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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 We have determined the dermal microvascular effects of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 nmol/site), endothelin-1 (ET-1, 0.1-10 pmol/site) and ET-3 (0.1-30 pmol/site) in rats with streptozotocin (STZ)-induced diabetes mellitus. Cutaneous blood flow changes as measured by a 133xenon (133Xe) clearance technique, were determined in diabetic rats four weeks after treatment with streptozotocin (STZ) and compared with responses measured in normal rats four weeks after treatment with saline. 2 Resting skin blood flow was similar in diabetic and in normal rats, as measured by 133Xe clearance and laser Doppler flowmetry. 3 Intradermal NG-nitro-L-arginine methyl ester (L-NAME) reduced skin blood flow in normal rats by 55.2 +/- 2.6% as measured by 133Xe clearance, (n = 9). L-NAME was significantly less effective in diabetic rats, inducing a 40.9 +/- 7.7% decrease in blood flow (n = 9, P less than 0.05). The enantiomer D-NAME had no effect in either group of rats. 4 Low doses of ET-1 and ET-3 injected intradermally induced dose-dependent decreases in blood flow, measured by 133Xe clearance, which were similar in both groups of rats. However, the responses to the highest doses of ET-1 (10 pmol/site) and ET-3 (10 and 30 pmol/site) were significantly reduced in the diabetic compared with the normal rats (P less than 0.05).In addition vasoconstriction to the highest doses of vasopressin (0.3 and 3 pmol/site) and vasodilatation to the neuropeptide calcitonin gene-related peptide (CGRP, 1O pmol/site) were similarly reduced in the diabetic rats (P <0.05).5. The decrease in blood flow induced by submaximal doses of ET-1 was enhanced by co-injection with L-NAME (100 nmol/site) in both diabetic and normal rats. However, this enhanced response was significantly reduced in the diabetic rats (P<0.05). A similar pattern of responses were observed to ET-3 in the presence and absence of L-NAME.6. These results indicate that the cutaneous microvasculature of rats with STZ-induced diabetes responds differently to intradermal ET-1 and ET-3 compared with normal rats; a similarly altered vascular reactivity was observed with vasopressin and CGRP. Hence, the diabetic microcirculation has impaired responses to several vasoconstrictors and a vasodilator. The effect of the nitric oxide synthase inhibitor L-NAME is also suppressed in the diabetics, suggesting that there may be decreased local production of, or response, to nitric oxide.
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PMID:Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus. 139 77

1. The response of the cutaneous microvasculature to intradermal injection of the endothelins (ET-1, ET-2 and ET-3) and the modulatory effect of endogenously produced nitric oxide (NO) have been determined in the rat. 2. Intradermal injection of endothelins (0.1- 10 pmol/site) induced dose-dependent local reductions in blood flow, measured by 133xenon clearance, with the following potency order; ET-1 = ET-2 greater than ET-3. 3. Laser Doppler blood flowmetry established that ET-1 (10 pmol/site) significantly (P less than 0.05) reduced microvascular blood flow for 3 h after injection. Over a wide dose-range, the response to the endothelins did not include any vasodilatation or visible flare. 4. A possible modulatory role of locally-produced NO was investigated by the intradermal injection of the potent inhibitor of NO generation NG-nitro-L-arginine methyl ester (L-NAME). L-NAME (100 nmol/site) injected alone induced a significant decrease in blood flow. The vasoconstriction induced by L-NAME was partially reversed by L-arginine (P less than 0.05) but not observed with NG-nitro-D-arginine methyl ester (D-NAME). 5. L-NAME significantly (P less than 0.05) enhanced the decrease in blood flow induced by submaximal doses of ET-1, ET-2 and ET-3 and vasopressin, although the results do not suggest that any of the vasoconstrictors stimulate NO release. The response to L-NAME was still observed 3.5 h after inducing a prolonged constriction with ET-1 (10 pmol/site).6. These results indicate that locally produced NO maintains a dilator tone in the cutaneous microvasculature of the rat and acts to modulate the effect of vasoconstrictors such as endothelins. Hence, it is suggested that in conditions where endogenous NO release is reduced, vasoconstrictor agents such as the endothelins could induce a dangerous decrease in blood flow possibly leading to ischaemia and tissue necrosis.
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PMID:Responses to endothelins in the rat cutaneous microvasculature: a modulatory role of locally-produced nitric oxide. 150 57

