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1.
1. Inhibition of nitric oxide (NO) synthesis with the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) was used as a tool to investigate further a possible endothelial defect in the New Zealand genetically hypertensive (GH) rat strain compared with its normotensive (N) control strain. 2. Nω-nitro-L-arginine methyl ester was given to GH and N groups in their drinking water from age 7–10 weeks (10 mg/kg per day for weeks 1 and 2 and then 5 mg/kg per day for week 3). Tail-cuff blood pressure (BP) was measured weekly and at the end of the experiment the mesentery was fixed by perfusion, second order branches of the mesenteric artery were embedded in Technovit and stained sections were used to quantify the structure of the mesenteric resistance arteries (MRA). The heart was removed and weighed for determination of left ventricular (LV) mass. 3. In GH rats, BP and LV mass were significantly raised by L-NAME, while in N rats L-NAME treatment significantly elevated BP, but had no effect on LV mass. 4. In GH rats, the media width was significantly increased by L-NAME treatment (P < 0.01) lumen diameter remained unchanged. Thus, the ratio of media width/lumen diameter (M/L) was significantly increased by exacerbation of the hypertrophic outward remodelling characteristic of the GH strain. There were no significant changes in the M/L ratio in L -NAME-treated N rats. 5. Thus, in the GH strain, cardiovascular structure is more sensitive to NOS inhibition than either its N control strain or (on evidence from the literature) the spontaneously hypertensive rat strain.  相似文献   

2.
1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine methyl ester (L-NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model. 2. Two groups of SHR (n= 8) with streptozotocin-induced diabetes were studied. One group was given L-NAME 5mg/kg body weight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay. 3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L-NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 ± 2.9 compared with 6.5 ± 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001). 4. Systolic blood pressure was significantly elevated in the L-NAME group throughout the study compared with the control group. 5. Plasma AngII was significantly elevated in the L-NAME group compared with controls (42.8 ± 10.3 vs 15.1 ± 1.9 pmol/L, respectively; P < 0.05). 6. Activation of the renin-angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.  相似文献   

3.
4.
1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with NG-nitro-l -arginine-methyl ester (l -NAME). 2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received l -NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail-cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [125I]-Sar8, Ile1)AngII. Data was analysed using the computer program ligand. 3. Mean systolic blood pressure was significantly elevated in rats treated with l -NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated with l -NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the l -NAME group compared with control. However, uterine AngII receptor affinity was unchanged. 4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.  相似文献   

5.
1. To elucidate the physiological role of nitric oxide (NO) in regulating vascular tone, the effects of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, on the vasoconstrictor response to noradrenaline (NA) in rat caudal artery was examined. 2. NG-Nitro-L-arginine methyl ester significantly potentiated the NA-induced increase in perfusion pressure in the perfused caudal artery, but did not affect the NA-induced contraction in caudal artery ring preparations. In addition, an increase in perfusion pressure mechanically produced by a stepwise increase in flow rate was not affected by L-NAME. 3. Noradrenaline evoked a significant increase in the release of endogenous ATP and its metabolites from the perfused artery, whereas increased perfusion pressure as a result of increased flow rate did not evoke release of endogenous ATP. 4. In the presence of exogenously applied ATP, L-NAME significantly potentiated the increase in perfusion pressure produced by increased flow rate. 5. These results indicate that perfused vascular tone is regulated by endogenous NO and suggest that extracellular ATP may participate in the synthesis and release of NO by shear stress in endothelial cells in the rat caudal artery.  相似文献   

