Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP +/- SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 +/- 3; LS, 110 +/- 5). However, on HS diet -/- mice had significantly higher ABP (135 +/- 3; P < 0.001) than both -/- (115 +/- 2) and +/+ (110 +/- 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I.ml-1.h-1) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 +/- 1.9; LS, 21 +/- 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 +/- 2.9; LS, 19 +/- 3.7). Independent of genotype, concentration of endothelin-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 micrograms protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 +/- 4.7 and +/+, 32 +/- 4.1; ecNOS -/-, 160 +/- 19 and +/+, 156 +/- 19) compared with mice fed on LS diet (ET-1 -/-, 19 +/- 1.9 and +/+, 21 +/- 1.8; ecNOS -/-, 109 +/- 13 and +/+, 112 +/- 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting the pressor effect of salt.
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PMID:Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity. 945 26

This study was performed in the opossum lower esophageal sphincter (LES) smooth muscle strips to determine the action of the heme oxygenase inhibitor zinc protoporphyrin IX (ZnPP IX) on the relaxant effect of vasoactive intestinal polypeptide and isoproterenol, which are known to stimulate adenylate cyclase (AC) via G protein coupling, and of the direct activator of AC catalytic subunit forskolin. To investigate the cGMP pathway, we examined the effect of atrial natriuretic factor known to activate the receptor linked to the particulate guanylate cyclase via G protein coupling and that of sodium nitroprusside [nitric oxide (NO) donor], authentic NO and carbon monoxide, which stimulate the intracellular soluble fraction of GC. The smooth muscle relaxation caused by nonadrenergic noncholinergic (NANC) nerve stimulation also was investigated. ZnPP IX caused concentration-dependent attenuation of the relaxant effect of vasoactive intestinal polypeptide, isoproterenol and atrial natriuretic factor without any effect on that of forskolin, sodium nitroprusside, NO and CO. Interestingly, ZnPP IX had no significant effect on the LES relaxation caused by NANC nerve stimulation and the smooth muscle contraction by bethanechol. From these results, we conclude that ZnPP IX attenuates the LES smooth muscle relaxation caused by the stimulation of G protein-coupled receptors to particulate AC and guanylate cyclase. The lack of effect of ZnPP IX on the NANC nerve-mediated LES relaxation suggests either lack of a role of heme oxygenase pathway in the response or an upregulation of NOS leading to normal LES relaxation.
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PMID:Inhibitory effect of zinc protoporphyrin IX on lower esophageal sphincter smooth muscle relaxation by vasoactive intestinal polypeptide and other receptor agonists. 958 May 85

Atrial natriuretic peptide (ANP) exerts a chronic hypotensive effect due to a decrease in total peripheral resistance (TPR). This study examines if chronic ANP-dependent vasodilation is attributable to differences in the cardiovascular regulatory activity of vascular endothelium (VE), based on evidence that ANP affects synthesis/release and target cardiovascular effects of endothelin-1 (ET-1), C-type natriuretic peptide (CNP), and nitric oxide (NO). To determine if the synthetic activity of resistance vasculature VE is chronically altered by plasma ANP activity, we measured ET-1, CNP, and endothelial constitutive NO synthase (ecNOS) concentration and total NOS enzyme activity in homogenates of kidney, heart, lung, hindquarter skeletal muscle, and brain from hypotensive transgenic mice with elevated plasma ANP, hypertensive knockout mice (-/-) characterized by the absence of ANP, and the corresponding normotensive wild-type (NT, +/+) mice. Tissue distribution and abundance patterns of ET-1, CNP, ecNOS, and NOS enzyme activity were comparable between the different genotypes and did not differ significantly between mutant and control mice. Antagonism of ETA/B receptors in -/- and +/+ mice in vivo with SB-209670 reduced arterial blood pressure (ABP) significantly and comparably in both genotypes (-27 +/- 4 and -25 +/- 2% change for -/- and +/+ mice, respectively) independent of any significant changes in heart rate (HR) (-6 +/- 8 and -4 +/- 4% change for -/- and +/+ mice, respectively). Immunoneutralization of CNP-specific guanylate cyclase-linked receptors (GC-B) with monoclonal antibodies (3G12) increased ABP slightly, but not significantly, by similar relative amounts in both -/- (10 +/- 6% change) and +/+ mice (8 +/- 3% change), without changing HR significantly (4 +/- 1% change for both +/+ and -/- mice). Inhibition of NOS activity (by NG-nitro-L-arginine methyl ester) significantly increased ABP, but the changes were comparable between -/- (53 +/- 5% change) and +/+ mice (50 +/- 6% change) and occurred in the absence of significant changes in HR (-1 +/- 5 and 7 +/- 5% change for -/- and +/+ mice, respectively). We conclude that the differences in ABP associated with chronic variations in endogenous ANP activity are not due to alterations in synthesis or responsiveness of the cardiovascular system to the effects of ET-1, CNP, or NO.
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PMID:Chronic regulation of arterial blood pressure by ANP: role of endogenous vasoactive endothelial factors. 981 91

