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Nitric Oxide Synthase Inhibition (nitric + oxide_synthase_inhibition)
Selected AbstractsSalt-Sensitive Hypertension Resulting From Nitric Oxide Synthase Inhibition is Associated with Loss of Regulation of Angiotensin II in the RatEXPERIMENTAL PHYSIOLOGY, Issue 1 2002G. Hodge In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008%, 2.2% or 4.4% sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg,1 day,1) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist. [source] Consequences of Nitric Oxide Synthase Inhibition During Bovine Oocyte Maturation on Meiosis and Embryo DevelopmentREPRODUCTION IN DOMESTIC ANIMALS, Issue 1 2010KRL Schwarz Contents The importance of nitric oxide synthase (NOS) in bovine oocyte maturation was investigated. Oocytes were in vitro matured with the NOS inhibitor Nw - l -nitro-arginine methyl-ester (10,7, 10,5 and 10,3 m l -NAME) and metaphase II (MII) rates and embryo development and quality were assessed. The effect of l -NAME (10,7 m) during pre-maturation and/or maturation on embryo development and quality was also assessed. l -NAME decreased MII rates (78,82%, p < 0.05) when compared with controls without l -NAME (96%). Cleavage (77,88%, p > 0.05), Day 7 blastocyst rates (34,42%, p > 0.05) and total cell numbers in blastocysts were similar for all groups (146,171 cells, p > 0.05). Day 8 blastocyst TUNEL positive cells (3,4 cells) increased with l -NAME treatment (p < 0.05). For oocytes cultured with l -NAME during pre-maturation and/or maturation, Day 8 blastocyst development (26,34%) and Day 9 hatching rates (15,22%) were similar (p > 0.05) to controls pre-matured and matured without NOS inhibition (33 and 18%, respectively), while total cell numbers (Day 9 hatched blastocysts) increased (264,324 cells, p < 0.05) when compared with the controls (191 cells). TUNEL positive cells increased when NOS was inhibited only during the maturation period (8 cells, p < 0.05) when compared with the other groups (3,4 cells). NO may be involved in meiosis progression to MII and its deficiency during maturation increases apoptosis in embryos produced in vitro. Nitric oxide synthase inhibition during pre-maturation and/or maturation affects embryo quality. [source] Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and TryptamineARCHIV DER PHARMAZIE, Issue 2 2009Dennis K. Wilkes Abstract This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50 values of aminoguanidine (IC50 = 2.306×10,3 M) and 8-imino- N -guanidino-pentacyclo-undecane 2 (IC50 = 8.803×10,5 M) revealed a more than 26-fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors. [source] Nitric oxide synthase inhibition in Thoroughbred horses augments O2 extraction at rest and submaximal exercise, but not during short-term maximal exerciseEQUINE VETERINARY JOURNAL, Issue S36 2006M. MANOHAR Summary Reason for performing study: Work is required to establish the role of endogenous nitric oxide (NO) in metabolism of resting and exercising horses. Objectives: To examine the effects of NO synthase inhibition on O2 extraction and anaerobic metabolism at rest, and during submaximal and maximal exertion. Methods: Placebo and NO synthase inhibition (with N,-nitro-L-arginine methyl ester [l -NAME] administered at 20 mg/kg bwt i.v.) studies were performed in random order, 7 days apart on 7 healthy, exercise-trained Thoroughbred horses at rest and during incremental exercise leading to 120 sec of maximal exertion at 14 m/sec on a 3.5% uphill grade. Results: At rest, NO synthase inhibition significantly augmented the arterial to mixed-venous blood O2 content gradient and O2 extraction as mixed-venous blood O2 tension and saturation decreased significantly. While NO synthase inhibition did not affect arterial blood-gas tensions in exercising horses, the exercise-induced increment in haemoglobin concentration and arterial O2 content was attenuated. In the l -NAME study, during submaximal exercise, mixed-venous blood O2 tension and haemoglobin-O2 saturation decreased to a greater extent causing O2 extraction to increase significantly. During maximal exertion, arterial hypoxaemia, desaturation of haemoglobin and hypercapnia of a similar magnitude developed in both treatments. Also, the changes in mixed-venous blood O2 tension and haemoglobin-O2 saturation, arterial to mixed-venous blood O2 content gradient, O2 extraction and markers of anaerobic metabolism (lactate and ammonia production, and metabolic acidosis) were not different from those in the placebo study. Conclusion: Endogenous NO production augments O2 extraction at rest and during submaximal exertion, but not the during short-term maximal exercise. Also, NO synthase inhibition does not affect anaerobic metabolism at rest or during exertion. Potential relevance: It is unlikely that endogenous NO release modifies aerobic or anaerobic metabolism in horses