Role of ANG II in hypertension produced by chronic inhibition of nitric oxide synthase in conscious rats

1996 ◽  
Vol 271 (2) ◽  
pp. H806-H811 ◽  
Author(s):  
M. G. Melaragno ◽  
G. D. Fink
Keyword(s):  
Nitric Oxide ◽  
Time Course ◽  
Low Dose ◽  
Pressor Effect ◽  
Ang Ii ◽  
At1 Receptors ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Delayed Time

These experiments tested the hypothesis that hypertension caused by chronic inhibition of nitiric oxide synthase (NOS) is associated with augmented pressor responsiveness to angiotensin II (ANG II). Antagonism of ANG II AT1 receptors with losartan caused a greater fall in blood pressure (BP) in rats treated for 2 wk with the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) than in normotensive rats. The delayed time course of the decline in BP implicated the slow pressor effect (SPE) of ANG II in L-NAME hypertension. Further experiments showed that direct elicitation of the SPE by continuous low-dose (4 ng/min) intravenous infusion of ANG II in enalapril-treated rats resulted in a larger chronic increase in BP if NOS was inhibited. However, L-NAME alone also caused a significant increase in BP in enalapril-treated rats. The combined effect on BP of ANG II and L-NAME was merely additive. These results confirm that ANG II is involved in L-NAME hypertension. However, chronic pressor responsiveness to the peptide is not augmented by L-NAME.

Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever

1996 ◽  
Vol 271 (2) ◽  
pp. R333-R338 ◽  
Author(s):  
T. E. Scammell ◽  
J. K. Elmquist ◽  
C. B. Saper
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Dependent Manner ◽  
Febrile Response ◽  
Bolus Intravenous Injection ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Higher Doses

The labile gas nitric oxide (NO) mediates a wide variety of thermoregulatory processes including vasomotor control, brown fat thermogenesis, and neuroendocrine regulation. Additionally, during endotoxemia, NO modulates the release of cytokines and hypothalamic peptides. To determine the role of NO in thermoregulation and fever, we intravenously injected the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and measured its effects on body temperature during normal thermoregulation and endotoxemia in awake, unrestrained rats. L-NAME produced a stereoselective, dose-dependent hypothermia that lasted up to 4 h after bolus intravenous injection. Intravenous lipopolysaccharide (LPS) produced fever in a dose-dependent manner, which was preceded by hypothermia at higher doses alpha-LPS. NOS inhibition reduced the febrile response to LPS and produced marked hypothermia with a low dose of LPS. These findings indicate that NO may play an important role in thermoregulation and suggest that NO is required for the production of fever.

scholarly journals Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles

2006 ◽  
Vol 290 (4) ◽  
pp. F873-F879 ◽  
Author(s):  
Ming-Guo Feng ◽  
L. Gabriel Navar
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Concomitant Treatment ◽  
Ang Ii ◽  
No Donor ◽  
Afferent Arterioles ◽  
Nos Inhibitor ◽  
The Difference ◽  
Oxide Synthase

Previous studies have shown that L-type Ca2+ channel (LCC) blockers primarily dilate resting and ANG II-constricted afferent arterioles (AA), but do not influence either resting or ANG II-constricted efferent arterioles (EA). In contrast, blockade of T-type Ca2+ channels (TCC) dilate EA and prevent ANG II-mediated efferent constriction. The present study determined the role of LCC and TCC in mediating the AA and EA constriction following inhibition of nitric oxide synthase (NOS) and tested the hypothesis that inhibition of NOS increases the influence of LCC on EA. With the use of an isolated blood-perfused rat juxtamedullary nephron preparation, single AA or EA were visualized and superfused with a NOS inhibitor, N-nitro-l-arginine (l-NNA), with or without concomitant treatment with an LCC blocker, diltiazem, or a TCC blocker, pimozide. In response to l-NNA (1, 10, and 100 μmol/l), AA and EA diameters decreased significantly by 6.0 ± 0.3, 13.7 ± 1.7, and 19.9 ± 1.4%, and by 6.2 ± 0.5, 13.3 ± 1.1, and 19.0 ± 1.9%, respectively. During TCC blockade with pimozide (10 μmol/l), l-NNA did not significantly constrict afferent (0.9 ± 0.6, 1.5 ± 0.5, and 1.7 ± 0.5%) or efferent (0.4 ± 0.1, 2.1 ± 0.7, and 2.5 ± 1.0%) arterioles. In contrast to the responses with other vasoconstictors, the l-NNA-induced constriction of EA, as well as AA, was reversed by diltiazem (10 μmol/l). The effects were overlapping as pimozide superimposed on diltiazem did not elicit further dilation. When the effects of l-NNA were reversed by superfusion with an NO donor, SNAP (10 μmol/l), diltiazem did not cause significant efferent dilation. As a further test of LCC activity, 55 mmol/l KCl, which depolarizes and constricts AA, caused only a modest constriction in resting EA (8.7 ± 1.3%), but a stronger EA constriction during concurrent treatment with l-NNA (23.8 ± 4.8%). In contrast, norepinephrine caused similar constrictions in both l-NNA-treated and nontreated arterioles. These results provide evidence that NO inhibits LCC and TCC activity and that NOS inhibition-mediated arteriolar constriction involves activation of LCC and TCC in both AA and EA. The difference in responses to high KCl between resting and l-NNA-constricted EA and the ability of diltiazem to block EA constriction caused by l-NNA contrasts with the lack of efferent effects in resting and SNAP-treated l-NNA-preconstricted arterioles and during ANG II-mediated vasoconstriction, suggesting a recruitment of LCC in EA when NOS is inhibited. These data help explain how endothelial dysfunction associated with hypertension may lead to enhanced activity of LCC in postglomerular arterioles and increased postglomerular resistance.

