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)

Exogenous nitric oxide (NO) has been shown to modulate the contractile force of rat cardiac myocytes. We sought to determine whether endogenous NO-production in the isolated normal rat heart has an effect on myocardial contractility. Hearts of male Wistar rats were investigated using a constant flow perfused non-paced Langendorff preparation. Changes of contractile parameters such as left ventricular peak pressure, dP/dtmax and dP/dtmin, and of coronary perfusion pressure and heart rate were recorded after infusion of the NO-synthase inhibitors N(omega)-nitro-L-arginine (L-NOARG, 0.1 mM, 1.0 mM, n = 6), N(omega)-methyl-L-arginine (L-NMMA, 0.1 mM, 1.0 mM, n = 9) and methylene blue (2 microM, 20 microM, n = 6), the NO-donor sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolat (DEA/NO, 0.01 microM, 0.1 microM, n = 12), the specific inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.1 microM, n = 7) and L-arginine (0.1 mM, 1.0 mM, n = 6). All NO-synthase inhibitors reduced the contractile function of the ventricular muscle before changes in coronary perfusion pressure were evident. The negative inotropic effect of L-NMMA was absent in the presence of an equimolar concentration of L-arginine. ODQ reduced contractile force and coronary perfusion pressure in parallel. By contrast, L-arginine and DEA/NO improved the contractile force of the left ventricle and DEA/NO decreased coronary perfusion pressure. Heart rate was reduced by L-NOARG (1 mM) and methylene blue (20 microM), while DEA/NO (0.1 microM) and L-arginine (1 mM) had a positive chronotropic effect. All these changes were significant (P < 0.05). These results suggest that endogenous NO-production exerts a positive effect on myocardial contraction that is mediated by activation of guanylate cyclase. In addition, NO might be involved in regulation of heart rate.
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PMID:Inhibition of nitric oxide synthase and soluble guanylate cyclase induces cardiodepressive effects in normal rat hearts. 936 47

We tested the hypothesis that increased O2 consumption and inotropy after reduction of myocardial cyclic guanosine monophosphate (cGMP) are mediated through L-type calcium channels. Anesthetized, open-chest New Zealand white rabbits were divided into four groups. Hearts were exposed to control vehicle (n = 8); LY83583 (LY, 10(-3) mol/l, guanylate cyclase inhibitor, (n = 9); nifedipine (nif, 10(-4) mol/l, L-type calcium channel blocker, n = 8), or nif+LY (n = 6). Vehicle or compound was applied topically to the epicardium for 15 min. Subepicardial (EPI) blood flow increased (from 213 +/- 22 to 323 +/- 24 ml/ min/100 g) in the presence of LY, as did subendocardial (ENDO) blood flow (from 238 +/- 20 to 333 +/- 38 ml/min/ 100 g). O2 consumption increased in the presence of LY:18.0 +/- 1.0 (EPI) and 17.0 +/- 0.6 (ENDO) ml O2/min/100 g as compared with 9.5 +/- 2.0 (EPI) and 10.6 +/- 2.5 (ENDO) in the control group. The increase in O2 consumption with LY was undiminished in the presence of nif (nif+LY group 21.0 +/- 3.0 ml O2/min/100 g EPI and 22.1 +/- 3.8 ENDO). Nif alone decreased left ventricular dP/dtmax from (2,762 +/- 197 to 2,413 +/- 316 mm Hg/s) and maximal rate of change in wall thickness (dW/dtmax from 13.5 +/- 2.0 to 9.5 +/- 0.8 mm/s), while percent change of wall thickness (from 21.3 +/- 3.3 to 31.3 +/- 7.2) and dW/dtmax (from 13.3 +/- 3.0 to 15.3 +/- 2.3 mm/s) increased in the nif+LY group. Thus, the positive O2 consumption and inotropic effects of decreasing cGMP were undiminished by nif. These results suggest that the cGMP reduction induced increases in O2 consumption and that inotropy may not be mediated through L-type calcium channels.
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PMID:Increased O2 consumption and positive inotropy caused by cyclic GMP reduction are not altered after L-type calcium channel blockade. 946 86