The vascular endothelium plays an essential role in regulating the contractility of the adjacent smooth muscle cell through its secretory and metabolic properties. One of these well known properties is the conversion of angiotensin I into angiotensin II. But the endothelium also secretes at least three compounds able to diffuse to the smooth muscle cell and exerting a paracrine action: these are the prostacyclin (PGI2), the endothelium derived relaxing factor (EDRF) and the endothelin 1. The secretion of these different vasoactive compounds by endothelial cells is triggered by mechanical events, such as the shear stress, or by the effect of several humoral factors locally released, for example from platelets. The compound NO (nitric oxide) is produced by the endothelial enzyme NO synthase from its precursor L-arginine, and is responsible for the vasodilatory and antiplatelets properties of EDRF. NO, by activating the soluble guanylate cyclase in the smooth muscle cell, is responsible for the endothelium dependent vasodilatation. We observed in an isolated perfused rat kidney that the compound L-NAME (NG-monomethyl-L-arginine methyl ester), a competitive inhibitor of NO synthase blocking the production of NO, induces renal vasoconstriction and inhibits renin release. This suggests that not only the renal vasoconstriction but also the renal vasodilatation are active processes, permanently regulated by vasoactive compounds such as EDRF. It seems also that EDRF plays an important role in maintaining the secretion of renin. It can be hypothetized that an abnormality in the release or fate of EDRF might perhaps contribute to high blood pressure, by both a direct effect on the vascular tone and an indirect effect on the release of renin, which in turn regulates also the renal and systemic hemodynamics.
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PMID:[Control of vascular tone by the endothelium: the coupling active vasodilation in the kidney to renin secretion]. 163 4

We investigated the endothelin (ET) receptors involved in the vasoconstrictor responses to ET-1 in rat pulmonary arteries and arterioles and the effect of endothelium removal, nitric oxide (NO) synthase inhibition, and hypoxia on ET-1-induced responses in the arteries. In isolated rat pulmonary artery rings (2-3 mm ID) prepared from the pulmonary artery branch before its entry into the lung, ET-1-induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were competitively antagonized by the ETA receptor antagonist FR 139317, and the ETB-receptor agonist sarafotoxin S6c (SXS6c) was a very weak vasoconstrictor in these vessels, inducing maximum contractions only 9% of those of ET-1. In contrast, in rat intrapulmonary resistance arteries (100-150 microns ID), SXS6c induced FR 139317-resistant contractions, and these vessels were more sensitive to SXS6c than to ET-1. SXS6c produced maximum contractions 92% those of ET-1, suggesting that ET-1-induced contractions were mediated by the ETB receptor in these resistance vessels. In the larger pulmonary arteries, the NO synthase inhibitor L-N omega nitroarginine methyl ester (L-NAME) (100 microM) potentiated responses to ET-1, an effect that was reversed by FR 139317. Endothelium removal also potentiated response to ET-1, and L-NAME had no effect on ET-1 responses in endothelium-denuded vessels, suggesting that in these vessels the ETA receptor-mediated responses to ET-1 are normally suppressed by endothelium-derived NO.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. 752 70

Neurohumoral changes influencing peripheral vascular resistance play a major role in congestive heart failure (CHF). We studied vascular function in 1-year-old cardiomyopathic syrian hamsters with pulmonary congestion and age-matched control hamsters. Aorta and mesenteric resistance arteries were suspended in organ chambers and myographs, respectively, for isometric tension recording. In aorta and mesenteric resistance arteries, contractile responses to norepinephrine (NE) were comparable in cardiomyopathic hamsters and controls. After inhibition of nitric oxide (NO) formation with nitro-L-arginine methylester (L-NAME), contractions to NE were enhanced in aorta of cardiomyopathic hamsters (p < 0.05); no effect was noted in controls or mesenteric resistance arteries. Low doses of endothelin-1 (ET-1 10(-10)-10(-9) M) caused stronger contractions in aorta of cardiomyopathic hamsters as compared with controls (p < 0.05). The sensitivity and maximal contraction to ET were more pronounced in mesenteric resistance arteries as compared with aorta in both cardiomyopathic and control hamsters (p < 0.05-0.001). In both aorta and mesenteric resistance arteries, acetylcholine (ACh 10(-9)-10(-5) M) induced concentration-dependent relaxation, which was prevented by L-NAME (p < 0.001). Maximal endothelium-dependent relaxation was more pronounced in aorta of cardiomyopathic hamsters (p < 0.05), but not different in mesenteric resistance arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activity of the L-arginine/nitric oxide pathway and endothelin-1 in experimental heart failure. 752 83