To study the role of endothelial nitric oxide synthase (eNOS) in cardiac function, we compared eNOS expression, contractility, and relaxation in the left ventricles of wild-type and eNOS-deficient mice. eNOS immunostaining is localized to the macro- and microvascular endothelium throughout the myocardium in wild-type mice and is absent in eNOS-/- mice. Whereas blood pressure is elevated in eNOS-/- mice, baseline cardiac contractility (dP/dt(max)) is similar in wild-type and eNOS-/- mice (9,673 +/- 2, 447 and 9,928 +/- 1,566 mmHg/s, respectively). The beta-adrenergic agonist isoproterenol (Iso) at doses of >/=1 ng causes enhanced increases in dP/dt(max) in eNOS-/- mice compared with wild-type controls in vivo (P < 0.01) as well as in Langendorff isolated heart preparations (P < 0.02). beta-Adrenergic receptor binding (B(max)) is not significantly different in the two groups of animals (B(max) = 41.4 +/- 9.4 and 36.1 +/- 5.1 fmol/mg for wild-type and eNOS-/-). Iso-stimulated ventricular relaxation is also enhanced in the eNOS-/- mice, as measured by dP/dt(min) in the isolated heart. However, baseline ventricular relaxation is normal in eNOS-/- mice (tau = 5.2 +/- 1.0 and 5.6 +/- 1.5 ms for wild-type and eNOS-/-, respectively), whereas it is impaired in wild-type mice after NOS inhibition (tau = 8.3 +/- 2.4 ms). cGMP levels in the left ventricle are unaffected by eNOS gene deletion (wild-type: 3.1 +/- 0.8 pmol/mg, eNOS-/-: 3.1 +/- 0.6 pmol/mg), leading us to examine the level of another physiological regulator of cGMP. Atrial natriuretic peptide (ANP) expression is markedly upregulated in the eNOS-/- mice, and exogenous ANP restores ventricular relaxation in wild-type mice treated with NOS inhibitors. These results suggest that eNOS attenuates both inotropic and lusitropic responses to beta-adrenergic stimulation, and it also appears to regulate baseline ventricular relaxation in conjunction with ANP.
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PMID:Modulation of mouse cardiac function in vivo by eNOS and ANP. 1071 Mar 67

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca(2+)](i)) is still unknown. Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains. Measuring [Ca(2+)](i) by imaging analysis of fura-2-loaded cells, we demonstrated that alpha-thrombin (3-180 U l(-1)) induced a superimposable dose-dependent calcium transient in ECs from both strains. In WKY ECs, S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose-dependently (10 - 100 microM) and 0.1 microM atrial natriuretic factor (ANF) reduced the maximum and the decay time of alpha-thrombin-induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP-dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of alpha-thrombin-induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. In SHR ECs, alpha-thrombin-induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 9. 3 and 51 fold respectively. In WKY ECs, SNAP dose-dependently (10 - 100 microM) reduced also bradykinin-induced calcium transient, while in SHR ECs was ineffective. We concluded that in SHR ECs, the cyclic GMP-dependent regulation of calcium transient is lost.
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PMID:Lack of nitric oxide- and guanosine 3':5'-cyclic monophosphate-dependent regulation of alpha-thrombin-induced calcium transient in endothelial cells of spontaneously hypertensive rat hearts. 1092 46