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

We have used a combination of biochemical and pharmacological techniques to investigate the role of the cyclic nucleotides, 3', 5'-cyclic adenosine monophosphate (cyclic AMP) and 3',5'-cyclic guanosine monophosphate (cyclic GMP), in mediating the cardioregulatory effects of FMRFamide and other neuropeptides encoded on exon II of the FMRFamide gene of Lymnaea stagnalis. The 'isoleucine' peptides (EFLRIamide and pQFYRIamide) produced complex biphasic effects on the frequency, force of contraction and tonus of the isolated heart of L. stagnalis, which were dependent on adenylate cyclase (AC) activity of the heart tissue. At a control rate of cyclic AMP production of less than or equal to 10 pmoles min(-)(1 )mg(-)(1) protein, the 'isoleucine' peptides produced a significant increase in AC activity in heart membrane preparations. This suggested that the enhanced AC activity is responsible for the stimulatory effects of the 'isoleucine' peptides on frequency and force of contraction of heart beat. This excitation sometimes followed an initial 'inhibitory phase' where the frequency of beat, force of contraction and tonus of the heart were reduced by the 'isoleucine' peptides. Hearts that showed the inhibitory phase of the 'isoleucine' response, but characteristically lacked the delayed excitatory phase, were found to have high levels of membrane AC activity (breve)10 pmoles min(-)(1 )mg(-)(1) protein in controls. Application of the 'isoleucine' peptides to membrane homogenate preparation from these hearts failed to increase AC activity. The addition of FMRFamide produced significant increases in the rate of cyclic AMP production in the heart membrane preparations, which could account, at least in part, for the cardioexcitatory effects of this peptide in the isolated whole heart. A membrane-permeable cyclic AMP analogue (8-bromo-cyclic AMP) and an AC activator (forskolin) were also cardioexcitatory. The peptide SEEPLY had no effects on the beat properties of the isolated heart and did not alter AC activity. The activity of the membrane-bound (particulate) guanylate cyclase (GC) was not significantly affected by any of the peptides.
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PMID:Cyclic AMP is involved in cardioregulation by multiple neuropeptides encoded on the FMRFamide gene. 1048 19

The purpose of this study was to examine the role of the nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) system in the regulation of the ductus arteriosus (DA) patency in fetal rats. Pregnant rats were administered N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, ip), an NO synthase (NOS) inhibitor; methylene blue (30, 50 and 100 mg/kg, ip), a soluble guanylate cyclase inhibitor; or indomethacin (3 mg/kg, po), a cyclooxygenase inhibitor, at various times before cesarean section. Dams were decapitated to obtain the fetuses by cesarean section, and fetuses were rapidly frozen in an acetone-dry ice mixture. Using rapid freezing and shaving methods, the calibers of the DA, pulmonary artery (PA) and descending aorta (Ao) were measured to evaluate the effects of treatment. L-NAME reduced the DA calibers to 86% of the initial values, but recovery to the control levels occurred 6 hr after the injection. Indomethacin decreased the DA calibers to 34% of the control values and sustained the DA constriction until 24 hr after the treatment. Methylene blue caused DA constriction to almost the same degree as indomethacin, but the levels normalized within 24 hr after the treatment. We conclude that L-NAME caused a slight constriction of the DA, whereas methylene blue and indomethacin caused marked constriction of the vessels, suggesting that the NO-cGMP system as well as prostaglandins contribute to the DA patency.
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PMID:Role of the nitric oxide-cGMP system in the regulation of ductus arteriosus patency in fetal rats. 1065 Oct 46

1. The effects of endotoxaemia on coronary vasodilator responses to bradykinin (BK), sodium nitroprusside (SNP) and nicardipine were investigated in the rat isolated heart perfused at constant flow ex vivo. 2. Dose-dependent reductions in coronary perfusion pressure reaching a maximum of 56+/-3 and 57+/-5 mmHg were observed for BK and SNP respectively. The BK response was biphasic, consisting of a rapid dilator response that was insensitive to N(G)nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and a second slower component whose duration was attenuated by L-NAME. 3. Hearts obtained from rats treated with endotoxin (2.5 mg kg(-1), i.p.) for 2 or 6 h had increased basal coronary perfusion pressure and reduced vasodilator responses to BK or SNP. Dilator responses to nicardipine were not affected by endotoxin treatment. In vitro perfusion of hearts from endotoxin-treated rats with L-NAME (0.1 mM) restored SNP responses to control values. 4. Treatment with dexamethasone (1 mg kg(-1)), 1 h before endotoxin did not alter the endotoxin-induced impairment of dilator responses to BK or SNP. 5. These results show that coronary microvascular responses are altered following endotoxin exposure. Endotoxin results in increased coronary microvascular tone despite induction of NO synthase and inhibits the dilator response to BK and SNP, vasodilators that act via the release of NO. Responses to SNP in endotoxin-treated hearts were restored to control values in the presence of L-NAME suggesting that enhanced endogenous NO synthesis might saturate guanylate cyclase resulting in reduced response to NO donors. The reduced response to vasodilators and increased coronary resistance might be important in determining the response of the coronary circulation to systemic inflammation and infection.
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PMID:Impaired vascular sensitivity to nitric oxide in the coronary microvasculature after endotoxaemia. 1078 Oct 6

