Effects of NG-substituted arginines on coronary vascular function after endotoxin

1993 ◽  
Vol 75 (1) ◽  
pp. 424-431 ◽  
Author(s):  
M. J. Winn ◽  
B. Vallet ◽  
N. K. Asante ◽  
S. E. Curtis ◽  
S. M. Cain
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Endotoxic Shock ◽  
No Synthase ◽  
Relaxing Factor ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Endothelium Derived Relaxing Factor ◽  
Constrictor Response

We investigated the responses of canine coronary rings to endothelium-derived relaxing factor-nitric oxide- (EDRF-NO) dependent agonists and NO synthase (NOS) inhibitors 3 h after endotoxic shock was induced in dogs by lipopolysaccharide infusion (LPS; 2 mg/kg). EDRF-NO-dependent relaxation to thrombin [control maximum response produced after administration of thrombin (Emax) was -85.2 +/- 7.0% of the constrictor response produced by the thromboxane analogue U-46619], acetylcholine (control Emax -88.4 +/- 3.4%), or bradykinin (control Emax -80.5 +/- 2.2%) was not inhibited by LPS (Emax thrombin -75.9 +/- 9.5%; Emax acetylcholine -90.2 +/- 2.4%; Emax bradykinin -91.6 +/- 3.4%). The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (10(-6)-3 x 10(-4) M) caused constriction of rings with endothelium (Emax 36.3 +/- 5.6%), an effect that was greater after LPS (Emax 59.2 +/- 4.1%; P < 0.05). D-NMMA had no effect in control, but it increased tension after LPS (Emax 20.8 +/- 9.7%). Contrary to expectations, L- and D-NMMA relaxed endothelium-denuded rings (-30.4 +/- 8.7% L-NMMA; -45.1 +/- 11.7% D-NMMA; P < 0.05). However, neither agent caused relaxation after in vivo LPS (10.2 +/- 3.4% L-NMMA; 8.9 +/- 5.2% D-NMMA). N omega-nitro-L-arginine-methylester (L-NAME) and nitro-L-arginine (10(-6)-3 x 10(-4) M) increased tension (Emax 82.3 +/- 23.9 and 73.1 +/- 8.8%, respectively) but only when endothelium was present, and the increases were no greater in LPS-treated groups than in controls (with LPS: Emax L-NAME 87.3 +/- 16.5%; Emax nitro-L-arginine 65.7 +/- 3.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of rat mesangial cell mitogenesis by nitric oxide-generating vasodilators

1989 ◽  
Vol 257 (1) ◽  
pp. F60-F66 ◽  
Author(s):  
U. C. Garg ◽  
A. Hassid
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Culture Medium ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Inhibitory Effect ◽  
Relaxing Factor ◽  
Growth Inhibitory ◽  
Endothelium Derived Relaxing Factor

Recent studies indicate that endothelium-derived relaxing factor (EDRF) may be identical with nitric oxide (NO). The purpose of this study was to investigate the antimitogenic effect of NO-generating drugs in cultured mesangial cells. S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and isosorbide dinitrate, which generate NO, dose dependently inhibited serum-stimulated DNA synthesis. All three drugs also inhibited the rate of cell proliferation, whereas sodium nitroprusside and S-nitroso-N-acetylpenicillamine decreased cell density at confluence. The antimitogenic activity of S-nitroso-N-acetylpenicillamine was labile in culture medium and could be inhibited by hemoglobin, supporting the view that NO, in free or bound form, was the ultimate effector. All three vasodilators increased cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels dose dependently; moreover, 8-bromo-cGMP mimicked the effects of the NO-generating drugs, suggesting that cGMP may be an intracellular mediator of antimitogenesis. The growth-inhibitory effect of S-nitroso-N-acetylpenicillamine was reversible and was not due to cell toxicity as shown by several criteria of cell viability. The results raise the possibility that EDRF/NO may be a modulator of mesangial cell growth in vivo.

Endothelium-derived contracting and relaxing factors contribute to hypoxic responses of pulmonary arteries

1993 ◽  
Vol 265 (4) ◽  
pp. H1139-H1148 ◽  
Author(s):  
K. L. Kovitz ◽  
T. D. Aleskowitch ◽  
J. T. Sylvester ◽  
N. A. Flavahan
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arteries ◽  
Initial Response ◽  
Isometric Tension ◽  
No Synthase ◽  
Moderate Hypoxia ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Increased Activity ◽  
Endothelium Dependent Relaxation