We examined the effect of endotoxin lipopolysaccharide (LPS) on the basal tone and on the effects of different stimuli and agonists and transcriptional and translational expression of nitric oxide (NO) synthase (NOS) isozymes in the lower esophageal sphincter (LES), pyloric sphincter (PS), and internal anal sphincter (IAS). NO release was also examined before and after LPS. LPS caused a dose-dependent fall in the basal tone and augmentation of the relaxation caused by nonadrenergic, noncholinergic (NANC) nerve stimulation in the LES and IAS. In the PS, LPS had no significant effect on the basal tone and caused an attenuation of the NANC relaxation and an augmentation of the contractile response of muscarinic agonist. Interestingly, the smooth muscle relaxation by atrial natriuretic factor was suppressed in the LES and IAS but not in the PS. These changes in the sphincteric function following LPS may be associated with increase in the inducible NOS (iNOS) expression since they were blocked by iNOS inhibitor L-canavanine. Augmentation of NANC relaxation in the LES and IAS smooth muscle by LPS may be due to the increased activity of neuronal NOS and NO production.
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PMID:Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction. 1112 95

Cellular localization patterns of NOS isoforms 1 and 3 (nNOS and eNOS, respectively) in the mammalian heart under basal (non-stimulated) working conditions are still a matter of discussion. Therefore, this issue was reinvestigated in rats using RT-PCR, Western blotting, catalytic histochemistry, immunohistochemistry and image analysis. Tongue and extensor digitorum longus muscles served as positive controls for NOS-1 and NOS-3. RT-PCR revealed NOS-1 mRNA and NOS-3 mRNA in atria and ventricles. Western blotting showed NOS-1 protein in atria and NOS-3 protein in the walls of both heart chambers. Localization of the activity of urea-resistant (and therefore specific) NADPH diaphorase (NADPH-D) and NOS-1 immunohistochemistry showed that NOS-1 is present in the sarcolemma region of a subpopulation of atrial cardiomyocytes but not in working and impulse-conducting cardiomyocytes of atria and ventricles. Atrial natriuretic peptide (ANP) immunohistochemistry revealed that a minority of the NOS-1-expressing atrial cardiomyocytes are myoendocrine cells. eNOS immunostaining was present in endothelial cells of capillaries of the conducting and working myocardium and endocardial cells. Image analysis of the activity of urea-resistant NOS diaphorase showed that NOS-1 activity is lower in the sarcolemma region of atrial cardiomyocytes than in that of tongue and extensor digitorum longus myofibers. These data suggest that, in the non-stimulated rat heart. NOS-1 is expressed in a subpopulation of atrial cardiomyocytes including myoendocrine cells, and that NOS-3 is expressed in the vascular and endocardial endothelium.
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PMID:Localization of NOS-1 in the sarcolemma region of a subpopulation of atrial cardiomyocytes including myoendocrine cells and NOS-3 in vascular and endocardial endothelial cells of the rat heart. 1266 87

Recently, we have shown that nitric oxide synthase-1 (NOS-1) and thus its product NO are present in the sarcolemma region of a subpopulation of atrial cardiomyocytes in the rat heart. In order to find out whether this newly discovered sarcolemma-associated NOS/NO system represents a general signalling mechanism in the murine rodent heart and whether its properties are comparable to those in skeletal muscle fibres, immunohistochemical and catalytic histochemical methods (including image analysis) were applied to the heart and extensor digitorum longus (EDL) and tongue muscles of wild type and mutant mice. In different strains of wild type mice and NOS-3 knockouts, urea-resistant (and therefore specific) NOS NADPH diaphorase histochemistry and NOS-1 immunohistochemistry revealed that NOS-1 activity and protein were present in the sarcolemma region of a subpopulation of atrial and ventricular working cardiomyocytes, but not in those of the impulse conducting system. Using image analysis, NOS-1 showed similar activities in the sarcolemma region of cardiomyocytes and in EDL type I myofibres. In mdx and NOS-1 knockout mice, NOS-1 was absent from the sarcolemma region of atrial and ventricular cardiomyocytes and of EDL and tongue muscle fibres, whereas NOS-1 was present in the hearts of NOS-3 knockouts. Atrial natriuretic peptide immunohistochemistry identified part of the atrial NOS-1-expressing cardiomyocytes as myoendocrine cells. In mdx mice as well as in NOS-1 - and NOS-3-deficient animals, the peptide was found in greater abundance than in wild type mice. These data suggest that NOS-1 is expressed in a subpopulation of working cardiomyocytes in the murine rodent heart, that the myoendocrine cells may be negatively modulated by NOS-1 - and NOS-3-produced NO, and that the anchoring mechanisms for NOS-1 in these cells (i.e. their confinement to the sarcolemma region) are comparable to those in skeletal muscle fibres.
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PMID:The nitric oxide synthase-1 and nitric oxide synthase-3/nitric oxide signalling systems in the heart of wild type mice and mouse mutants. 1276 67