Nitric oxide-dependent and -independent components of cerebrovasodilation elicited by hypercapnia

1994 ◽  
Vol 266 (2) ◽  
pp. R546-R552 ◽  
Author(s):  
C. Iadecola ◽  
F. Zhang
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Time Course ◽  
Slow Time ◽  
Independent Components ◽  
Arterial Partial Pressure ◽  
Partial Pressure Of Co2 ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Doppler Flowmeter

We studied the effect of nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on the increases in cerebral blood flow (CBF) elicited by stepwise elevations in arterial partial pressure of CO2 (PaCO2) from normocapnia up to 204 mmHg. Rats were anesthetized with halothane and ventilated. CBF was monitored over the parietal cortex using a laser-Doppler flowmeter. Increasing levels of hypercapnia elicited graded elevations in CBF that reached a plateau at PaCO2 = 82 +/- 1 mmHg (CBF +215 +/- 25%; n = 8; P < 0.05, analysis of variance). L-NAME (40 mg/kg i.v.; n = 8), but not nitro-D-arginine methyl ester (n = 8), reduced resting CBF (-42 +/- 4%) and attenuated the increase in CBF elicited by hypercapnia. The attenuation occurred only at PaCO2 40-80 mmHg and was maximal (-75 +/- 8%; P < 0.05) at 54 +/- 2 mmHg. At PaCO2 > or = 100 mmHg, L-NAME (40-80 mg/kg) did not attenuate the response (P > 0.05). Reduction of resting CBF (-50 +/- 4%; n = 6) by administration of chloralose (20-40 mg/kg i.v.) did not attenuate the CBF response to hypercapnia (P > 0.05). We also found that the attenuation by L-NAME of resting CBF (n = 5) and of the cerebrovasodilation elicited by hypercapnia (n = 6) has a relatively slow time course, the effects reaching a maximum 45-60 min after intravenous administration of the drug. We conclude that L-NAME does not attenuate the CBF response to CO2 uniformly at all levels of hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

Parasite killing in murine malaria does not require nitric oxide production

Parasitology ◽  
1999 ◽  
Vol 118 (2) ◽  
pp. 139-143 ◽  
Author(s):  
N. FAVRE ◽  
B. RYFFEL ◽  
W. RUDIN
Keyword(s):  
Nitric Oxide ◽  
Blood Stage ◽  
No Production ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Stage Parasite ◽  
Blood Stage Malaria ◽  
Inducible Nitric Oxide

Nitric oxide (NO) production has been suggested to play a role as effector molecule in the control of the malarial infections. However, the roles of this molecule are debated. To assess whether blood-stage parasite killing is NO dependent, we investigated the course of blood-stage Plasmodium chabaudi chabaudi (Pcc) infections in inducible nitric oxide synthase (iNOS)-deficient mice. Parasitaemia, haematological alterations, and survival were not affected by the lack of iNOS. To exclude a role of NO produced by other NOS, controls included NO suppression by oral administration of aminoguanidine (AG), a NOS inhibitor. As in iNOS-deficient mice, no difference in the parasitaemia course, survival and haematological values was observed after AG treatment. Our results indicate that NO production is not required for protection against malaria in our murine experimental model. However, C57BL/6 mice treated with AG lost their resistance to Pcc infections, suggesting that the requirement for NO production for parasite killing in murine blood-stage malaria might be strain dependent.