performing short-term maximal exertion. [source] Nitric oxide synthase inhibition reduces O2 cost of force development and spares high-energy phosphates following contractions in pump-perfused rat hindlimb musclesEXPERIMENTAL PHYSIOLOGY, Issue 3 2006David J. Baker The purpose of the present experiments was to test the hypotheses that: (i) nitric oxide synthase (NOS) inhibition reduces the O2 cost of force development across a range of contractile demands; and (ii) this reduced O2 cost of force development would be reflected in a sparing of intramuscular higher energy phosphates. Rat distal hindlimb muscles were pump perfused in situ and electrically stimulated (200 ms trains with pulses at 100 Hz, each pulse 0.05 ms duration) for 1 min each at 15, 30 and 60 tetani min,1 and for 2 min at 90 tetani min,1 in three groups: 0.01 mm adenosine; 1 mm d -NAME and 0.01 mm adenosine (d -NAME); and 1 mm l -NAME and 0.01 mm adenosine (l -NAME). The gastrocnemius,plantaris,soleus muscle group was freeze clamped post-contractions for metabolite analyses. Force was 19% higher and oxygen uptake was 20% lower with l -NAME versus adenosine, and there was a 35% reduction in /time-integrated tension versus adenosine and 24% versusd -NAME that was independent of contraction frequency. l -NAME treatment produced a 33% sparing of muscle phosphocreatine (PCr), and intramuscular lactate was no different between groups. In contrast, d -NAME reduced force by 30%, by 29% and the O2 cost of force development by 15% compared with adenosine, but had no effect on the degree of intramuscular ATP and PCr depletion. These results show that NOS inhibition improved the metabolic efficiency of force development, either by improving the ATP yield for a given O2 consumption or by reducing the ATP cost of force development. In addition, these effects were independent of contraction frequency. [source] Noninvasive Imaging of Angiogenesis Inhibition Following Nitric Oxide Synthase Blockade in the Ischemic Rat Heart in VivoMICROCIRCULATION, Issue 4 2005CHRISTIANE WALLER MD ABSTRACT Objective: Nitric oxide synthase inhibition has anti-angiogenic properties. Magnetic resonance (MR) imaging was used to image the functional significance of these microvascular changes in a rat model of chronic ischemic myocardium in vivo. Methods: The authors quantitatively determined myocardial perfusion and regional blood volume, left ventricular geometry, and function using MR imaging. Animals received either L-NAME + hydralazine or no treatment and were investigated 1 and 2 weeks after induction of coronary artery stenosis or sham operation at rest and during vasodilatation. Double-labeling immunohistochemistry was used to visualize angiogenesis and to compare with data obtained by MR imaging. Results: Left ventricular mass and end-diastolic volumes were comparable in both groups 2 weeks after treatment. However, basal and maximum perfusion in animals with L -NAME + hydralazine treatment were reduced compared to animals not treated (p < .05). Basal regional blood volume remained constant in all groups, whereas maximum regional blood volume was reduced by L -NAME + hydralazine (p < .05). Endothelial cell proliferation, a direct marker for angiogenesis, was reduced by L -NAME + hydralazine (p < .01). Conclusions: MR imaging allows noninvasive quantification of functional microcirculation and angiogenesis in the rat heart in vivo. Nitric oxide synthase blockade results in changes in functional microcirculation and in an inhibition of angiogenesis in both ischemic and nonischemic myocardial tissue. [source] Consequences of Nitric Oxide Synthase Inhibition During Bovine Oocyte Maturation on Meiosis and Embryo DevelopmentREPRODUCTION IN DOMESTIC ANIMALS, Issue 1 2010KRL Schwarz Contents The importance of nitric oxide synthase (NOS) in bovine oocyte maturation was investigated. Oocytes were in vitro matured with the NOS inhibitor Nw - l -nitro-arginine methyl-ester (10,7, 10,5 and 10,3 m l -NAME) and metaphase II (MII) rates and embryo development and quality were assessed. The effect of l -NAME (10,7 m) during pre-maturation and/or maturation on embryo development and quality was also assessed. l -NAME decreased MII rates (78,82%, p < 0.05) when compared with controls without l -NAME (96%). Cleavage (77,88%, p > 0.05), Day 7 blastocyst rates (34,42%, p > 0.05) and total cell numbers in blastocysts were similar for all groups (146,171 cells, p > 0.05). Day 8 blastocyst TUNEL positive cells (3,4 cells) increased with l -NAME treatment (p < 0.05). For oocytes cultured with l -NAME during pre-maturation and/or maturation, Day 8 blastocyst development (26,34%) and Day 9 hatching rates (15,22%) were similar (p > 0.05) to controls pre-matured and matured without NOS inhibition (33 and 18%, respectively), while total cell numbers (Day 9 hatched blastocysts) increased (264,324 cells, p < 0.05) when compared with