The response of porcine pulmonary arteries to hypoxia depended on their location in the vasculature and the degree and duration of the hypoxic challenge. In rings of pulmonary artery suspended for isometric tension recording (37 degrees C, 16% O2 and 5% CO2), moderate hypoxia (10% and 4% O2) caused endothelium-dependent relaxation in distal arteries but transient endothelium-dependent contraction in proximal arteries. In both proximal and distal arteries, the initial response to anoxia (0% O2) was a transient endothelium-dependent contraction. This was followed by a slowly developing, sustained endothelium-dependent contraction in proximal arteries, or by an endothelium-independent relaxation in distal arteries. The endothelium-dependent relaxation to moderate hypoxia in distal arteries was inhibited only by combined inhibition of endothelium-derived relaxing factor (EDRF)-nitric oxide (NO) synthase [N omega-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (indomethacin), suggesting mediation by EDRF-NO and prostacyclin. Transient endothelium-dependent contractions to moderate hypoxia (proximal arteries) or anoxia (all arteries) were abolished by L-NAME, but the late endothelium-dependent anoxic contraction observed in proximal arteries was not reduced by L-NAME and/or indomethacin. Therefore, hypoxia/anoxia may initiate contraction of pulmonary arteries by decreasing the activity of EDRF-NO, but the contractions appear to be maintained by an increased activity of an endothelium-derived contracting factor.

Nitric oxide mediates human chorionic gonadotrophin-induced prostaglandin E generation in rat oocyte - cumulus complexes

1997 ◽  
Vol 9 (4) ◽  
pp. 391 ◽  
Author(s):  
Alicia Jawerbaum ◽  
Elida T. Gonzalez ◽  
Alicia Faletti ◽  
Virginia Novaro ◽  
Martha A. F. Gimeno
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
No Synthase ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Prostaglandin E ◽  
No Donors ◽  
Nos Inhibitors ◽  
Preovulatory Follicles

To determine whether nitric oxide (NO) generation mediates human chorionic gonadotrophin (hCG)-induced prostaglandin E (PGE) secretion by oocyte–cumulus complexes (OCC), the secretion of PGE by cultured rat OCC in the presence of NO donors and NO synthase (NOS) inhibitors was characterized. NO donors (sodium nitroprusside and 3-morpholino-sydnonimine- hydrochloride) increased PGE accumulation in OCC to values similar to those obtained in the presence of hCG. The three NOS inhibitors tested (N G -nitro-L-arginine methyl ester, NG -monomethyl-L-arginine and aminoguanidine) prevented the hCG-induced PGE accumulation in cultured OCC. This effect appears to be specific since D-enantiomers NG -nitro-D-arginine methyl ester and NG -monomethyl-D-arginine had no effect. The present results suggest that NO mediates the hCG-induced accumulation of PGE in rat OCC, a process which may occur in vivo in preovulatory follicles prior to ovulation.

scholarly journals Endothelium-derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus.

1993 ◽  
Vol 3 (8) ◽  
pp. 1435-1441
Author(s):  
L Raij ◽  
P J Shultz
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor

The endothelium-derived relaxing factor nitric oxide (EDRF/NO) is a labile, endogenous vasodilator that is important in the control of systemic vascular tone. This review focuses on the effects of EDRF/NO on glomerular mesangial cells in vitro and on the role of EDRF/NO in mesangial and glomerular physiology and pathophysiology in vivo. It was concluded that EDRF/NO can stimulate increases in cGMP, inhibit mesangial cell contraction, and inhibit growth factor-induced proliferation of mesangial cells in culture. Furthermore, incubation with endotoxin or cytokines stimulates mesangial cells to produce EDRF/NO, via an inducible NO synthase enzyme. Therefore, it is likely that NO could play a role in the inflammatory response within the glomerulus. Finally, recent studies providing evidence that EDRF/NO is functional within the glomerulus in vivo, especially during endotoxemia and inflammation are also reviewed.

Abstract 1286: Neuronal Nitric Oxide Synthase Regulates Basal Vascular Tone in the Healthy Human Forearm in vivo.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mike Seddon ◽  
Phil Chowienczyk ◽  
Barbara Casadei ◽  
Ajay Shah
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Vascular Tone ◽  
Venous Occlusion ◽  
No Synthase ◽  
Healthy Human ◽  
Vasodilator Response ◽  
Nos Inhibitors ◽  
Human Forearm