scholarly journals 108 THE ROLE OF NITRIC OXIDE SYNTHASE IN IN VITRO DEVELOPMENT OF BOVINE OOCYTES AND PRE-IMPLANTATION EMBRYOS

2005 ◽  
Vol 17 (2) ◽  
pp. 204
Author(s):  
A.K. Kadanga ◽  
D. Tesfaye ◽  
S. Ponsuksili ◽  
K. Wimmers ◽  
M. Gilles ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Culture Medium ◽  
Bovine Embryos ◽  
Nos Inhibitor ◽  
Blastocyst Rate ◽  
Oxide Synthase ◽  
Vitro Development ◽  
Bovine Oocytes

Nitric oxide (NO) is a free radical that serves as a key-signal molecule in various physiological processes including reproduction. Four isoforms of nitric oxide synthase (NOS) have been characterized: endothelial (eNOS), inducible (iNOS), neuronal (nNOS), and mitochondrial (mtNOS). The first two isoforms are reported to be expressed in mouse follicles, oocytes, and pre-implantation embryos (Nishikimi A et al. 2001 Reproduction 122, 957–963). However, the role of any of these isoforms have not yet been investigated in bovine embryos. Here we aimed to examine the role of NOS in in vitro development of bovine embryos by treating embryos with NOS inhibitor, N-omega-L-nitro-arginine methyl esther (L-NAME), and examining the localization of the protein in pre-implantation embryos. Oocytes and embryos were grown in the media with NOS inhibitor added at a level of 0 mM (control), 1 mM, and 10 mM to either maturation or culture medium. Each experiment was conducted in four replicates each containing 100 oocytes for IVP. Cleavage and blastocyst rate were recorded at Days 2 and 7, respectively. Data were analyzed using the General Linear Model in SAS version 8.02 (SAS Institute, Inc., Cary, NC, USA) with the main factors being the level of L-NAME and the point of application. Pairwise comparisons were done using the Tukey test. Protein localization in bovine oocytes and embryos was performed by immunocytochemistry using eNOS- and iNOS-specific antibodies. Embryos were fixed in 3.7% paraformaldehyde, permeabilized in 0.1% Triton-X100, and washed three times in PBS supplemented with BSA. They were incubated with eNOS and iNOS primary antibody (1:200 dilutions) and washed before incubation with secondary antibody conjugated to FITC. After washing they were mounted on glass slides and examined under a confocal laser scanning microscope (Carl Zeiss Jena, Carl Zeiss AG, Oberkochen, Germany). In the controls the primary antibodies were omitted. As shown in the table below, the presence of L-NAME in the maturation medium significantly reduced the cleavage and blastocyst rate independent of the dosage applied. However the presence of L-NAME in the culture medium had an influence only on the blastocyst rate. The immunocytochemical staining results showed that both eNOS and iNOS are expressed in the cytoplasm of the MII oocytes, and during the pre-implantation stage the fluorescence signal was observed in nuclei and cytoplasm. However, the nuclear signal was much weaker. In conclusion, the present study is the first to determine the role of NO and to detect NOS protein in bovine oocytes and pre-implantation embryos. These results indicate that nitric oxide may play an important role as diffusible regulator of bovine oocyte maturation and preimplantation embryo development. Table 1. Effect of l-name addition in maturation or culture medium on embryo development

scholarly journals Regulation of nitric oxide synthase isoforms and role of nitric oxide during prostaglandin F2alpha-induced luteolysis in rabbits

Reproduction ◽  
2003 ◽  
pp. 807-816 ◽  
Author(s):  
C Boiti ◽  
G Guelfi ◽  
D Zampini ◽  
G Brecchia ◽  
A Gobbetti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Time Course ◽  
Plasma Concentrations ◽  
Physiological Role ◽  
Total Activity ◽  
Corpora Lutea ◽  
Prostaglandin F ◽  
Oxide Synthase

