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. Relaxant responses to nitroprusside were examined on U46619-contracted pulmonary artery ring preparations from rats exposed to hypoxia, in chambers containing 10% oxygen, for 1, 3, or 14 days, or for 14 days followed by 12 days in room air. Control rats were housed in room air. 2. After 3 days of hypoxia (but not 1 day), rats had elevated pulmonary artery pressure, right ventricular hypertrophy and polycythemia. After 14 days of hypoxia there was, in addition, hypertrophy of the pulmonary artery. In rats returned to room air for 12 days after 14 days of hypoxia, there was still some right ventricular and vascular hypertrophy but no increase in pulmonary artery pressure or polycythemia. 3. The potency (neg log EC50) of nitroprusside on pulmonary arteries taken from rats after 3 or 14 days of hypoxia was significantly less than on preparations from control rats (3 and 11 fold, respectively). This was not seen after 1 day of hypoxia or after 14 days of hypoxia followed by 12 days in room air. Removal of the endothelium from the preparations had no effect on the potency of nitroprusside in control or hypoxic rats (14 days). 4. In preparations from hypoxic, but not control, rats (14 days), the maximum response to nitroprusside was > 100% (177% reversal of the U46619 contraction) in the absence, but not in the presence, of the endothelium, indicating that pulmonary arteries from hypoxic rats had inherent tone which could be counteracted by a relaxing factor from the endothelium. 5. Exposure of rats to hypoxia (14 days) did not affect the potency of nitroprusside on aorta or trachea.6. It is concluded that exposure of rats to hypoxia results in reversible desensitization of the vascular smooth muscle of pulmonary artery to nitroprusside. The time course of this desensitization suggests that it is probably associated with the elevated pulmonary artery pressure or maintained hypoxaemia rather than with the vascular hypertrophy.7. It is postulated that the increase in pulmonary artery pressure and/or the maintained hypoxaemia may cause chronic release of nitric oxide from the pulmonary vascular endothelium or smooth muscle resulting in desensitization of soluble guanylate cyclase to the action of nitroprusside.
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PMID:Reduced relaxant potency of nitroprusside on pulmonary artery preparations taken from rats during the development of hypoxic pulmonary hypertension. 142 89

Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 microgram/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 +/- 0.04 to 0.28 +/- 0.04 mM [EC50]) and maximal activity (10.1 +/- 2.9 to 25.5 +/- 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 +/- 0.12 to 1.48 +/- 0.19 pmol/gram) and a greater increase in the LVH group (1.78 +/- 0.16 to 3.58 +/- 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 +/- 290 to 855 +/- 211 grams x mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase.
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PMID:Increased guanylate cyclase activity is associated with an increase in cyclic guanosine 3',5'-monophosphate in left ventricular hypertrophy. 869 76

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

This study was designed to test whether increased inotropy caused by raising intracellular cAMP would add to the positive inotropy caused by reducing cGMP and whether this relationship was affected by experimental hypertrophy. We used open chest anesthetized dogs with left ventricular hypertrophy (LVH) induced by valvular aortic stenosis and age matched controls (CON). Hearts were instrumented to measure local segment shortening, force, and regional work. Milrinone (MIL), a selective cyclic AMP-phosphodiesterase inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, were used to alter cAMP and cGMP levels. Ten CON and 11 LVH animals were randomly assigned to receive first either MIL (1 microg/kg/min) or MB (2 mg/kg/min) intracoronary (i.c.) infusion. After 10 min, simultaneous i.c. infusion of the other agent was begun. MIL increased regional minute work (g x mm/min) in both CON (1311 +/- 207 to 2072 +/- 285) and LVH (1052 +/- 136 to 1371 +/- 351) hearts. MB did not increase work significantly, but did increase contractile force. MIL + MB increased work from baseline; however, the combination did not increase work more than either agent alone (1961 +/- 510 CON; 1390 +/- 285 LVH). Myocardial cAMP levels (pmol/g) were significantly increased by MIL in both CON (329 +/- 53 to 437 +/- 13) and LVH hearts (351 +/- 67 to 538 +/- 32), and the addition of MB further raised cAMP (879 +/- 115 CON; 741 +/- 96 LVH). MB resulted in decreased myocardial cGMP (pmol/g) (3.20 +/- 0.61 to 2.16 +/- 0.92 CON; 5.21 +/- 1.15 to 2.46 +/- 0.56 LVH), while MIL increased cGMP (3.20 +/- 0.61 to 6.24 +/- 1.79 CON; 5.21 +/- 1.15 to 6.53 +/- 0.41 LVH). Both MIL and MB caused increases in O2 consumption, with MIL + MB together increasing O2 consumption further. The current findings demonstrate a potentiation of cAMP production in the presence of MIL + MB above either agent alone, but this did not lead to potentiation of positive functional effects. High levels of cGMP caused by milrinone may have limited the positive functional effects of cAMP.
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PMID:Positive functional effects of milrinone and methylene blue are not additive in control and hypertrophic canine hearts. 969 27

