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. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established. 2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin. 3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-L-arginine methyl ester or NG-nitro-monomethyl-L-arginine (inhibitors of nitric oxide synthase) and by 10 mumol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 mumol/l ouabain (inhibitor of Na+, K(+)-ATPase), and, when combined with NG-nitro-L-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 mumol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-L-arginine methyl ester-resistant endothelium-dependent relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. 754 95

1. ANP (atrial natriuretic peptides)- or ANP/ATP-stimulated guanylyl cyclase activities were compared in adult (2 month old) and neonatal (5-7 day old) rat lung membrane fractions. 2. The enzyme activities of both membranes depended on the incubation time and ATP concentration: although the activities of both membranes were similar after a short incubation time (4 min), those in adult membranes were lower than those of neonatal membranes after longer incubation times (10 and 30 min) or at lower concentrations of ATP. 3. ANP/ATP gamma S-stimulated guanylyl cyclase activities, which were much higher than ANP/ATP-stimulated activities, were similar in both membranes. 4. ATPase activity of adult membranes was higher than that of neonatal membranes, suggesting that hydrolysis of ATP leads to a decrease of ANP/ATP-guanylyl cyclase activity in adult membranes. Triton X-100 enhanced and diminished ANP/ATP-stimulated guanylyl cyclase activities of adult and neonatal membranes, respectively, and thereby abolished the adult/neonatal difference in the membrane response to ATP. 5. ANP-stimulated activities of both membranes were much more activated by pre-incubation with ATP gamma S than those induced by simultaneous addition of ATP gamma S. The former activities were decreased to levels of the latter by Triton X-100. The latter activities were not affected by Triton X-100. 6. The present results suggested that conformation of lung plasma membranes is related to activation of the ANP receptor/guanylyl cyclase system.
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PMID:Developmental changes in ANP-stimulated guanylyl cyclase activity enhanced by ATP in rat lung membrane fractions. 783 9

Studies were designed to determine the extent of the involvement of endothelium-derived relaxing factor(s) other than nitric oxide (NO) in vascular relaxation in response to acetylcholine (ACh) in the rabbit renal artery. ACh (10(-9)-10(-6) M) induced concentration-dependent relaxation of isolated endothelium-intact arterial rings preconstricted with noradrenaline. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, partly inhibited the ACh-induced endothelium-dependent relaxation, whereas it almost completely abolished the production of cyclic-3', 5'-guanosine monophosphate (cGMP) in these rings in response to ACh. Methylene blue, an inhibitor of guanylate cyclase, had an essentially similar effect to L-NAME on the relaxation. Indomethacin, an inhibitor of cyclooxygenase, had no effect. High concentrations of potassium chloride (to inhibit endothelium-dependent hyperpolarization), tetraethylammonium (TEA) or 4-aminopyridine (4-AP), a voltage-dependent or Ca(2+)-dependent K+ channel blocker, partly inhibited the relaxation while, in contrast, glibenclamide, an ATP-sensitive K+ channel blocker, had no effect. Ouabain, an inhibitor of Na+, K(+)-ATPase, also partly inhibited the ACh-induced relaxation, especially the higher concentration effect. Application of L-NAME together with ouabain, TEA, or a high concentration of potassium chloride completely abolished the relaxation. These results suggest that ACh-induced endothelium-dependent relaxation in the rabbit renal artery is mediated by NO, and by an other factor(s), which relaxes the vascular smooth muscle through opening K+ channels other than ATP-sensitive ones, and/or through the activation of a Na+, K(+)-pump.
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PMID:NG-nitro-L-arginine-resistant endothelium-dependent relaxation induced by acetylcholine in the rabbit renal artery. 804 Dec 28

The authors have previously shown that atrial natriuretic peptide (ANP) mediates its cellular effects in part by changes in Ca2+ homeostasis in kidney cortex and that Ca2+ + Mg2+ ATPase is linked to ANP receptors, being reciprocally modulated by the guanylate cyclase system. The present study was designed to examine the status of this coupling in diabetes-induced congestive heart failure and the effect of its alterations on the functional integrity of the renal cell. Ca2+ + Mg2+ ATPase and guanylate cyclase were tested in hypertensive-diabetic rats (D + H), which develop congestive heart failure (CHF) at ten weeks following streptozotocin (65 mg/kg) injection and abdominal aortic constriction. The ATPase activity was measured by the release of 32P from [gamma-32P]ATP in the medium. While the guanylate cyclase activity was decreased very rapidly in the hypertensive-diabetic group, the sensitivity of the Ca2+ pump to ANP was increased at an early stage (three weeks) and decreased at a late stage (ten weeks) of CHF. The authors conclude that a defect in coupling between the Ca2+ pump and the ANP-receptor system as observed in the D + H group may contribute to the development of nephropathy and CHF.
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PMID:Renal Ca2+ + Mg2+ ATPase in congestive heart failure due to diabetes. 810 29

Thapsigargin induced endothelium-dependent relaxation and cGMP production in rat thoracic aorta, and these effects were inhibited by nitric oxide (NO) pathway inhibitors, a calmodulin inhibitor and removal of Ca2+, suggesting that NO is involved in the thapsigargin-induced relaxation. Thapsigargin may deplete Ca2+ stores in the endothelial cells by inhibiting the Ca(2+)-ATPase, a Ca2+ pump, which in turn triggers influx of extracellular Ca2+, leading to activation of constitutive NO synthase and resultant NO generation. The NO thus formed may activate soluble guanylate cyclase to produce cGMP in the vascular smooth muscle.
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PMID:Thapsigargin, a Ca(2+)-ATPase inhibitor, relaxes rat aorta via nitric oxide formation. 811 11