Nitric oxide (NO) has an established role in the maintenance of vascular tone, generally assumed to be mediated by endothelial NO synthase (eNOS). Previous studies using the non-selective NOS inhibitor N G monomethyl-L-arginine (L-NMMA) in humans confirmed the in vivo importance of NO but the contribution of neuronal NO synthase (nNOS) is unknown due to the lack of available selective NOS inhibitors for human use. In this study, we investigated for the first time in humans the effects of S-methyl-L-thiocitrulline (SMTC), a competitive nNOS-selective inhibitor with 17-fold selectivity over eNOS. SMTC or L-NMMA were infused into the brachial artery of healthy male volunteers and forearm blood flow was measured by venous occlusion plethysmography. SMTC 0.025, 0.05, 0.1 and 0.2 μmol/min caused a dose-dependent reduction in basal blood flow in the infused arm of 9.2±1.9, 16.2±2.9, 22.9±3.9 and 30.1±3.8% respectively (n=10; mean±SE; all P<0.01). Substantially higher doses of L-NMMA of 0.5, 1, 2 and 4 μmol/min were required to reduce basal flow by 11.5±3.0, 25.1±3.0, 33.7±3.0 and 37.4±3.1% respectively (n=10). The highest dose of SMTC (ie, 0.2 μmol/min) tested had no significant effect on the vasodilator response to acetylcholine (ACh): Ach 40 and 80nmol/min increased blood flow by 3.93±0.64 and 5.54±0.69 ml/min/100mls tissue above baseline during saline co-infusion versus 3.95±0.69 and 4.90±0.71 ml/min/100mls tissue during SMTC co-infusion (n=10; P=NS). In contrast, L-NMMA significantly reduced the response to these doses of ACh by 64±9.9 and 60±10% (n=10; both P<0.01). The effect of SMTC on basal blood flow was completely abolished in the presence of the NOS substrate L-arginine (n=6; P<0.001) but was unaffected by the stereoisomer D-arginine (n=6). SMTC had no effect on the vasodilator response to sodium nitroprusside (n=5). In conclusion , SMTC reduced basal blood flow by stereospecific inhibition of the L-arginine:NO pathway but did not affect the eNOS-mediated vasodilator response to ACh. These results indicate that nNOS has a crucial role in the regulation of basal vascular tone in the human forearm in vivo .

Inhibition of nitric oxide synthase attenuates NNMU-induced alveolar injury in vivo

1997 ◽  
Vol 273 (6) ◽  
pp. L1167-L1173 ◽  
Author(s):  
Wilhelm S. Cruz ◽  
Michael A. Moxley ◽  
John A. Corbett ◽  
William J. Longmore
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Methyl Ester ◽  
Lung Injury ◽  
Protein Ratio ◽  
Nos Inhibitors ◽  
Elevated Expression ◽  
Nos Inhibitor ◽  
Oxide Synthase

The purpose of this study was to determine if the acute alveolar injury induced by subcutaneous injections of N-nitroso- N-methylurethane (NNMU) in rats is mediated by nitric oxide (NO ⋅). We show that intraperitoneal injections of the NO ⋅ synthase (NOS) inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) or aminoguanidine significantly attenuate the NNMU-induced alveolar injury as assessed by 1) normalization of the alveolar-arterial O2difference, 2) attenuation of the lowered phospholipid-to-protein ratio in the crude surfactant pellet (CSP), 3) attenuation of the elevated minimal surface tension of the CSP, and 4) attenuation of polymorphonuclear neutrophilic infiltration into the alveolar space. Injections of N ω-nitro-d-arginine methyl ester, the inactive stereoisoform ofl-NAME, did not affect the acute lung injury. Western blot analysis of whole lung homogenates demonstrate an elevated expression of transcriptionally inducible, Ca2+-independent NOS (iNOS) in NNMU-injected rats compared with control saline-injected rats. NOS inhibitors did not affect NNMU-induced iNOS expression. These investigations demonstrate that the inhibition of NOS attenuates NNMU-induced acute lung injury, suggesting a role for NO ⋅ in the progression of acute respiratory distress syndrome.

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats

1994 ◽  
Vol 267 (3) ◽  
pp. F374-F379 ◽  
Author(s):  
D. Schwartz ◽  
M. Blum ◽  
G. Peer ◽  
Y. Wollman ◽  
A. Maree ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Therapeutic Approach ◽  
No Synthase ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Synthase Inhibitor ◽  
Novel Therapeutic

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Differential effects of l-NAME on rat venular hydraulic conductivity

2000 ◽  
Vol 279 (4) ◽  
pp. H2017-H2023 ◽  
Author(s):  
Rolando E. Rumbaut ◽  
Jianjie Wang ◽  
Virginia H. Huxley
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Methyl Ester ◽  
Hydraulic Conductivity ◽  
No Synthase ◽  
Vascular Effects ◽  
Nos Inhibitors ◽  
Before And After ◽  
Nos Inhibitor