the controls (191 cells). TUNEL positive cells increased when NOS was inhibited only during the maturation period (8 cells, p < 0.05) when compared with the other groups (3,4 cells). NO may be involved in meiosis progression to MII and its deficiency during maturation increases apoptosis in embryos produced in vitro. Nitric oxide synthase inhibition during pre-maturation and/or maturation affects embryo quality. [source] Salt-Sensitive Hypertension Resulting From Nitric Oxide Synthase Inhibition is Associated with Loss of Regulation of Angiotensin II in the RatEXPERIMENTAL PHYSIOLOGY, Issue 1 2002G. Hodge In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008%, 2.2% or 4.4% sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg,1 day,1) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist. [source] Activity-induced tissue oxygenation changes in rat cerebellar cortex: interplay of postsynaptic activation and blood flowTHE JOURNAL OF PHYSIOLOGY, Issue 1 2005Nikolas Offenhauser Functional neuroimaging relies on the robust coupling between neuronal activity, metabolism and cerebral blood flow (CBF), but the physiological basis of the neuroimaging signals is still poorly understood. We examined the mechanisms of activity-dependent changes in tissue oxygenation in relation to variations in CBF responses and postsynaptic activity in rat cerebellar cortex. To increase synaptic activity we stimulated the monosynaptic, glutamatergic climbing fibres that excite Purkinje cells via AMPA receptors. We used local field potentials to indicate synaptic activity, and recorded tissue oxygen partial pressure (Ptiss,O2) by polarographic microelectrodes, and CBF using laser-Doppler flowmetry. The disappearance rate of oxygen in the tissue increased linearly with synaptic activity. This indicated that, without a threshold, oxygen consumption increased as a linear function of synaptic activity. The reduction in Ptiss,O2 preceded the rise in CBF. The time integral (area) of the negative Ptiss,O2 response increased non-linearly showing saturation at high levels of synaptic activity, concomitant with a steep rise in CBF. This was accompanied by a positive change in Ptiss,O2. Neuronal nitric oxide synthase inhibition enhanced the initial negative Ptiss,O2 response (,dip'), while attenuating the evoked CBF increase and positive Ptiss,O2 response equally. This indicates that increases in CBF counteract activity-induced reductions in Ptiss,O2, and suggests the presence of a tissue oxygen reserve. The changes in Ptiss,O2 and CBF were strongly attenuated by AMPA receptor blockade. Our findings suggest an inverse relationship between negative Ptiss,O2 and CBF responses, and provide direct in vivo evidence for a tight coupling between activity in postsynaptic AMPA receptors and cerebellar oxygen consumption. [source] Influence of nitric oxide synthase inhibition on pulmonary O2 uptake kinetics during supra-maximal exercise in humansTHE JOURNAL OF PHYSIOLOGY, Issue 2 2004Daryl P. Wilkerson We have recently reported that inhibition of nitric oxide synthase (NOS) with NG -nitro- l -arginine methyl ester (l -NAME) accelerates the ,phase II' pulmonary O2 uptake kinetics following the onset of moderate and heavy intensity submaximal exercise in humans. These data suggest that the influence of nitric oxide (NO) on mitochondrial function is an important factor in the inertia to aerobic respiration that is evident in the transition from a lower to a higher metabolic rate. The purpose of the present study was to investigate the influence of l -NAME on pulmonary kinetics following the onset of supra-maximal exercise, where it has been suggested that O2 availability represents an additional limitation to kinetics. Seven healthy young men volunteered to participate in this study. Following an incremental cycle ergometer test for the determination of , the subjects returned on two occasions to perform a ,step' exercise test from a baseline of unloaded cycling to a work rate calculated to require 105%, preceded either by systemic infusion of l -NAME (4 mg kg,1 in 50 ml saline) or 50 ml saline as a control (Con). Pulmonary gas exchange was measured on a breath-by-breath basis throughout the exercise tests. The duration of ,phase I' was greater with l -NAME (Con: 14.0 ± 2.1 versusl -NAME: 16.0 ± 1.6 s; P= 0.03), suggestive of a slower cardiovascular adaptation following the onset of exercise. However, the phase II time constant was reduced by 44% with l -NAME (Con: 36.3 ± 17.3 versusl -NAME: 20.4 ± 8.3 s; P= 0.01). The accumulation of blood lactate during exercise was also reduced with l -NAME (Con: 4.0 ± 1.1 versusl -NAME: 2.7 ± 2.1 mm; P= 0.04). These data indicate that skeletal muscle NO production represents an important limitation to the acceleration of oxidative metabolism following the onset of supra-maximal exercise in humans. [source] The Effect of Ovariectomy on Rat