)-dependent Ca2+ influx by 72 +/- 2%. The particulate guanylate cyclase agonist, atriopeptin III, and the soluble guanylate cyclase activator, glyceryltrinitrate, also inhibited both basal and angiotensin II-stimulated Na+Ca2+ exchange (to a maximum of 53 +/- 5 and 62 +/- 3%, respectively). Dibutyryl-cGMP (1 mM) mimicked the effects of cGMP stimuli, reducing stimulated Na+/Ca2+ exchange by 79 +/- 2%. Therefore, similar to PKC, cyclic nucleotide activation of PKA and PKG regulates Na+/Ca2+ exchange, providing a functional link between transmembrane signalling systems for vasoactive agents in cultured human mesangial cells.
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PMID:Cyclic nucleotides inhibit Na+/Ca2+ exchange in cultured human mesangial cells. 752 69

It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240-960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7 +/- 0.1 to 2.6 +/- 0.4 pmol/10(6) cells, p = 0.0001; cGMP: from 1.3 +/- 0.2 to 3.4 +/- 0.7 pmol/10(6) cells, p = 0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p = 0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor NG-monomethyl-L-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost (p = 0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate (p = 0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.
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PMID:Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. 758 79

1. Carbon monoxide (CO), produced by haem oxygenase through degradation of haem, has been claimed to be a neuromessenger and a possible regulator of vascular tone. We examined whether the haem oxygenase inhibitor, zinc protoporphyrin-IX (ZnPP) and other porphyrins affect the relaxation evoked by various agents in the rat isolated aorta. 2. Pretreatment with ZnPP (0.1 mM) virtually abolished the relaxation evoked by vasoactive intestinal peptide (VIP) and atrial natriuretic peptide (ANP). ZnPP also evoked a rightward shift of the concentration-response curve for the relaxation induced by acetylcholine. 3. In contrast, ZnPP did not affect the relaxation evoked by forskolin and 3-morpholino-sydnonimine, agents which directly activate adenylate and guanylate cyclase, respectively. 4. Although, less effective than ZnPP, tin protoporphyrin-IX (SnPP; 0.1 mM) and protoporphyrin-IX (PP; 0.1 mM) also attenuated the VIP-evoked relaxation. 5. The elevation of cyclic AMP and cyclic GMP levels evoked by VIP and ANP, respectively, were abolished by pretreatment with ZnPP (0.1 mM). 6. ZnPP, SnPP and PP did not affect the contraction evoked by phenylephrine. 7. The results show that ZnPP inhibits relaxation induced by VIP, ANP and acetylcholine, probably by interfering with membrane receptor-coupled signal transduction pathways. This inhibition does not seem to be dependent upon inhibition of haem oxygenase. The lack of specificity of the haem oxygenase inhibiting metalloporphyrins makes them less suitable as pharmacological tools in the investigation of a messenger role for CO.
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PMID:Inhibition by zinc protoporphyrin-IX of receptor-mediated relaxation of the rat aorta in a manner distinct from inhibition of haem oxygenase. 764 74