Peroxynitrite (ONOO(-)) formation during acute reperfusion of the ischemic heart contributes to the poor recovery of mechanical function. As glutathione (GSH) detoxifies ONOO(-), we studied whether it could protect isolated rat hearts subjected to exogenous ONOO(-)or to ischemia-reperfusion. We showed that GSH (300 microm, n=5) abolished the detrimental effect of ONOO(-)(80 microm, n=5) on mechanical function of aerobically perfused hearts. Hearts were subjected to 25 min aerobic perfusion, 20 min global, no-flow ischemia and 30 min reperfusion. GSH (3-300 microm, n=7-12) or saline vehicle (control, n=22) were infused for 10 min prior to ischemia and throughout reperfusion. During reperfusion, GSH caused a concentration-dependent improvement in the recovery of mechanical function, which was not associated with significant changes in the intracellular concentration of GSH. The concentration of dityrosine (a marker of ONOO(-) formation) in the coronary effluent during reperfusion was significantly reduced in GSH-treated hearts. The concentration of myocardial cGMP was significantly elevated by GSH during ischemia and early reperfusion. GSH improves the recovery of myocardial mechanical function after ischemia-reperfusion, an effect which may be related to the detoxification of ONOO(-)by GSH and the stimulation of soluble guanylate cyclase.
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PMID:Glutathione protects against myocardial ischemia-reperfusion injury by detoxifying peroxynitrite. 1096 29

The role of NO in the classic ischemic preconditioning phenomenon of the myocardium is not well defined, and was investigated by using the isolated perfused rat heart as a model. Hearts were preconditioned with 3 x 5 minute ischemia in the presence and absence of the NOS inhibitors L-NAME (50 microM) and L-NNA (50 microM), and the guanylyl cyclase inhibitor ODQ (20 microM). These inhibitors significantly attenuated the protective effect of preconditioning against 25-min global ischemia (as measured by functional recovery), specifically if administered during the triggering phase. Cyclic infusions (3 x 5 min) of the NO-donors SNAP (50 microM) and SNP (100 microM) elicited protection against both 25-min global or low-flow ischemia. Hearts preconditioned with NO donors displayed significantly superior functional reserve, if stimulated with adrenaline, compared to hearts preconditioned with ischemia. Although the NO donors SNAP and SNP both activated p38 MAPK during the preconditioning protocol, protection was accompanied by significantly decreased p38 MAPK activity during sustained ischemia, as was the case in ischemic preconditioning. We conclude that (1) NO is a trigger for classic preconditioning, (2) cGMP generation plays an important role in its protection, (3) attenuation of p38 MAPK during sustained ischemia accompanies NO preconditioning and may mediate cardiac protection, and (4) preconditioning with NO may be more advantageous than using ischemia.
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PMID:Nitric oxide triggers classic ischemic preconditioning. 1207 91

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.
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PMID:Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. 1535 Aug 50

Endothelial dysfunction underlies cardiovascular disease (CVD) in humans and is reported in animal models of developmental origins of such disease. We have investigated whether impaired antioxidant defences and NO generation underlie the genesis of endothelial dysfunction and operate as part of the normal processes of developmental plasticity regulating the induction of phenotype in the offspring. Female Wistar rats were fed either a control (C, 18% protein) or protein-restricted (PR, 9% protein) diet throughout pregnancy. Dams and pups were returned to standard laboratory chow post partum. In male offspring, PR resulted in a reduced endothelial responsiveness to acetylcholine (P < 0.05) in resistance arteries, with vascular remodelling evident from a reduction in smooth muscle content. mRNA expression of endothelial NO synthase (eNOS) was increased (P < 0.05) but there was no change in mRNA levels of manganese superoxide dismutase (MnSOD) or glutamate cysteine ligase (GCL) expression. Interestingly, expression of the antioxidant enzyme haem oxygenase-1 (HO-1) was reduced in the liver (P < 0.05). Female PR offspring also showed a reduced endothelial responsiveness but exhibited no changes in expression of eNOS, iNOS, soluble guanylate cyclase (sGC) or antioxidant genes. Thus, in this model of the developmental origins of CVD, the structure and function of resistance arteries in offspring is altered in complex ways which cannot simply be explained by attenuation in vascular eNOS or in antioxidant protection afforded by GCL or MnSOD. The dysfunction in male offspring may partially be counteracted by an up-regulation of eNOS expression; however, PR does lead to reduced HO-1 expression in these offspring, which may affect both their growth and vascular function. Our findings have established that PR induces significant phenotypic changes in male offspring that may be indicative of an adaptive response during development.
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PMID:Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease. 1882 46


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