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)

Atrial natriuretic factor (ANF) is actively involved in the control of blood pressure and fluid homeostasis as a physiological antagonist of the renin-angiotensin system. To evaluate a possible interaction between ANF and angiotensin II (Ang-II) receptors, we investigated the effect of long term pretreatment (18 h) of rat cultured vascular smooth muscle cells with Ang-II. Binding of 125I-labeled ANF and cyclic GMP production induced by ANF were measured. After preincubation of the cells with Ang-II (1, 10, and 100 nM), the number of ANF binding sites (Bmax) was decreased by 30, 59, and 71%, respectively, with a slight decrease of the Kd values. Sar1-Ile8-Ang-II (100 nM), a specific Ang-II receptor antagonist, totally inhibited the down-regulation induced by Ang-II (10 nM). Moreover, the regulatory effect of Ang-II on ANF receptors appeared more slowly as compared to ANF homologous receptor regulation. Ang-II pretreatment did not desensitize but increased cyclic GMP production elicited by ANF, implying that only the number of non-guanylate cyclase-coupled receptors was affected. These findings, which were not observed with 100 nM of epinephrine, norepinephrine, histamine, serotonin, and Arg-vasopressin, demonstrate a specific and functional link between ANF and Ang-II receptors. This study also shows that the regulation of ANF receptors is heterogeneous, providing new evidence of multiple classes of ANF receptors.
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PMID:Regulation of atrial natriuretic factor receptors by angiotensin II in rat vascular smooth muscle cells. 284 14

Recently we have shown that atrial natriuretic peptide (ANP) inhibits renin release from isolated rat renal juxtaglomerular (JG) cells. ANP in general is thought to act on its target cells by the binding to specific membrane receptors. It is the objective of this contribution to summarize our present knowledge about the sequence of events by which the occupancy of ANP receptors could lead to an inhibition of renin release from juxtaglomerular (JG) cells. It was found that ANP did not affect the intracellular concentration of calcium. ANP led to a dose dependent increase in the intracellular concentration of cyclic GMP and to a dose dependent decrease of cAMPi. Inhibition of renin release from the JG-cells by ANP was clearly correlated to the level of cGMPi and not to the level of cAMPi. Concerning the mechanism by which ANP causes a rise in cGMPi in JG-cells it was found that the effect of ANP on cGMPi was potentiated by the cGMP phosphodiesterase specific inhibitor M & B 22,948. This finding suggests that ANP enhances cGMPi by the stimulation of a guanylate cyclase rather than by the inhibition of a cGMP phosphodiesterase. Moreover, evidence was obtained that the effect of ANP on cGMP, was markedly attenuated after pretreatment of the JG-cells with pertussis toxin. Since pertussis toxin is considered to inactivate guanine nucleotide binding proteins (G-proteins), this result could indicate that ANP receptors are coupled to a guanylate cyclase via a G-protein. Experimental evidence suggests that the G-protein in question might be the inhibitory unit (Ni) of the adenylate cyclase.
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PMID:Transmembrane signalling of atrial natriuretic peptide in rat renal juxtaglomerular cells. 287 65

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

Since the seminal discovery by deBold that atria contain factors that produce diuresis and natriuresis, the biologic effects attributed to ANF have expanded to the point where the name "atrial natriuretic factor" seems inappropriate. In addition to promoting diuresis and natriuresis, ANF has been shown to produce vascular smooth muscle relaxation and to inhibit the secretion of aldosterone from the adrenal cortex, renin from the juxtaglomerlular apparatus, vasopressin from the hypothalamus, and salt and water intake after central administration. ANF also promotes intestinal secretion and stimulates testosterone synthesis in Leydig cells. However, the cellular mechanisms whereby ANF elicits these diverse effects are poorly understood. ANF has been reported to inhibit adenylate cyclase in a number of tissues. However, the significance of ANF inhibition of adenylate cyclase is unknown. This effect cannot be associated with vascular relaxation since decreased cyclic AMP would be expected to promote contraction rather than relaxation. ANF inhibition of adenylate cyclase may mediate the inhibitory effects of ANF on hormone secretion from the anterior pituitary gland. The inhibition of adenylate cyclase could also explain the inhibitory effect of ANF on aldosterone synthesis, since agents that stimulate cyclic AMP increase aldosterone synthesis. However, ANF also inhibits the dibutyryl-cyclic AMP-induced stimulation of aldosterone secretion, suggesting that an inhibition of adenylate cyclase cannot account fully for the inhibitory effects of ANF on aldosterone synthesis. There is no evidence to support a role for cyclic AMP in the diuretic and natriuretic action of ANF. An inhibition of membrane phosphoinositide breakdown by ANF and the subsequent formation of IP3 and intracellular calcium release could explain the inhibitory effects of ANF on vascular contraction and steroid synthesis. However, there is very little evidence to suggest that ANF regulates phosphoinositide metabolism, while some recent studies suggest that ANF may regulate calcium fluxes in vascular tissue. Clearly, cyclic GMP has emerged as the most likely intracellular mediator of ANF effects. ANF increases cyclic GMP in a wide range of tissues by selectively activating particulate guanylate cyclase. However, it is not known which effects of ANF are mediated by cyclic GMP. The discovery that ANF increases cyclic GMP in vascular tissue clearly suggests that cyclic GMP mediates the vascular relaxation effect of ANF, since other classes of vasodilators also increase cyclic GMP. There is preliminary evidence that cyclic GMP may inhibit renin secretion and sodium transport in kidney cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Atrial natriuretic factor receptor heterogeneity and stimulation of particulate guanylate cyclase and cyclic GMP accumulation. 289 71