Atrial natriuretic peptide (ANP) is a hormone secreted in response to atrial or ventricular volume expansion and pressure overload, respectively. However, it has been found in studies with animals and patients an increase in ANP plasma concentration, during advanced septic shock, despite the fall in mean arterial pressure (MAP). Several studies support the hypothesis that NO may be involved in the regulation of ANP release. Since NO may have an effect on ANP release, we hypothesized that NO pathway may participate in the control of the ANP release induced by the endotoxemic shock. Thus, the purpose of the present study was to assess the effect of the intravenous (i.v.) and intracereboventricular (i.c.v.) administration of aminoguanidine, an iNOS blocker, on plasma ANP levels and MAP during experimental endotoxemic shock. Experiments were performed on adult male Wistar rats weighing 180-240 g. Rats were injected i.v. by bolus injection with 1.5 mg/kg of Lipopolysaccharide (LPS) or saline (0.5 mL) and were decapitated 2, 4 and 6 h after LPS injection for ANP determination by radioimmunoassay. In a separate set of experiments, rats received intravenous (i.v.) (100 mg/kg) or intracerebroventricular (i.c.v.) (250 microg in a final volume of 2 microL) injection of aminoguanidine (AG). Thirty minutes after the i.c.v. or i.v. injections, animals received LPS and were decapitated 2, 4 and 6 h later to determine plasma ANP concentration. In the two set of experiments MAP and heart rate (HR) were measured each 15 min for a period of 6 h using a polygraph. When animals were injected with LPS, a reduction (p<0.01) in MPA and an increase in HR occurred. A significant increase in plasma ANP concentration occurred, coinciding with the period of drop in blood pressure. We found a significant increase in plasma ANP concentration after AG plus LPS injection, when compared to the rats treated with LPS plus saline. Further, the administration of AG plus LPS attenuated the decrease in the MAP after LPS and attenuated the increase in the HR when compared to the rats treated with LPS plus saline. Our study suggests that inducible NOS pathway may activate an inhibitory control mechanism that attenuates ANP secretion, which is not regulated by the changes in blood pressure.
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PMID:Participation of the inducible nitric oxide synthase on atrial natriuretic peptide plasma concentration during endotoxemic shock. 1722 8

Nitric oxide (NO) induces vascular relaxation via cGMP in vascular smooth muscle (VSM) and is an important mediator of vascular tone during sepsis, as endothelial NO synthase (eNOS) may be upregulated during the early stages. Atrial natriuretic peptide (ANP) also stimulates cGMP via eNOS hence, this study aimed to investigate the role of NO in time-dependent altered vascular responses to ANP during the first 4h of exposure to bacterial lipopolysaccharide (LPS). We used male rat saphenous arteries [internal relaxed diameter 63-152 microm, n=48], mounted on a wire myograph and pre-constricted with phenylephrine. At 2h in the presence of LPS, there was increased relaxation to ANP in arteries exposed to LPS [16.3+/-2.4%, P<0.05]. However the response to ANP was not altered by the NOS inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 10(-4)M) and following denudation (vessels without endothelium). At 4h there was no longer increased relaxation to ANP in the presence of LPS. Moreover the vasodilator response to ANP was significantly reduced following L-NAME or denudation [4.4+/-1.0% and 4.3+/-1.1% respectively, P<0.05]. However, the non-specific endothelin-1 (ET-1) receptor antagonist Bosentan [10(-5)M] increased dilatation in LPS exposed arteries at 1 and 2h, reaching significance at 4h [14.0+/-3.4%, P<0.05]. In summary, an endothelial and NO dependent mechanism is responsible for increased relaxation to ANP following 2h exposure to LPS. However after 4h an endothelial and NO independent process involving ET-1 is responsible for decreased relaxation to ANP. The enhanced response to ANP may exacerbate early systemic vasodilatation during early sepsis.
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PMID:Lipopolysaccharide alters vasodilation to atrial natriuretic peptide via nitric oxide and endothelin-1: time-dependent effects. 1973 54


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