The role of nitric oxide (NO) in microvascular permeability remains unclear because both increases and decreases in permeability by NO synthase (NOS) inhibitors have been reported. We sought to determine whether blood-borne constituents modify venular permeability responses to the NOS inhibitor N G-nitro-l-arginine methyl ester (l-NAME). We assessed hydraulic conductivity ( L p) of pipette-perfused rat mesenteric venules before and after exposure to 10−4 M l-NAME. In the absence of blood-borne constituents, l-NAME reduced L p by nearly 50% (from a median of 2.4 × 10−7cm · s−1 · cmH2O−1, n = 17, P < 0.001). The reduction in L p by l-NAME was inhibited by a 10-fold molar excess of l-arginine but notd-arginine ( n = 6). In a separate group of venules, blood flow was allowed to resume during exposure tol-NAME. In vessels perfused by blood duringl-NAME exposure, L p increased by 78% (from 1.4 × 10−7cm · s−1 · cmH2O−1, n = 10, P < 0.01). N G-nitro-d-arginine methyl ester did not affect L p in either of the two groups. These data imply that NO has direct vascular effects on permeability that are opposed by secondary changes in permeability mediated by blood-borne constituents.

Release of EDRF and NO in ex vivo perfused aorta: inhibition by in vivo E. coli endotoxemia

1995 ◽  
Vol 268 (3) ◽  
pp. H955-H961 ◽  
Author(s):  
P. R. Myers ◽  
Q. Zhong ◽  
J. J. Jones ◽  
M. A. Tanner ◽  
H. R. Adams ◽  
...  
Keyword(s):  
Ex Vivo ◽  
No Synthase ◽  
No Production ◽  
Gram Negative ◽  
E Coli ◽  
Relaxing Factor ◽  
A 23187 ◽  
Endothelium Derived Relaxing Factor ◽  
Endothelium Dependent Relaxation

Previous studies have yielded contradictory results about interrelations between endotoxin and endothelium-derived relaxing factor (EDRF). We tested the hypothesis that in vivo endotoxemia inhibits basal and/or agonist-mediated release of EDRF and nitric oxide (NO). EDRF bioactivity, NO production, and NO synthase (NOS) activity were measured in aorta from guinea pigs following 16 h of Escherichia coli endotoxemia (4 mg/kg endotoxin i.p.). Endothelium-dependent relaxation of aortic rings was studied under standard isometric conditions. Endotoxemia resulted in an 89% reduction in basal EDRF bioactivity and a 62% reduction in basal NO production in perfused aorta. EDRF bioactivity and NO production in response to the receptor-dependent agonists acetylcholine and ADP were significantly reduced in perfused aorta from endotoxemic animals. In contrast, endotoxin did not significantly inhibit EDRF bioactivity and NO production by the receptor-independent agonist A-23187. Aortic rings from endotoxemic animals likewise showed decreased vasodilator responses to acetylcholine and ADP but not to A-23187. Inducible (Ca2+ independent) NOS activity was not significantly different in control and endotoxin-treated animals. These findings indicate that prolonged endotoxemia resulted in diminution of release of EDRF, consistent with the interpretation that endotoxemia decreases basal and agonist-stimulated EDRF bioactivity and NO production with loss of endothelium-dependent vasodilator reserves during gram-negative sepsis.

scholarly journals Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses

1990 ◽  
Vol 258 (3) ◽  
pp. H655-H662 ◽  
Author(s):  
J. P. Tolins ◽  
R. M. Palmer ◽  
S. Moncada ◽  
L. Raij
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Intravenous Infusion ◽  
Soluble Guanylate Cyclase ◽  
Hemodynamic Responses ◽  
Relaxing Factor ◽  
Renal Hemodynamic ◽  
Endothelium Derived Relaxing Factor

An endothelium-derived relaxing factor (EDRF) has recently been identified as nitric oxide (NO), originating from endothelial cell metabolism of L-arginine. In vitro studies suggest that EDRF/NO stimulates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels in vascular smooth muscle cells, resulting in the vasorelaxant effects of endothelium-dependent vasodilators such as acetylcholine (ACh). The importance of EDRF/NO in normal physiology or disease states remains uncertain. We therefore investigated the relationship between ACh-induced hemodynamic responses, synthesis of EDRF/NO, and changes in the rate of urinary cGMP excretion in the anesthetized rat in vivo. Intravenous infusion of ACh resulted in hypotension, maintenance of glomerular filtration rate, and renal vasodilatation. ACh induced a dose-dependent increase in urinary cGMP excretion, an effect that was not observed with equihypotensive doses of the endothelium-independent vasodilator, prostacyclin. Rates of cGMP excretion were significantly correlated with the fall in systemic blood pressure induced by ACh. Treatment with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of enzymatic synthesis of nitric oxide from L-arginine, prevented the ACh-induced increase in urinary cGMP excretion as well as the systemic and renal hemodynamic effects of ACh. Plasma levels of atrial natriuretic peptide were unchanged by ACh infusion. Intravenous infusion of L-NMMA was associated with increased blood pressure and decreased basal rates of urinary cGMP excretion. This hypertensive effect was reversed by administration of L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Sign in / Sign up

Export Citation Format

Share Document