Total activity of nitric oxide synthase (NOS) and the gene expression of both endothelial NOS (eNOS) and inducible NOS (iNOS) isoforms in corpora lutea of pseudopregnant rabbits were examined during prostaglandin F(2alpha) (PGF(2alpha))-induced luteolysis. Corpora lutea were collected at 0, 6, 12, 24 and 48 h after an injection of PGF(2alpha) at day 9 of pseudopregnancy. At 12 h after PGF(2alpha) administration, luteal mRNA encoding eNOS decreased (P0.05) by 40% and remained low throughout the subsequent 36 h, whereas eNOS protein increased (P0.05) two- to threefold. By contrast, expression of mRNA encoding iNOS was poor and remained fairly constant, but transcription increased eightfold (P0.01) within 6 h after PGF(2alpha) treatment and then decreased to values similar to those of controls. Total NOS activity increased twofold (P0.01) at 6 h after treatment and remained high thereafter, whereas progesterone concentrations in explanted corpora lutea decreased (P0.01) from 302.4+/-42.3 pg x mg(-1) at day 9 to 58.6+/-8.3 at 48 h later, and peripheral plasma concentrations of progesterone declined too. Long-term administration of Nomega-nitro-L-arginine methyl ester (0.6 g l(-1) per os) from day 2 of pseudopregnancy onward partially blocked the luteolytic action of PGF(2alpha) administered at day 9 of pseudopregnancy. In nitric oxide (NO)-deficient rabbits, progesterone concentrations remained higher (P0.01) than in controls at 24-48 h after PGF(2alpha) administration (4.5 to 3.2 ng x ml(-1), respectively). These data are the first to characterize NOS activity. The time course of expression of eNOS and iNOS in rabbit corpora lutea during PGF(2alpha)-induced luteolysis gives additional support to a physiological role of NO in the regulation of regression of corpora lutea in rabbits.

scholarly journals Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation

2012 ◽  
Vol 302 (2) ◽  
pp. E201-E208 ◽  
Author(s):  
Jeong-a Kim ◽  
Hyun-Ju Jang ◽  
Luis A. Martinez-Lemus ◽  
James R. Sowers
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Vascular Endothelium ◽  
Endothelial Nitric Oxide Synthase ◽  
Point Mutations ◽  
Ang Ii ◽  
Cardiovascular Tissues ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. However, the role of ANG II-stimulated mTOR/p70S6K in vascular endothelium is poorly understood. In the present study, we observed that ANG II stimulated p70S6K in bovine aortic endothelial cells. ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser636/639 and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser636/639) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. Moreover, point mutations of IRS-1 at Ser636/639 to Ala prevented the ANG II-mediated inhibition of insulin signaling. From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser636/639. This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension.

scholarly journals Nitric oxide synthase acutely regulates progesterone production by in vitro cultured rabbit corpora lutea

1999 ◽  
Vol 160 (2) ◽  
pp. 275-283 ◽  
Author(s):  
A Gobbetti ◽  
C Boiti ◽  
C Canali ◽  
M Zerani
Keyword(s):  
Nitric Oxide ◽  
In Vitro Release ◽  
Inhibitory Effect ◽  
Corpora Lutea ◽  
No Donor ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Vitro Release

We examined the presence and the regulation of nitric oxide (NO) synthase (NOS) using in vitro cultured corpora lutea (CL) obtained from rabbits at days 4 and 9 of pseudopregnancy. The role of NO and NOS on steroidogenesis was also investigated using the same CL preparations after short-term incubations (30 min and 2 h) with the NO donor, sodium nitroprusside (NP), the NOS inhibitor, Nomega-nitro-l-arginine methyl ester (l-NAME) and prostaglandin (PG) F-2alpha. The basal NOS activity was greater in CL at day 4 than at day 9, and was also differently modulated by PGF-2alpha, depending on the age of the CL. The addition of PGF-2alpha to day 4 CL had no effect, but PGF-2alpha on day 9 caused a threefold increase in NOS activity. NP caused a two- to fivefold decrease in release of progesterone from CL of both ages, and this inhibitory effect on steroidogenesis was reversed by l-NAME. All treatments failed to modify basal androgens and 17beta-oestradiol was not detectable in either control or treated CL. These results suggest that NO is effectively involved in the regulation process of steroidogenesis, independently of 17beta-oestradiol. PGF-2alpha had no effect on day 4, but induced luteolysis on day 9, by reducing progesterone (P</=0. 01) to about 18% of control. The luteolytic action of PGF-2alpha was completely reversed by co-incubation with l-NAME, thus supporting the hypothesis that luteolysis is mediated by NO. The addition of NP or l-NAME did not modify the in vitro release of PGF-2alpha. We hypothesised that PGF-2alpha upregulates NOS activity and, consequently, the production of NO, which acutely inhibits progesterone release from day 9 CL of pseudopregnant rabbits.