6.
1. We evaluated the haemodynamic effects and systemic disposition of the nitric oxide synthase (NOS) inhibitor NL-nitro-L-arginine (NOLA) after intravenous (i.v.) administration of two different doses (5 and 20 mg/kg) in awake healthy sheep and awake sheep given a continuous i.v. infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i.v., for 18 h). In addition, we determined the systemic disposition of another NOS inhibitor, NL-nitro-L-arginine methylester (L-NAME; 20 mg/kg, i.v.) in awake healthy sheep only. 2. ArL-Nitro-L-arginine produced a dose-dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose-dependent increase in mean arterial pressure (MAP) and peripheral vascular resistance (PVR) when compared to baseline. In endotoxic sheep NOLA produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP). 3. In healthy sheep there was a dose-related increase in total body clearance (CI) of NOLA. The CI increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose. The infusion of endotoxin caused an increase in CI of NOLA to 0.040 and 0.047 L/min, respectively, and a decrease in plasma slow half-life (t1/2 from 825 to 546 min and from 780 to 453 min, respectively. 4. NL-Nitro-L-arginine methylester was rapidly cleared from the plasma with a slow half-life of approximately 7.5 min and there was a simultaneous appearance of NOLA in the plasma. 5. These results support the view that nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in CI of NOLA with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical studies.  相似文献   

7.
1. The vasodilator effects of hydralazine in vitro, using the Krebs’ perfused human placental lobule was studied. Single placental lobules were bilaterally perfused (maternal and fetal sides 5 mL/min each, 95% O2, 5% CO2, 37°C) and changes in fetal arterial pressure (FAP) and venous outflow (VO) were recorded. 2. Submaximal vasoconstriction was induced by KCl (20–50 mmol/L), which increased basal FAP from 22.8 ± 1.7 to 91.3 ± 3.9 mmHg (n = 9 , P<0.001), and decreased VO from 4.1 ± 0.6 to 0.2 ± 0.1 mL/min (n = 6 , P<0.01). 3. Hydralazine caused vasodilatation (IC50 1.9 mmol/L, n = 9) and increased VO in the presence of KCl-induced vasoconstriction. 4. Infusion of Nω-nitro-L-arginine (100 μmol/ L) to block nitric oxide synthase caused the basal FAP to increase from 30.9 ± 5.9 to 47.4 ± 6.7 (n = 6 , P<0.05) and significantly potentiated hydralazine-induced vasodilatation (n = 7 , P<0.05). 5. The soluble guanylate cyclase inhibitor LY 83583 (6-anilino-5,8-quinolinedione) (1 μmol/L) significantly antagonized the vasodilatation produced by hydralazine (n = 5 , P<0.05). 6. Thus, hydralazine appears to activate guanylate cyclase, leading to increased cyclic GMP in fetal arterial vascular smooth muscle to cause vasorelaxation. No evidence was obtained to suggest that hydralazine exerted its action by either releasing nitric oxide from endothelial cells in the placenta or acting as a nitric oxide donor.  相似文献   

8.
1. Pressure-induced tone and flow-induced dilations were studied in a rat perfused epicardial coronary artery mounted in an arteriograph. Spontaneous tone was assessed in arteries submitted either to 60 or 90 mmHg intraluminal pressure either under control conditions, after incubation with NG-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L) or after endothelial denudation. Flow-induced dilation was quantified under these conditions in preparations either submitted to 60 mmHg and preconstricted with 10 mumol/L 5-hydroxytryptamine (5-HT) or exhibiting spontaneous tone at 90 mmHg. 2. Spontaneous tone was greater at 90 mmHg compared with tone obtained at 60 mmHg (21 +/- 2 vs 10 +/- 2% reduction of the fully dilated diameter after sodium nitroprusside incubation, respectively). Incubation with L-NAME or removal of the endothelium significantly increased spontaneous tone at both pressures compared with control. 3. In arteries submitted to 60 mmHg and preconstricted with 10 mumol/L 5-HT, flow (0-800 microL/min) induced a continuous dilation (maximal value 63 +/- 4%). As a function of flow, shear stress first increased and then plateaued at values of approximately 76 +/- 6 dyn/cm2. After L-NAME incubation or endothelial denudation, the flow-induced dilation was reduced to the same extent and was obtained for higher values of shear stress (172 +/- 14 and 150 +/- 14 dyn/cm2, respectively). 4. In arteries exhibiting spontaneous tone, starting flow led, first, to a constriction followed by a dilation up to 76 +/- 4% of the initial tone. Incubation with L-NAME greatly altered flow-induced dilation. Endothelium removal further reduced the dilation obtained for very high values of shear stress (up to 300 dyn/cm2). 5. The present study shows that different patterns of vasodilation induced by flow can be observed, depending on the initial vasoconstrictor stimulus. In 5-HT-preconstricted arteries, flow-induced dilation appears to be fully dependent on the synthesis and release of nitric oxide. In arteries with spontaneous tone, a vasoconstrictor substance could be released for low values of flow. Nitric oxide is mainly, but not exclusively, responsible for the vasodilation. For both experimental conditions, removal of the endothelium greatly reduced the response, but a dilation was still observed.  相似文献   

