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)

This study aimed to examine the direct influence of native endothelium derived relaxing factor (EDRF) on renin secretion. To this end isolated mouse renal juxtaglomerular cells were cocultured with bovine aortic endothelial cells which produced and released significant amounts of EDRF as assayed by guanylate cyclase activities which were measured separately in endothelial and juxtaglomerular cells as well as in the cocultures of juxtaglomerular with endothelial cells. EDRF production was blunted in the absence of extracellular L-arginine and in the presence of N omega-nitro-L-arginine (L-NAG; 200 microM). Inhibition of endothelial EDRF production by removal of arginine or addition of L-NAG was associated with a significant decrease of renin secretion from the cocultures while the same regimen had no effect on renin secretion from JG cells alone. Exogenous generation of nitric oxide by the addition of sodium nitroprusside (100 microM) stimulated renin secretion in the cocultures both at normal and inhibited EDRF formation as well as from juxtaglomerular cells alone. These findings suggest that native EDRF released from vascular endothelial cells is a stimulatory signal for renin secretion from renal juxtaglomerular cells.
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PMID:Effect of endothelium-derived relaxing factor on renin secretion from isolated mouse renal juxtaglomerular cells. 790 75

To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.
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PMID:Comparison of the hemodynamic responses to molsidomine and isosorbide dinitrate in congestive heart failure. 807 20

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.
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PMID:Biological actions of brain natriuretic peptide in thoracic inferior vena caval constriction. 828 86

The cardiovascular and diuretic actions of carperitide were studied in experimental animals. Carperitide relaxed various canine arteries and veins that were contracted by high K+ or norepinephrine. Carperitide stimulated particulate guanylate cyclase from rat thoracic aortas. Carperitide had almost no effect on coronary perfusion pressure or heart rate, but caused a slight decrease in contractile force in isolated guinea pig hearts. Carperitide tended to decrease isoproterenol-induced renin release from isolated rat kidney slices and elicited decreases in angiotensin II-induced aldosterone release from bovine zona glomerulosa cells. Intravenous injection of carperitide elicited decreases in arterial blood pressure and total peripheral resistance in the anesthetized and conscious dogs. Carperitide also elicited transient increases in cardiac output and coronary blood flow followed by slight decreases in them. Intravenous infusion of carperitide elicited decreases in pulmonary capillary wedge pressure, pulmonary pressure and right atrial pressure in association with elevating plasma carperitide (ANP like immuno-reactivity) level in dogs with heart failure induced by coronary artery occlusion and saline loading. These results suggest that carperitide decreases both preload and afterload and can improve the untoward hemodynamic alterations in animals with acute experimental heart failure.
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PMID:[Effect of carperitide (alpha-human atrial natriuretic polypeptide) on the cardiovascular system in experimental animals]. 833 Aug 1

Using isolated rat kidneys perfused at controlled pressure, we examined a potential role of endothelium-derived relaxing factor (EDRF) in the pressure control of renin secretion. We found that stimulation of EDRF release by acetylcholine (1 mumol/liter) increased mean perfusate flow rates from 15.0 +/- 0.5 to 18.0 +/- 0.5 ml/min per g and average renin secretion rates from 3.5 +/- 0.5 to 16.0 +/- 2.0 ng angiotensin I/h per min per g at a perfusion pressure of 100 mmHg (mean +/- SEM, n = 6). Those effects of acetylcholine were significantly reduced during inhibition of EDRF formation with NG-nitro-L-arginine (100 mumol/liter), but they were not affected with the cyclooxygenase inhibitor indomethacin (10 mumol/liter). Lowering of the perfusion pressure from 100 mmHg to 40 mmHg resulted in an increase of average renin secretion rates from 3.5 +/- 0.5 to 79 +/- 12 ng AngI/h per min per g under control conditions (n = 8), and to 171 +/- 20 ng AngI/h per min per g in the presence of 10 mumol/liter acetylcholine (n = 3). The rise of renin secretion in response to a reduction of the renal artery pressure was markedly attenuated with inhibitors of EDRF formation such as NG-nitro-L-arginine (100 mumol/liter) and related compounds. During inhibition of EDRF formation, addition of sodium nitroprusside (10 mumol/liter) increased mean perfusate flow rates from 12.0 +/- 0.5 to 23.0 +/- 2.0 ml/min per g and average renin secretion rates from 2.0 +/- 0.5 to 18.0 +/- 1.5 ng AngI/h per min per g at 100 mmHg (n = 5). Lowering of the perfusion pressure from 100 mmHg to 40 mmHg under those conditions increased average renin secretion rates to 220 +/- 14 ng AngI/h per min per g (n = 5). Taken together, our findings suggest that EDRF and related activators of soluble guanylate cyclase stimulate renin secretion from isolated kidneys, predominantly at lower perfusion pressure. Moreover, pressure control of renin secretion appears to require the tonical stimulation by intrarenal EDRF.
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PMID:Involvement of endothelium-derived relaxing factor in the pressure control of renin secretion from isolated perfused kidney. 838 97