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a primary signaling molecule in neurovascular communication. In the present study, the authors examined cerebrovascular responses to CGRP and its related second messenger systems during cerebral vasospasm induced by subarachnoid hemorrhage (SAH). Tension measurements were performed in vitro on ring strips of basilar arteries obtained from rabbits subjected to artificial SAH and from control (non-SAH) animals. In vessels from SAH animals, which were preconstricted with serotonin, the vasorelaxant response to CGRP was attenuated. Because it has been suggested that vasodilation elicited by CGRP is mediated by cyclic 3',5'-adenosine monophosphate (cAMP) and/or cyclic 3',5'-guanosine monophosphate (cGMP), the vascular effects of directly activating these second messenger systems were also examined. The relaxant effect of forskolin, which activates adenylate cyclase directly, was slightly enhanced after SAH. In contrast, the relaxant effect of nitroglycerin (GTN), which activates soluble guanylate cyclase directly, was unchanged after SAH. The attenuation of CGRP-induced vasorelaxation could be the result of a modification in its ability to stimulate the production of second messengers. Experiments testing the capacity of CGRP to elevate cAMP levels showed no significant differences between vessels from non-SAH and SAH animals. Similarly, the resting levels of cAMP and the forskolin-induced elevations of cAMP did not differ between non-SAH and SAH animals. In contrast, cGMP levels were lower in resting and CGRP-treated vessels from SAH animals than in those from non-SAH animals. No significant differences in the levels of cGMP were observed between non-SAH and SAH vessels treated with GTN. This study indicates that CGRP-induced vasodilation is attenuated during vasospasm in a rabbit model of SAH. The findings also demonstrate that vasodilatory responses mediated by cAMP and cGMP are intact, although the levels of cGMP in SAH vessels are reduced. Together, these observations suggest that an attenuation in the capacity of vessels to dilate in response to CGRP occurs during cerebral vasospasm, and this change in CGRP vasoactivity is a result of modifications prior to, or independent of, the elevation of cyclic nucleotide second messengers.
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PMID:Effects of subarachnoid hemorrhage on vascular responses to calcitonin gene-related peptide and its related second messengers. 766 31

The localization of some membrane-associated enzymes such as alkaline phosphatase, 5'-nucleotidase, glucose-6-phosphatase, Na+,K(+)-adenosine triphosphatase, adenylate cyclase and guanylate cyclase in the Merkel cell-axon complexes, trigeminal ganglia and the principal trigeminal sensory nucleus of the cat was determined at light and electron microscopic level using cytochemical techniques. In the sinus hair follicles (vibrissae), the reaction end product marking alkaline phosphatase and adenosine triphosphatase activities was visualized on the axons running through external follicle epithelium and the 5'-nucleotidase, adenylate- and guanylate cyclase positive reaction was seen to stain the plasma membranes of Merkel cells. In the trigeminal ganglia, the strongest alkaline phosphatase and adenosine triphosphatase activities showed the corresponding areas between the ganglion and satellite cells. 5'-nucleotidase activity was more intense on the neurilemmas and the surrounding glial plasma membranes. In the principle sensory trigeminal nucleus, the central neurons exhibited an intense alkaline phosphatase, 5'-nucleotidase and adenosine triphosphatase activities and much smaller amount of reaction product for adenylate cyclase and guanylate cyclase was observed. In conclusion, membrane-bound enzymes could be histo- and cytochemically demonstrated in all components of primary trigeminal afferent units. Our results have confirmed that the receptor function and the nerve impulses conductance need an intensive molecular and cation exchange, and energy supply.
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PMID:Primary trigeminal afferent neuron of the cat: I. Studies on membrane-bound enzyme histochemistry. 798 69

This study measured the values of cyclic nucleotides and adenylate and guanylate cyclase activities in duodenal mucosa homogenates to verify if they played a part in coeliac disease. Nine controls, 13 patients who did not receive treatment and nine patients who received treatment were studied. Cyclase activity assays were performed under basal conditions and in the presence of gliadin derived peptides. Duodenal mucosa cyclic nucleotide values and adenylate cyclase activity were significantly higher in patients who did not receive treatment than in those who did and in controls, whereas guanylate cyclase activity was similar in all groups. Gliadin derived peptides did not affect guanylate cyclase activity, but significantly increased adenylate cyclase activity in homogenates from patients who did not receive treatment. As extracellular cyclic nucleotide concentrations could reflect changes in their intracellular metabolism, plasma and urine cyclic nucleotide values were also measured in 25 controls and in 55 patients studied at different stages of their disease. Extracellular cyclic nucleotides were considerably high in patients who were not healed and became normal after about one year of treatment. These data suggest that cyclic nucleotides may participate in the pathophysiological processes of coeliac disease.
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PMID:Duodenal mucosa and extracellular cyclic nucleotide pattern in coeliac disease. 810 Feb 4


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