The role of guanosine 3',5'-cyclic monophosphate (cGMP) as an inhibitory mediator of tissue renin release was examined in two different in vitro preparations. In rat superficial cortical slices, renin release stimulated by isoproterenol (10(-5) M) was ablated by atriopeptin III (ANP, 2.1 x 10(-8) M), nitroprusside (NP, 10(-3) M), and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 10(-3) and 10(-6) M). Arachidonic acid (10(-3) M)-stimulated renin release was also inhibited by ANP and 8-BrcGMP (10(-3) and 10(-6) M). Both ANP and NP increased tissue cGMP concentrations significantly (P less than 0.05), but neither had an effect on adenosine 3',5'-cyclic monophosphate (cAMP) concentrations. When methylene blue (10(-5) M), an inhibitor of guanylate cyclase, was added to slices incubated with isoproterenol and ANP, the inhibition of renin release by ANP was abolished. These results were confirmed in a preparation of isolated cultured rat juxtaglomerular cells. In these cells, isoproterenol induced a significant increase (58%, P less than 0.01) in renin release, which was inhibited by the addition of 8-BrcGMP (10(-6) M). These data demonstrate a direct inhibitory effect of ANP on isoproterenol- and arachidonic acid-induced renin release. The results with NP, 8-BrcGMP, and methylene blue suggest that cGMP is an intracellular mediator of this inhibition.
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PMID:Guanosine 3',5'-cyclic monophosphate as a mediator of inhibition of renin release. 290 Dec 30

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.
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PMID:George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis. 301 7

We have examined the effect of a synthetic analogue of human alpha-atrial natriuretic peptide (ANP), APII, on renin release in cultured renal juxtaglomerular cells (JGA cells). Using cell cultures containing 80-90% renal juxtaglomerular cells, we found that ANP (10(-13)-10(-9) M) strongly inhibited renin release from the cells in a dose-dependent fashion (ki, 10 pM) to about 10% of control. Inhibition of renin release by ANP was paralleled by an increase in cellular cGMP levels; while in the presence of the cGMP-phosphodiesterase inhibitor M&B 22948 (1 mM), concentrations of ANP lower by a factor of 100 were required to obtain the same effects on renin release and cGMP levels. The guanylate cyclase inhibitor methylene blue (10 microM), on the other hand, shifted the dose-response curves for renin release and cGMP levels to 100-fold higher concentrations of ANP. Neither the influx of 45Ca into the cells nor the intracellular quin-2 signal, which is a measure for changes of intracellular Ca concentration, was in any way altered by ANP. Our results suggest that ANP inhibits renin release from juxtaglomerular cells by a cGMP-dependent process that does not involve changes in intracellular calcium.
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PMID:Atrial natriuretic peptide inhibits renin release from juxtaglomerular cells by a cGMP-mediated process. 301 9

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.
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PMID:Cyclic GMP-linked pathway for renin secretion. 770 14

Experiments were performed on juxtaglomerular granular cells (JGC) in short-term primary culture to determine the direct immediate effect of NO on renin secretion and to test whether JGC are able to generate NO. Renin secretion was measured repeatedly over short time intervals in a cell superfusion system. Renin release did not significantly decrease over a 40-min observation period in untreated JGC. Addition of sodium nitroprusside (SNP) caused a reduction in renin release (measured in nano-Goldblatt hog units vs. time, i.e., nGU/min) from 479 +/- 25, 423 +/- 70, and 388 +/- 54 nGU/min to 295 +/- 19 (n = 5), 102 +/- 21 (n = 7), and 71 +/- 9 nGU/min (n = 6) with 10(-5), 10(-4), and 10(-3) M SNP, respectively. In the presence of the guanylate cyclase inhibitor methylene blue at 10(-4) M, SNP at 10(-4) M had no significant effect on renin secretion. 8-Bromoguanosine 3',5'-cyclic monophosphate at 10(-4) M in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-3) M) caused a reduction of renin secretion to 50.1 +/- 3.6% of control. To examine the possibility that renin secretion is affected by NO release from JGC, we assessed the effect of the NO synthase (NOS) substrate L-arginine (10(-3) M) and the NOS blocker N omega-nitro-L-arginine (10(-4) M) on renin secretion. Renin release was not significantly altered by either stimulation or inhibition of NOS activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of nitric oxide on renin secretion. I. Studies in isolated juxtaglomerular granular cells. 777 23

Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.
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PMID:A functional role for endogenous atrial natriuretic peptide in a canine model of early left ventricular dysfunction. 788 58


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