9.
1. We have compared the effect of aminoguanidine with that of Nω-nitro-L-arginine methyl ester on isolated thoracic aortic rings obtained either from endotoxin (lipopolysaccharide, 10 mg/kg, i.v. for 3 h) or vehicle (saline) treated rats. 2. Administration of endotoxin for 3h resulted in a hypo tension and a significant reduction of pressor responses to nor-epinephrine (1 μg/kg, i.v.) in the anaesthetized rat. 3. In intact rings obtained from vehicle treated rats, amino guanidine (0.3 and 1mmol/L) had no significant effect on acetylcholine-induced relaxation (10-9–10-5mol/L), whereas Nω-nitro-L-arginine methyl ester (0.3mmol/L and 1mmol/L) abolished that response, suggesting that aminoguanidine does not inhibit the activity of constitutive nitric oxide synthase. 4. Relaxation induced by L-arginine (10-6–10-2mol/L) was competitively inhibited by both aminoguanidine (0.3 mmol/L) and Nω-nitro-L-arginine methyl ester (0.3 mmol/L) in endo thelium-denuded aortic rings obtained from endotoxin treated rats. 5. Three hours of endotoxaemia was associated with an impairment of contraction to norepinephrine (10-9–10-6 mol/L) in the endothelium-denuded aorta ex vivo. This hyporeactivity to norepinephrine was partially restored by treatment of the vessels either with aminoguanidine (0.3 mmol/L) or with Nω-nitro-l-arginine methyl ester (0.3 mmol/L) in vitro. 6. These results in isolated thoracic aortae of the rat reinforce that aminoguanidine is a selective inhibitor of the inducible nitric oxide synthase, whereas Nω-nitro-L-arginine methyl ester is a non-selective inhibitor of both the inducible and constitutive nitric oxide synthase.  相似文献   

10.
1. Nicotine (10 mumol/L) produced rapidly developing but transient contractions of anococcygeus muscle isolated from rats. The magnitude of the response varied considerably between preparations. Tachyphylaxis occurred, such that no response was elicited by the same or a larger concentration in the continued presence of 10 mumol/L nicotine. 2. Contractions produced by nicotine were not affected by atropine, but were abolished by Hexamethonium and the alpha-adrenoceptor antagonists prazosin and phentolamine. Contractions were absent in the anococcygeus muscles of rats pretreated with reserpine. 3. The alpha 2-adrenoceptor agonist UK14304, or guanethidine, raised the tone of the anococcygeus muscle, and converted responses to field stimulation and nicotine to relaxations. Nicotine-induced relaxations were more pronounced in the presence of UK14304 than guanethidine. 4. Relaxations produced by nicotine (1-18 mumol/L) were transient, and tachyphylaxis occurred. When precautions were taken to avoid tachyphylaxis, concentration-response curves could be constructed. The relaxations elicited by nicotine were abolished or greatly reduced by hexamethonium, tetrodotoxin or omega-conotoxin GVIA. 5. The nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (90 mumol/L) enhanced contractile responses to field stimulation and nicotine, and markedly reduced relaxations elicited by field stimulation and nicotine in the presence of UK14304. These relaxations were restored by L-arginine (270 mumol/L). 6. The results suggest that nicotine acts on nicotinic receptors of noradrenergic and nitrergic nerve terminals in the rat anococcygeus muscle, resulting in the release of noradrenaline and nitric oxide respectively.  相似文献   