This study aimed to examine the role of nitric oxide (NO) in the regulation of renin secretion from renal juxtaglomerular (JG) cells. Using primary cultures of mouse renal JG cells, we found that sodium nitroprusside (SNP) and 3-morpholino-sydnonimin-hydrochloride (SIN-1), two structurally different liberators of NO, led to a transient inhibition during the first hour followed by a marked dose-dependent stimulation of renin secretion lasting for an additional 20 h. This stimulatory effect was blunted by methylene blue (50 microM) and was reversible within minutes after removal of the NO liberators. SNP and SIN-1 also stimulated guanylate cyclase activity in the cultures with a maximum within the first hour of incubation. Increasing intracellular guanosine 3',5'-cyclic monophosphate levels by 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (100 microM) or by atrial natriuretic peptide (10 nM) decreased basal renin secretion but did not inhibit the effect of SNP. The stimulatory effect of SNP was not related to adenosine 3',5'-cyclic monophosphate levels in the JG cells and was blunted after chelation of extracellular calcium by 2 mM ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N'N'-tetraacetic acid. Taken together, our findings suggest that liberators of NO have two effects on renin secretion from isolated JG cells: an inhibitory effect mediated by stimulation of soluble guanylate cyclase activity and a stimulatory effect mediated by an as yet unknown pathway that requires extracellular calcium.
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PMID:Liberators of NO exert a dual effect on renin secretion from isolated mouse renal juxtaglomerular cells. 839 40

Hamsters with cardiomyopathy (CMO), an experimental model of congestive heart failure, display stimulated renin-angiotensin-aldosterone and enhanced sympathetic nervous activity, all factors that lead to sodium retention, volume expansion and subsequent elevation of plasma atrial natriuretic factor (ANF) by the cardiac atria. However, sodium and water retention persist in CMO, indicating hyporesponsiveness to endogenous ANF. These studies were undertaken to fully characterize renal ANF receptor subtypes in normal hamsters and to evaluate whether alterations in renal ANF receptors may contribute to renal resistance to ANF in cardiomyopathy. Transcripts of the guanylyl cyclase-A (GC-A) and guanylyl cyclase B (GC-B) receptors were detected by quantitative polymerase chain reaction (PCR) in renal cortex, and outer and inner medullas. Compared to normal controls, the cardiomyopathic hamster's GC-A mRNA was similar in cortex but significantly increased in outer and inner medulla. Levels of GC-B mRNA were not altered by the disease. On the other hand, competitive binding studies, autoradiography, and affinity cross-linking demonstrated the absence of functional GC-B receptors in the kidney glomeruli and inner medulla. Also, C-type natriuretic peptide (CNP), the natural ligand for the GC-B receptors, failed to stimulate glomerular production of its second messenger cGMP. In CMO, sodium and water excretion were significantly reduced despite elevated plasma ANF (50.5 +/- 11.1 vs. 309.4 +/- 32.6 pg/ml, P < 0.001). Competitive binding studies of renal glomerular ANF receptors revealed no change in total receptor density, Bmax (369.6 +/- 27.4 vs. 282.8 +/- 26.2 fmol/mg protein), nor in dissociation constant, Kd (647.4 +/- 79.4 vs. 648.5 +/- 22.9 pM). Also, ANF-C receptor density (254.3 +/- 24.8 vs. 233.8 +/- 23.5 fmol/mg protein), nor affinity were affected by heart failure. Inner medullary receptors were exclusively of the GC-A subtype with Bmax (153.2 +/- 26.4 vs. 134.5 +/- 21.2 fmol/mg protein) and Kd (395.7 +/- 148.0 vs. 285.8 +/- 45.0 pM) not altered by cardiomyopathy. The increase in ANF-stimulated glomerular cGMP production was similar in normal and CMO hamsters (94- vs. 75-fold). These results demonstrate that renal ANF receptors do not contribute to the attenuated renal responses to ANF in hamster cardiomyopathy.
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PMID:Renal atrial natriuretic factor receptors in hamster cardiomyopathy. 858 47