Cardiac growth and contractility is profoundly altered in response to various hormones and neurotransmitters as well as by changes in electrolyte balance, blood volume, and blood pressure. In turn, the endocrine heart contributes to body homeostasis by secreting a number of biologically active peptide hormones that act on several target tissues. Atrial natriuretic peptide (ANP) and B-type natiuretic peptide (BNP) are the major secretory products of the endocrine myocardium. These peptide hormones act on many target organs via guanylate cyclase-linked membrane receptors to produce natriuresis, diuresis, vasodilatation, and hypotension. ANP and BNP receptors are found on most organs involved in cardiovascular homeostasis (e.g., kidney, adrenal, vasculature, brain). They are also present in gonads and in pituitary, where they alter steroidogenesis and pituitary hormone secretion. Not surprisingly, changes in blood pressure, volume, or hormone status influence ANP and BNP expression, which is also altered in almost all diseases that affect cardiac function. Thus, studies of ANP and BNP gene expression are relevant for many clinical settings. Moreover, transcription of the ANP and BNP genes characterizes cardiac cells at very early stages of development and is tightly linked to cardiac growth--be it proliferation, as in the fetal heart, or trophic growth, as in postnatal ventricular hypertrophy. Thus, analysis of the molecular circuitry that controls ANP and BNP expression might shed important insight into the complex regulatory pathways that underlie normal and pathologic heart development. Indeed, over the past few years, we have analysed transcriptional control of the ANP and BNP genes in embryonic and postnatal cardiomyocytes and in cardiomyocytes treated with hormones and neurotransmitters that cause cardiomyocyte hypertrophy. These studies have lead to the identification of distinct cis-acting DNA elements that modulate basal and hormone-stimulated transcription. Most importantly, the work also resulted in the isolation and characterization of cardiac-specific transcription factors that play critical roles for cardiac cell differentiation and survival.
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PMID:Regulation of gene expression in the endocrine heart. 976

The aim of the current study was to determine if lowering myocardial cyclic GMP by guanylate cyclase inhibition would add independently to the positive inotropic effects caused by raising cyclic AMP and if these effects are modified in left ventricular hypertrophy (LVH) produced by aortic valve plication. Isoproterenol (ISO) (0.1 mg x kg(-1) x min(-1)) was infused into a branch of the left anterior descending coronary artery of seven control and eight hypertrophy open-chest anesthetized dogs. After 10 min, simultaneous infusion of methylene blue (MB) (2 mg x kg(-1) x min(-1)) was initiated at the same site. Hypertrophy increased heart weight and heart weight/body weight ratio. While both drugs increased left ventricular dP/dt(max), no additional global effects were observed in either group. Changes in regional variables followed the same pattern in both groups, i.e., ISO produced an increase that was enhanced by the addition of MB. ISO increased segment shortening, with a significant change in the control group. ISO increased regional force in both groups. The addition of MB increased force above ISO levels, with a significant change in the LVH group. ISO increased regional minute work (g x mm x min(-1)) (control, 1779 +/- 428 to 2541 +/- 500; LVH, 1157 +/- 253 to 1839 +/- 404) and O2 consumption. MB further increased regional work (control, 2993 +/- 952; LVH, 2416 +/- 853) and O2 consumption. ISO raised cyclic AMP (pmoles x g(-1)) (control, 468 +/- 41 to 580 +/- 84; LVH, 445 +/- 43 to 562 +/- 71) and had no effect on cyclic GMP (pmoles x g(-1)) (control, baseline 3.27 +/- 0.22, ISO 2.87 +/- 0.23; LVH, baseline 6.84 +/- 1.12, ISO 5.66 +/- 0.54). The addition of MB lowered cyclic GMP (control, 2.41 +/- 0.26; LVH, 3.68 +/- 0.35), but also increased cyclic AMP (control, 1021 +/- 121; LVH, 1107 +/- 134). Similar results were observed in control hearts using a specific soluble guanylate cyclase inhibitor (ODQ) in terms of changes in local work, O2 consumption, and cyclic nucleotides. Thus, at least part of the positive inotropic response to lowering cyclic GMP was mediated by changes in cyclic AMP in the current model. This was true in both control and LVH animals, although baseline cyclic GMP levels were higher, and a larger reduction in cyclic GMP was observed with MB in the LVH group.
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PMID:Positive inotropy due to lowering cyclic GMP is also mediated by increases in cyclic AMP in control and hypertrophic hearts. 992 98