11.
1. The effects of diphenylene iodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate-dependent oxidases (which generate superoxide anions), were studied on nitric oxide (NO)-mediated responses in isolated preparations of the rat aorta and anococcygeus muscle. 2. In aortic rings, the endothelium-dependent relaxant action of acetylcholine was reduced by DPI (0.3–10 μmol/L) in a concentration-dependent manner and abolished by the NO synthase (NOS) inhibitor L-nitro-NG-arginine methylester (l-NAME; 100 μmol/L). Relaxations induced by sodium nitroprusside (SNP) or NO were not affected by DPI or l-NAME. 3. In anococcygeus muscles, DPI (0.3–10 μmol/ L) as well as l-NAME (5–100 μmol/L) produced concentration-dependent reductions of relaxations produced by nitrergic nerve stimulation. Relaxations induced by NO and SNP were not affected by either DPI or l-NAME. l-Arginine (1 mmol/L) prevented the reduction of nitrergic relaxations by l-NAME but not by DPI. 4. Contractions of anococcygeus muscles elicited by exogenous noradrenaline (1 μmol/ L) were not affected or were inhibited by DPI (0.3–10 μmol/L), but the contractions elicited by noradrenergic nerve stimulation were significantly enhanced by DPI and l-NAME. When noradrenergic contractions had already been maximally enhanced by l-NAME (100 μmol/L), DPI produced no further enhancement. l-Arginine (1 mmol/L) prevented the enhancement of noradrenergic contractions by l-NAME but not by DPI. 5. The efflux of radioactivity induced by field stimulation from anococcygeus muscles previously incubated with [3H]-noradrenaline was not affected by either DPI or l-NAME. 6. Superoxide dismutase (SOD, 100 U/mL) had no significant effects on noradrenergic contractions, nitrergic relaxations, relaxations induced by NO or the actions of DPI in the rat anococcygeus muscle. 7. The results suggest that the effects of DPI in reducing the NO-mediated relaxations produced by acetylcholine in rat aortic rings and stimulation of nitrergic nerves in the rat anococcygeus muscle are due to the inhibition of NOS in these tissues. The effects of DPI were not sensitive to l-arginine, and thus the mechanism of inhibition of NOS differs from that of l-NAME.  相似文献   

12.
1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor NG-monomethyl -l -arginine (l -NMMA) and the endothelin ETA receptor antagonist BQ123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 μg/kg per min) was examined after l -NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. NG-Monomethyl-l -arginine (20mg/kg) increased BP (26–48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11 %; P < 0.05). 3. NG -Monomethyl-l -arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, l -NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following l -NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following l -NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, l -NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ETA receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ETA blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.  相似文献   

13.
1. Little is known about spontaneous slow rhythms in regional circulations. The present study was aimed at characterizing low-frequency (LF; 78–269 mHz) oscillations in the mesenteric and hindquarter circulations of conscious rats. 2. Mean arterial pressure (MAP) and indices (pulsed Doppler technique) of mesenteric (n= 25) and hindquarter (n= 23) blood flows were recorded in conscious, freely moving rats during 1 h periods. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205 s time series. 3. A major oscillation centred at 164±4mHz was present in the mesenteric, but not in hindquarter, circulation. Consequently, LF power accounted for approximately 43% of the overall variability of mesenteric blood flow. Cross-spectral analysis performed between MAP and mesenteric blood flow indicated that fractional changes in flow were approximately two-fold of those in MAP, in pressure, at the peak frequency. 4. Acute blockade of the autonomic, renin-angiotensin and vasopressin systems combined with noradrenaline infusion (n= 7) reduced the frequency of the mesenteric blood flow oscillation (115 ± 6 mHz) but did not change its contribution to overall flow variability (approximately 48%). A clear oscillation was still present after acute inhibition of nitric oxide (NO) synthesis with NG-nitro-l -arginine methyl ester (n= 8), but was virtually absent in chronically guanethidine-sympathectomized rats (n= 12). 5. In conclusion, the mesenteric blood flow of conscious rats exhibits a major slow oscillation that originates in the mesenteric vasculature and is not secondary to the activity of the major pressor systems or to the cyclic release of NO. Because of the strong attenuation of the oscillation in sympathectomized rats, we suggest that adrenergic vasoconstrictor tone plays a permissive role in its genesis.  相似文献   

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