The permeability of higher molecular weight substances was investigated in mouse chorioallantoic labyrinthine hemotrichorial placenta, using horseradish peroxidase as a tracer. At the same time, ultrastructural localizations of some important enzymes, such as alkaline phosphatase (ALP), acid phosphatase (ACP), Ca(++)-ATPase and guanylate cyclase were elucidated in this organ by means of the enzyme-cytochemical technique. Peroxidase easily entered the space between layers I and II, and no penetration of this tracer beyond layer II was observed. The reaction products for ALP activity were found mainly on the maternal side of the plasma membrane of the layer II trophoblast. ACP activity was confined to the lysosomes of this layer II cell. In short, peroxidase stopped at the cell surface of the layer II trophoblast, and both ALP and ACP coexisted in this layer II cell. These observations strongly suggest that the layer II trophoblast, especially the surface plasma membrane of this cell, may have an important role in regulating the materno-fetal transfer of substances in mouse chorioallantoic placenta.
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PMID:Studies on the permeability and enzyme-cytochemistry of the mouse hemotrichorial placenta. 813 78

The inner medullary collecting duct (IMCD) is the final arbiter of renal Na+ excretion, and Na+ transport in this segment is controlled by a wide variety of hormones and renal autacoids. This review examines the mechanisms of IMCD Na+ transport and its regulation using results obtained from micropuncture and microcatheterization studies in the intact animal, as well as data from isolated perfused tubules, freshly prepared cell suspensions, and cultured IMCD cells. Where appropriate, results from closely related tissues such as the cortical collecting duct and model urinary epithelia are examined. Na+ reabsorption in this segment occurs predominantly via apical amiloride-sensitive Na+ channels and basolateral Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase). Although there is some evidence for the activities of other transporters such as Na(+)-K(+)-2Cl- and Na-Cl cotransporters and Na+/H+ exchanger, their role in Na+ homeostasis remains undefined. Mineralocorticoids augment the activities of both apical Na+ channels and basolateral Na(+)-K(+)-ATPase by a variety of complex mechanisms. Prostaglandin E2 inhibits Na(+)-K(+)-ATPase and appears to mediate the actions of several peptide hormones, including endothelin, interleukin-1, and atrial natriuretic peptide [ANP-(31-67)]. Several peptides in the ANP family [ANP-(99-126), urodilatin, and brain natriuretic peptide] bind to guanylate cyclase-linked receptors, leading to inhibition of apical Na+ channel function. These mechanisms of regulation of IMCD Na+ transport likely play important roles in total body Na+ balance in health and disease.
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PMID:Hormonal regulation of inner medullary collecting duct sodium transport. 836 30

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

1. Simultaneous recordings of tension and [Ca2+]i during NANC-mediated relaxation were made in the rat anococcygeus muscle under various conditions. 2. In muscles precontracted with guanethidine, nitrergic stimulations at 2 Hz produced a rapid decrease in both the tension and [Ca2+]i. 3. The nitric oxide synthase inhibitor, NG-nitro-L-Arginine (NOLA, 100 mumol/L) completely abolished the decreases in the [Ca2+]i and force response of the NANC-mediated relaxation. 4. Noradrenergic-mediated contractions elicited by electrical field stimulation were potentiated by the addition of NOLA. In the absence of NOLA, the motor responses were larger in magnitude at 10 Hz stimulation than at 2 Hz. After NOLA, both the force response and the associated rise in [Ca2+]i were substantially increased in comparison to the control stimulations. Proportionately the potentiation of the 2 Hz response was of a far greater magnitude than that of the 10 Hz response. 5. The guanylate cyclase inhibitor methylene blue (10 mumol/L), partially inhibited the force and [Ca2+]i response of the NANC relaxation. 6. Following exposure of the muscles to the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, cyclopiazonic acid, (10 mumol/L) the responses to NANC stimulation were inhibited. The attenuated relaxation response displayed a bi-phasic timecourse and the Ca2+ change in comparison to that of the control was markedly smaller. In some cases, a relaxation was observed with no detectable change in the [Ca2+]i. 7. The results suggest that part of the relaxation response observed with NANC-mediated relaxation in the rat anococcygeus is dependent on Ca2+ sequestration into the sarcoplasmic reticulum. However, other Ca2+ lowering mechanisms and possible Ca2+ independent mechanisms may also contribute to the NANC relaxation response.
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PMID:Force and intracellular Ca2+ during NANC-mediated relaxation of rat anococcygeus muscle and the effects of cyclopiazonic acid. 857 7

The cellular distribution of guanylyl cyclase coupled natriuretic peptide receptors type A (GC-A) and type B (GC-B) was examined by immunocytochemistry in normal rat kidney, and compared with the distribution of the vacuolar H(+)-ATPase. Staining for GC-A was found in glomeruli, thin limbs of Henle's loop, cortical collecting tubule, and inner medullary collecting duct. Staining for GC-B was found in glomeruli and the same nephron sections as GC-A, with the exception of the thin limbs. In the cortical collecting tubule, GC-A was found in both principal and intercalated cells; GC-B was restricted to the apical pole of alpha intercalated cells. In inner medullary collecting duct cells, GC-A was located on the basal membrane, whereas GC-B was found in the apical pole. The different pattern of polarization of natriuretic peptide receptors in the inner medulla provides a plausible basis for the different physiologic effects of atrial natriuretic factor and C-type natriuretic peptide. The results also suggest the possibility that GC-B is involved in the regulation of bicarbonate transport in the cortical collecting tubule.
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PMID:Natriuretic peptide receptors A and B have different cellular distributions in rat kidney. 858 68


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