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.
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PMID:Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. 768 6

1. Using isolated pulmonary resistance vessels from mature fetal lamb and chronically instrumented lambs (8-17 days old), we have examined whether hypoxic pulmonary vasoconstriction is sustained by activation of a constrictor mechanism or suppression of a dilator mechanism. 2. Hypoxia contracted both arteries and veins in vitro, and the contraction was greater with the former. After removing the endothelium, arteries responded faster to hypoxia, but the magnitude of the response remained unchanged. 3. Hypoxic arteries, unlike normally oxygenated arteries, did not contract with either indomethacin (2.8 microM) or N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM). The same vessels relaxed with sodium nitroprusside (SNP, 0.001-10 microM) but not with bradykinin (0.1-100 nM). 4. Endothelin-1 (ET-1, 0.01-10 nM) contracted isolated arteries and veins under normoxic and hypoxic conditions. In both vessels, the contraction was fast in onset and subsidence, and was inhibited by the ETA receptor antagonist BQ123 (1 microM). The ET-1 precursor, big ET-1 (100 nM), also contracted arteries and veins, but compared with ET-1 its action was slower in development. Big ET-1 contraction, unlike ET-1 contraction, was curtailed by the inhibitor of the ET-1-converting enzyme, phosphoramidon (50 microM). 5. ET-1 (0.1-10 nM) had no effect on isolated arteries precontracted with a thromboxane A2 (TXA2) analogue (ONO-11113) and treated with BQ123 (10 microM). Under the same conditions, ET-1 relaxed the veins. Accordingly, in the absence of BQ123 treatment, the selective ETB receptor agonist IRL-1620 (0.1-100 nM) relaxed the contracted veins but not the arteries. 6. BQ123 (10 microM) inhibited the constriction of isolated arteries and veins to hypoxia. Likewise, in the conscious lamb a bolus of BQ123 (0.4 mg kg-1, injected into the pulmonary artery) curtailed the rise in pulmonary vascular resistance (Rpa) brought about by alveolar hypoxia without changing significantly systemic vascular resistance (Rao). Under normoxia, Rpa was insignificantly affected by BQ123. 7. The results indicate that pulmonary resistance arteries are more susceptible to hypoxia than the veins, and that hypoxic vasoconstriction does not require an intact endothelium to occur. Hypoxic tone is ascribed primarily to intramural generation of ET-1, while removal of the tonic action of a relaxant may only have an accessory role in the response.
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PMID:Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. 771 33

1. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L-arginine analogues was tested in isolated blood-perfused lungs of normal rats and rats exposed chronically to 10% O2. 2. In both groups of rats the analogues (N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine methyl ester (L-NAME)) enhanced hypoxic vasoconstriction. In normal rats, with rare exceptions, these analogues had little or no effect on pulmonary artery pressure (Ppa) at constant blood flow during normoxia. However, chronically hypoxic rats have pulmonary hypertension and in these rats the analogues always raised Ppa; the rise in Ppa after L-NMMA but not L-NAME could be partially reversed by L-arginine. L-NAME was more potent than L-NMMA. 3. To see whether the difference between rat groups was due to the high Ppa in chronically hypoxic rats, in control rats we raised Ppa passively by lung inflation to values higher than found in chronically hypoxic rats. L-NAME did not alter the effects of lung inflation on Ppa. 4. Ppa was also raised passively by plotting pressure-flow lines up to high flow rates; the lines were changed minimally by both analogues in control rats but in chronically hypoxic rats the lines were raised to higher pressures and steepened substantially. 5. In control rats, during vasoconstriction caused by hypoxia, endothelin 1 and almitrine, L-NAME caused further rises in pressure. We conclude that a stimulus for nitric oxide release in control rats is the narrowing of vessels caused by vasoconstriction rather than passive increases in intravascular pressure. 6. In chronically hypoxic rats arterioles are narrowed by growth of new muscle and there is some muscle tone even in normoxia. Thus narrowing of the vascular lumen is the stimulus common to both groups of rats which leads to nitric oxide synthesis and attenuation of Ppa by a negative feedback process. Narrowing is associated with a large increase in shear stress due to two factors; the pressure drop along a vessel segment is increased and the surface area of the lining of the affected segment is decreased. 7. Atrial natriuretic peptide caused dose-dependent pulmonary vasodilation in both rat groups but had a greater effect in chronically hypoxic rats. The action persisted and was enhanced after blockade of NO synthesis.
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PMID:Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats. 824 76

1. In order to investigate the control of renal vascular tone by endothelin (ET) and endothelium-derived relaxing factor (EDRF) under basal conditions, we infused intravenously anti-ET-1/3 antibodies (a-ET-1/3) and NG-nitro-L-arginine methyl ester (L-NAME) in split hydronephrotic rat kidneys. 2. A 25 min I.V. infusion of a-ET-1/3 (4.0 x 10(-13) mol kg-1 min-1) induced a time-dependent vasodilatation of arcuate (16.5%) and interlobular arteries (18.6%) as well as an increase of glomerular blood flow (GBF) by 32%. 3. Inhibition of EDRF synthesis by L-NAME produced a marked vasoconstriction of arcuate arteries (17.1%) and efferent (20.1%) arterioles and a decrease of GBF by 43%. 4. Co-infusion of a-ET-1/3 and L-NAME induced efferent vasoconstriction by 19.5%, whereas preglomerular vessel diameters remained unchanged. 5. The specificity of a-ET-1/3 effects was confirmed by simultaneous I.V. application of a-ET-1/3 and ET-1 (160 ng I.V.) which produced no significant vascular effects. Injection of ET-1 alone constricted arcuate arteries and decreased glomerular blood flow by 25%. 6. Experiments in normal rat kidneys with a-ET-1/3 I.V. revealed an increase of renal blood flow by 21%. 7. Our results demonstrate a physiological control of basal vascular tone in larger preglomerular arterioles by ET and EDRF. Efferent arteriolar tone is predominantly controlled by EDRF.
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PMID:Endothelin and endothelium-derived relaxing factor control of basal renovascular tone in hydronephrotic rat kidneys. 827 Dec 16

Although it is clear that vascular endothelial cells synthesize and release endothelin (ET), the contribution of this vasconstrictor peptide to the regulation of vascular tone appears limited in normal conditions. One possibility to explain this moderate effect is that continuous production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we tested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ETA and ETB receptors, or BQ-123 (3 mg/kg), an antagonist of ETA receptors, affected the hypertensive response induced by the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or NG-nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosentan or BQ-123 did not affect blood pressure. L-NAME significantly increased mean arterial pressure (% increase from baseline: 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; p < 0.05) or by BQ-123 (14 +/- 5%; p < 0.01). In contrast, bosentan did not affect the pressor response to phenylephrine. The response to L-NAME (3 mg/kg) was also reduced by bosentan in ganglion-blocked (chlorisondamine: 2.5 mg/kg; controls 89 +/- 10; bosentan: 45 +/- 7%) or pithed rats (controls: 165 +/- 9; bosentan 85 +/- 12%; p < 0.01). Bosentan also inhibited the pressor response to NG-nitro L-arginine (3 mg/kg-1) in normal (controls 24 +/- 5, bosentan 10 +/- 3%; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME induced a modest increase in plasma levels of ET-1 (controls: 26.8 +/- 4.1; L-NAME: 38.5 +/- 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.
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PMID:[Demonstration of a vasopressor role of endogenous endothelin after inhibition of nitric oxide synthesis in rats]. 857 76


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