Vaginal Tissue Contractility and HistomorphologyTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006F. Fatih Önol MD ABSTRACT Introduction., Ovarian hormones have an important role in age-related genital arousal disorders; however, our knowledge regarding possible vaginal wall morphology and contractility changes in low-hormonal states is limited. Aims., To investigate morphological and functional alterations in the vaginal tissue in a rat ovariectomy model and to show the differences between proximal and distal vagina. Methods., Six weeks following ovariectomy, vaginal tissues were examined under light and electron microscopy. Circularly cut distal and proximal tissues were studied in the organ bath under isometric tension and compared with age-matched controls. Contractile responses to electrical field stimulation (EFS), phenylephrine, carbachol, and the effects of alpha-1 and alpha-2 blockade on EFS-induced contractility were investigated. Relaxation responses to EFS and vardenafil were investigated in precontracted strips. Main Outcome Measures., Differences between control and ovariectomy groups in terms of vaginal tissue contractility and histomorphological properties. Results., Distal vagina showed different epithelial characteristics and a better-developed muscularis compared with proximal vagina. Ovariectomy caused thinning of the epithelium, severe degeneration in epithelial architecture, and smooth muscle atrophy. Contraction and relaxation responses of distal strips were significantly lower in ovariectomized rats. Contractile responses to neuropharmacological stimulation were insignificant in proximal strips of both groups. EFS-induced contractions in distal strips diminished significantly after alpha-1 and alpha-2 adrenergic blockade. EFS caused frequency-dependent relaxation responses in precontracted distal strips, which were significantly decreased after nitric oxide synthase inhibition. Conclusions., Ovariectomy causes significant alteration in rat vaginal tissue morphology and contractility. Contraction and relaxation responses of distal vagina are significantly greater compared with morphologically distinct proximal vagina. Alpha-1 and alpha-2 receptors are the main mediators of contraction in distal rat vaginal tissue whereas nitric oxide pathway may have at least a partial role in relaxation. Main mediators of the rat vaginal tissue relaxation and the effect of ovariectomy on this regulation are yet to be defined. Önol FF, Ercan F, and Tarcan T. The effect of ovariectomy on rat vaginal tissue contractility and histomorphology. J Sex Med 2006;3:233,241. [source] Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and TryptamineARCHIV DER PHARMAZIE, Issue 2 2009Dennis K. Wilkes Abstract This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50 values of aminoguanidine (IC50 = 2.306×10,3 M) and 8-imino- N -guanidino-pentacyclo-undecane 2 (IC50 = 8.803×10,5 M) revealed a more than 26-fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane 4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors. [source] Effect of nitric oxide synthase inhibition and nerve stimulation frequency on autonomous choroidal vasodilationACTA OPHTHALMOLOGICA, Issue 2009HA REITSAMER Purpose To investigate the effect of non selective nitric oxide synthase inhibition and the influence of nerve stimulation frequencies on parasympathetic choroidal vasodilation. Methods Stimulations of parasympathetic nerve fibers of the greater petrosal nerve with 8 and 20 Hz were performed simultaneously with continuous measurements of intraocular pressure (IOP), choroidal blood flow (ChorBF), orbital venous pressure (OVP) and arterial pressure at the eye level (MAP). Stimulations were perfomed at baseline, after non selective inhibition of all nitric oxide synthases with L-NAME and after systemic administration of atropine in an anesthetized acute rabbit model. Results Baseline values (mean ± sem, n=6): MAP 66.9 ± 1.8 mmHg, IOP 17.3 ± 0.8 mmHg, ChorBF 467 ± 54 P.U. Facial nerve stimulation with 8 Hz under baseline conditions causes a significant increase of ChorBF 660 ± 80 P.U. and IOP 20.7 ± 1.6 mmHg and a non significant decrease of MAP 61.1 ± 5.0 mmHg. The effects of 20 Hz stimulation did not differ significantly from the 8 Hz results (MAP 68.1 ± 5.0, IOP 22.86 ± 2.0, ChorBF 688 ± 73). Non selective inhibition of the nitric oxide synthases with L-NAME (20 mg/kg) changed the vasodilatory effects of the two stimulation frequencies. The relative effect of 8 Hz stimulation was significantly smaller than the effect of 20 Hz stimulation. However, baseline blood flow after L-NAME was lower than under baseline conditions. Conclusion 8Hz and 20 Hz parasympathetic stimulation had similar effects before but not after non selective NOS inhibition. However, no dose of L-NAME completely suppressed the effect of parasympathetic stimulation. [source] | |||||||||||||