Evidence that nitric oxide increases glucose transport in skeletal muscle

1997 ◽  
Vol 82 (1) ◽  
pp. 359-363 ◽  
Author(s):  
Thomas W. Balon ◽  
Jerry L. Nadler ◽  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Type I ◽  
Stimulation Protocol ◽  
No Donor ◽  
Nos Inhibitor ◽  
Exercise Induced ◽  
Oxide Synthase

Balon, Thomas W., and Jerry L. Nadler. Evidence that nitric oxide increases glucose transport in skeletal muscle. J. Appl. Physiol. 82(1): 359–363, 1997.—Nitric oxide synthase (NOS) is expressed in skeletal muscle. However, the role of nitric oxide (NO) in glucose transport in this tissue remains unclear. To determine the role of NO in modulating glucose transport, 2-deoxyglucose (2-DG) transport was measured in rat extensor digitorum longus (EDL) muscles that were exposed to either a maximally stimulating concentration of insulin or to an electrical stimulation protocol, in the presence of N G-monomethyl-l-arginine, a NOS inhibitor. In addition, EDL preparations were exposed to sodium nitroprusside (SNP), an NO donor, in the presence of submaximal and maximally stimulating concentrations of insulin. NOS inhibition reduced both basal and exercise-enhanced 2-DG transport but had no effect on insulin-stimulated 2-DG transport. Furthermore, SNP increased 2-DG transport in a dose-responsive manner. The effects of SNP and insulin on 2-DG transport were additive when insulin was present in physiological but not in pharmacological concentrations. Chronic treadmill training increased protein expression of both type I and type III NOS in soleus muscle homogenates. Our results suggest that NO may be a potential mediator of exercise-induced glucose transport.

Nitric Oxide Is an Autocrine Regulator of Na+Currents in Axotomized C-Type DRG Neurons

2000 ◽  
Vol 83 (4) ◽  
pp. 2431-2442 ◽  
Author(s):  
M. Renganathan ◽  
T. R. Cummins ◽  
W. N. Hormuzdiar ◽  
J. A. Black ◽  
S. G. Waxman
Keyword(s):  
Nitric Oxide ◽  
Current Density ◽  
Current Amplitude ◽  
Fluorescent Label ◽  
Drg Neurons ◽  
Na Currents ◽  
Current Densities ◽  
Nos Inhibitor ◽  
Oxide Synthase

In this study, we examined whether nitric oxide synthase (NOS) is upregulated in small dorsal root ganglion (DRG) neurons after axotomy and, if so, whether the upregulation of NOS modulates Na+ currents in these cells. We identified axotomized C-type DRG neurons using a fluorescent label, hydroxystilbamine methanesulfonate and found that sciatic nerve transection upregulates NOS activity in 60% of these neurons. Fast-inactivating tetrodotoxin-sensitive (TTX-S) Na+(“fast”) current and slowly inactivating tetrodotoxin-resistant (TTX-R) Na+ (“slow”) current were present in control noninjured neurons with current densities of 1.08 ± 0.09 nA/pF and 1.03 ± 0.10 nA/pF, respectively (means ± SE). In some control neurons, a persistent TTX-R Na+ current was observed with current amplitude as much as ∼50% of the TTX-S Na+ current amplitude and 100% of the TTX-R Na+ current amplitude. Seven to 10 days after axotomy, current density of the fast and slow Na+ currents was reduced to 0.58 ± 0.05 nA/pF ( P < 0.01) and 0.2 ± 0.05 nA/pF ( P < 0.001), respectively. Persistent TTX-R Na+ current was not observed in axotomized neurons. Nitric oxide (NO) produced by the upregulation of NOS can block Na+ currents. To examine the role of NOS upregulation on the reduction of the three types of Na+ currents in axotomized neurons, axotomized DRG neurons were incubated with 1 mM N G-nitro-l-arginine methyl ester (l-NAME), a NOS inhibitor. The current density of fast and slow Na+ channels in these neurons increased to 0.82 ± 0.08 nA/pF ( P < 0.01) and 0.34 ± 0.04 nA/pF ( P < 0.05), respectively. However, we did not observe any persistent TTX-R current in axotomized neurons incubated with l-NAME. These results demonstrate that endogenous NO/NO-related species block both fast and slow Na+ current in DRG neurons and suggest that NO functions as an autocrine regulator of Na+ currents in injured DRG neurons.

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