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

We have recently reported in normal isolated-perfused rat lungs that low basal tone appears to be regulated by nitric oxide (NO)-dependent and -independent mechanisms of soluble guanylate cyclase activation. In this study, we examined the role of NO in the regulation of pulmonary artery (PA) tone from rats with renin-dependent hypertension. Rats were made hypertensive by ligating the abdominal aorta above the left and below the right renal artery (aortic coarctation, AC). Mean arterial pressure significantly increased from 119 +/- 8.4 mmHg in control animals to 156 +/- 15 mmHg 7-14 days after AC surgery. PA pressures, however, remained unchanged (8.5 +/- 3.4 mmHg in control animals vs. 11 +/- 3.3 mmHg in AC animals). Hypoxic contractions in U-46619 precontracted isolated small PA (160-260 microns diameter) were significantly increased from 51 +/- 13 mg in the control group to 142 +/- 38 mg (P < or = 0.05) in AC animals. Nitro-L-arginine (NLA; 100 microM) contractions were also enhanced in the AC animal. The enhanced NLA response may correlate with an increase in endothelial cell NO synthase (NOS) as detected by Western blotting (132 +/- 28% of control; P < 0.05). These data suggest that, in this renin-dependent model of systemic hypertension, there is increased endothelial cell NOS activity that maintains low PA tone, preventing the lung from developing increased pressures.
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PMID:Peripheral hypertension and alterations in pulmonary vascular regulation. 925 47

This study aimed to characterize the cellular pathways along which nitric oxide (NO) stimulates renin secretion from the kidney. Using the isolated perfused rat kidney model we found that renin secretion stimulated 4- to 8-fold by low perfusion pressure (40 mmHg), by macula densa inhibition (100 micromol/liter of bumetanide), and by adenylate cyclase activation (3 nmol/liter of isoproterenol) was markedly attenuated by the NO synthase inhibitor nitro-L-arginine methyl ester (L-Name) (1 mM) and that the inhibition by L-Name was compensated by the NO-donor sodium nitroprusside (SNP) (10 micromol/liter). Similarly, inhibition of cAMP degradation by blockade of phosphodiesterase 1 (PDE-1) (20 micromol/liter of 8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine) or of PDE-4 (20 micromol/liter of rolipram) caused a 3- to 4-fold stimulation of renin secretion that was attenuated by L-Name and that was even overcompensated by sodium nitroprusside. Inhibition of PDE-3 by 20 micromol/liter of milrinone or by 200 nmol/liter of trequinsin caused a 5- to 6-fold stimulation of renin secretion that was slightly enhanced by NO synthase inhibition and moderately attenuated by NO donation. Because PDE-3 is a cGMP-inhibited cAMP-PDE the role of endogenous cGMP for the effects of NO was examined by the use of the specific guanylate cyclase inhibitor 1-H-(1,2,4)oxodiazolo(4,3a)quinoxalin-1-one (20 micromol). In the presence of 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-1-one the effect of NO on renin secretion was abolished, whereas PDE-3 inhibitors exerted their normal effects. These findings suggest that PDE-3 plays a major role for the cAMP control of renin secretion. Our findings are compatible with the idea that the stimulatory effects of endogenous and exogenous NO on renin secretion are mediated by a cGMP-induced inhibition of cAMP degradation.
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PMID:Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3. 953 9


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