1. We hypothesized that acetylcholine would attenuate the metabolic effect of increasing cAMP and decreasing cGMP on cardiac myocyte O2 consumption (VO2) in dog, and this effect would be altered in left ventricular hypertrophy (LVH) produced by aortic valve placation. 2. Steady-state VO2 of a suspension of ventricular myocytes from control (n = 7) and LVH (n = 6) dogs was measured by Clark O2 electrodes during electrical stimulation (5 ms, 1 Hz, in 2 mm Ca2+). Cyclic AMP and cyclic GMP were determined by radioimmunoassay. Cellular cAMP was increased by forskolin (adenylate cyclase stimulator) and cGMP was decreased by LY83583 (guanylate cyclase inhibitor) both at 10(-7,-6,-5,-4) M with and without 10(-6) M acetylcholine. 3. Baseline cGMP level in LVH (62 +/- 10 fmol 10(-5) myocytes) was significantly greater than that in control (20 +/- 3), although the myocyte VO2 (356 +/- 39 nL O2 min(-1) 10(-5) myocytes) and cAMP levels (3.9 +/- 0.6 nmol 10(5-1) myocytes) were similar to control (312 +/- 23 and 6.9 +/- 3.1). 4. Forskolin increased myocyte cAMP in both control and LVH myocytes and increased VO2 by 51 +/- 13 in control and 91 +/- 65 in LVH myocytes. LY83583 decreased myocyte cGMP levels in control and LVH myocytes and increased VO2 by 128 +/- 57 in control and 43 +/- 26 in LVH myocytes. 5. Acetylcholine altered the cAMP, cGMP, and VO2 levels in control to 2.4 +/- 0.4, 30 +/- 3 and 213 +/- 27 and LVH to 2.5 +/- 0.3, 85 +/- 9 and 261 +/- 32. Acetylcholine attenuated the maximal effects of forskolin on VO2 to 32 +/- 27 in control and 66 +/- 56 in LVH myocytes. Acetylcholine also decreased the maximal effects of LY83583 to 82 +/- 50 in control and 19 +/- 19 in LVH myocytes. 6. The positive metabolic effects of both increases in myocyte cAMP and decreases in cGMP were blunted by acetylcholine. There was a significant increase in myocyte cGMP with forskolin in LVH myocytes. Acetylcholine decreased the increased myocyte VO2 caused by elevated cAMP or decreased cGMP in both control and LVH myocytes, although the absolute decrease in cAMP was reduced and the absolute values of cGMP were higher in LVH myocytes.
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PMID:Altered effects of acetylcholine on cyclic AMP and GMP induced changes in O2 consumption of hypertrophic dog cardiac myocytes. 1038 66

Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium are suggested to be involved in regulating myocardial contractility. However, the characteristics and modulation of NPRs in relation to cardiac failure are not well defined. This study examined the properties of NPRs in ventricular endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were localized in right (RV) and left ventricular (LV) endocardium. Binding affinities of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by Southern blot analysis. Production of cGMP by particulate GC in endocardial cell membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22) >> brain NP (BNP)(1-26) > ANP(1-28). We also examined the modulation of these NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to hypertrophied RV endocardium almost disappeared and cGMP production by NPs was significantly decreased. In rats with pulmonary hypertension, plasma levels of ANP and BNP were increased by fivefold compared with controls. The results indicate that there is a differential distribution of NPRs in the cardiac chambers, with the most abundant binding sites in RV endocardium, that NPR-B is the predominant GC-coupled NPR in ventricular endocardium, and that endocardial NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may be associated with an increment of endogenous NP production caused by mechanical overload in hypertrophied ventricle.
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PMID:Modulation of endocardial natriuretic peptide receptors in right ventricular hypertrophy. 1060 Aug 47

The nitric oxide-cyclic guanosine monophosphate signal-transduction mechanism plays a key role in the regulation of vascular tone and structure. Monocrotaline-induced pulmonary hypertension is associated with low bioavailability of nitric oxide. To characterize the mechanism(s) involved in this dysfunction, rats received a single subcutaneous injection of monocrotaline, normal saline (control), or monocrotaline plus daily L-arginine, a precursor of nitric oxide, in drinking water. Pulmonary artery pressure and right ventricular hypertrophy were assessed 2 weeks later. In addition, the authors evaluated the expression of endothelial nitric oxide synthase messenger RNA, endothelial nitric oxide synthase protein, cyclic guanosine monophosphate, and sulfhydryl levels in the lungs. Sulfhydryls are needed for the dynamic modulation of soluble guanylate cyclase by nitric oxide, which results in cyclic guanosine monophosphate formation. L-arginine treatment did not attenuate monocrotaline-induced pulmonary hypertension or right ventricular hypertrophy. Monocrotaline did not alter the expression of endothelial nitric oxide synthase messenger RNA or endothelial nitric oxide synthase protein in the lungs. Protein-bound sulfhydryls (28 +/- 5 vs. 75 +/- 16 pmol/microg protein) and cyclic guanosine monophosphate (0.63 +/- 0.05 vs. 1.06 +/- 0.017 pmol/microg protein) levels in the monocrotaline group were significantly low compared with controls. The low sulfhydryl levels, an indicator of oxidant stress, may account for the impaired availability of bioactive nitric oxide and low cyclic guanosine monophosphate levels. These results suggest that oxidative stress may, in part, contribute to the pathogenesis of pulmonary hypertension in the monocrotaline model.
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PMID:Effects of monocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs. 1202 99

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
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PMID:Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. 1240 81


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