UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
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Increasing evidence suggests that endogenous NO inhibits sympathetic outflow in anesthetized animals. However, in a recent study from this laboratory, we were unable to find any evidence of increased renal sympathetic nerve activity (RSNA) in response to blockade of NO synthesis in conscious rabbits. Because angiotensin II (Ang II) increases sympathetic outflow, one factor for this discrepancy may be the difference in the resting level of Ang II, which may be lower in well-trained conscious animals. In the present study, the effects of blockade of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg IV) on resting RSNA with and without a background intravenous infusion of Ang II (10 ng.kg(-1).min(-1)) was investigated in conscious rabbits. Intravenous administration of L-NAME (30 mg/kg) caused an increase in mean arterial blood pressure (MAP, from 80.4+/-2.9 to 92.8+/-2.5; P=.0001) and a decrease in RSNA (from 100+/-0% to 53.4+/-8.6%, P=.0016). When the elevated blood pressure was returned to control by infusion of hydralazine (0.01 to 0.06 mg.kg(-1).min(-1)), RSNA returned to the level before L-NAME administration. During a sustained infusion of Ang II (10 ng.kg(-1).min(-1)), L-NAME increased MAP from 89.2+/-2.9 to 109.0+/-4.3 mm Hg (P=.0101) and decreased RSNA from 100.0+/-0% to 53.7+/-7.5% (P=.0013). Under this circumstance, however, when the MAP was returned to the level that existed before the administration of L-NAME, RSNA increased significantly above the level that existed before the administration of L-NAME (164.5+/-17.7% versus 100+/-0%, P=.0151). The enhancement of the sympathetic response by Ang II was completely blocked by the AT1 receptor antagonist, losartan. In contrast, during a background infusion of phenylephrine, which increased MAP to the same level as produced by Ang II, L-NAME had no effect on RSNA when MAP was returned to the control level. Nomega-Nitro-D-arginine methyl ester had no effect on MAP and RSNA. Intravenous infusion of Ang II alone for 75 minutes had no effect on RSNA when MAP was returned to control levels. These data suggest that an elevated level of Ang II is critical for the inhibitory effect of NO on sympathetic outflow in conscious rabbits and imply that these two substances have a major impact on the regulation of sympathetic outflow.
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PMID:Angiotensin II-nitric oxide interaction on sympathetic outflow in conscious rabbits. 950 10

Central inhibition of nitric oxide synthase (NOS) by intracerebroventricular (i.c.v.) administration of NG-nitro-l-arginine methyl ester (L-NAME; 150 microg/5 microl) to conscious rats produced a biphasic pressor response characterized by an initial transient increase within 5 min, and a delayed response starting between 60-90 min. The effect was stereospecific, as D-NAME (250 microg/5 microl) did not modify the resting arterial blood pressure, nor did L-arginine (323 microg/5 microl, i.c.v.), indicating the substrate for NOS is not rate-limiting. Intracerebroventricular pretreatment with losartan (25 microg/5 microl), a non-peptide antagonist of the angiotensin II AT1 receptor subtype, or indomethacin (100 microg/5 microl), a blocker of cyclooxygenase, however, prevented the initial increase in blood pressure without affecting the delayed pressor response. In contrast, neither intravenous losartan (10 mg/kg b.wt) nor prazosin, an alpha1 adrenergic receptor antagonist, at doses of 5 microg/5 microl (i.c.v.) or 0.3 mg/kg b.wt (i.v.) were effective in altering the pressor responses. These results indicate that centrally produced NO maintains the resting arterial blood pressure at least partially through modulation of the brain angiotensin system and prostaglandins.
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PMID:Brain ANG II and prostaglandins mediate the pressor response after central blockade of nitric oxide synthase. 951 69

Previous reports correlate plasma levels of estrogen with increased nitric oxide (NO) production. To investigate whether the hemodynamic effects of estrogens are mediated by NO, we compared the hemodynamic changes induced by 17 beta-estradiol (100 micrograms/kg) in the absence and presence of the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). All protocols were performed in ovariectomized, conscious rats. Estradiol alone resulted in no significant changes in cardiac index (CI) or mean arterial pressure (MAP). However, in the presence of L-NAME, estradiol induced a significant increase in total peripheral resistance (TPR) of 37.3 +/- 11.7% and a decrease in CI of 27 +/- 4.9%, without changes in MAP. Previous blockade of angiotensin II AT1 receptors with losartan prevented any change in CI and TPR induced by 17 beta-estradiol in the presence of L-NAME. These observations suggest that NO is necessary to offset a vasoconstrictor action of angiotensin II, which is stimulated by estradiol administration.
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PMID:Hemodynamic effect of 17 beta-estradiol in absence of NO in ovariectomized rats: role of angiotensin II. 957 58

Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1 angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1 receptor blocker losartan did not modify the decreases in RBF or PBF secondary to L-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.
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PMID:Role of AT1 receptors in the renal papillary effects of acute and chronic nitric oxide inhibition. 958 Jan 45

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
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PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

1. We showed earlier that NO inhibition caused a left-shift and augmented Emax of the concentration-response curve of AT1-mediated (angiotensin II)-induced vasoconstrictions (AII-VC) in the rat kidney. The 0.01-0.1 nM AII-VC unmasked by the potentiating effect of NO inhibition, were sensitive not only to AT1 (L158809), but also to AT2 receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO-masked AT1/AT2-mediated component of the AII-VC in isolated indomethacin-perfused kidneys of the rat. 2. L-NAME increased 0.1 nM AII-VC 7.2 fold. Pretreatment of the kidneys with factor VIII antibody/complement or with the detergent CHAPS to damage endothelium, decreased carbachol-induced vasodilatation and blunted by 60 and 30% respectively, the enhancement of AII-VC during NO inhibition. 3. L-NAME also increased 3 microM noradrenaline (NA)-induced vasoconstriction (NA-VC) 8.1 fold. In contrast to AII-VC, endothelium damage was without effect on the enhancement of NA-VC by L-NAME, suggesting a dominant role of endothelium-derived NO in the enhancement of NA-VC. 4. During NO inhibition, ETYA (2 microM; an inhibitor of all arachidonic acid derived pathways) and alpha-naphtoflavone (10 microM; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 nM AII-VC. 5. In conclusion, during NO inhibition, the AT1-mediated constriction to low concentrations of AII, which is sensitive to AT2 antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII-mediated vasoconstriction through AT1 receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT2 receptors.
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PMID:AT2 antagonist-sensitive potentiation of angiotensin II-induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature. 969 80

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation. 2. Intrarenal artery (i.r.a.) infusion of Ang II (1-30 ng kg(-1) min(-1)) elicited a dose-dependent decrease in renal vascular conductance (RVC; -38+/-3% at 30 ng kg(-1) min(-1); P < 0.01) and increase in filtration fraction (FF; +49+/-8%; P < 0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1-30 ng kg(-1) min(-1) (+6+/-17%, +11+/-17%, +22+/-23%, and -5+/-9%, respectively, at 30 ng kg(-1) min(-1)). At higher doses, Ang II (100 and 300 ng kg(-1) min(-1)) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV. 3. Pretreatment with indomethacin (10 mg kg(-1) i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (-25+/-7% vs -38+/-3% at Ang II 30 ng kg(-1) min(-1)). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (-38+/-10% at 30 ng kg(-1) min(-1)); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1-30 ng kg(-1) min(-1), and was not accompanied by any significant changes in Uv, UNaV or FENa (-21+/-12%, -18+/-16% and +36+/-38%, respectively). 4. Pretreatment with L-NAME (10 microg kg(-1) min(-1) i.v.) tended to reduce basal RVC (control -11.8+/-1.4, +L-NAME -7.9+/-1.8 ml min(-1) mmHg(-1) x 10(-2)), and significantly increased basal FF (control +15.9+/-0.8, +L-NAME +31.0+/-3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (-38+/-3% vs -35+/-13% at 30 ng kg(-1) min(-1)), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (-51+/-11%, -41+/-14% and -31+/-17%, respectively, at an infusion rate of Ang II, 30 ng kg(-1) min(-1)). When evaluated over the range of 1-30 ng kg(-1) min(-1), the effect of Ang II on GFR and Uv were statistically significant (P < 0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO. 5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1-30 ng kg(-1) min(-1)) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT1 receptor antagonist, GR117289 (1 mg kg(-1) i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT1 receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv. 6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.
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PMID:Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat. 972 60

We recently reported that administration of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) production, activates the vascular and cardiac renin-angiotensin systems and causes vascular thickening and myocardial hypertrophy in rats with perivascular and myocardial fibrosis. It has been reported that aldosterone may contribute to the development of cardiac fibrosis, but it is not known whether inhibition of NO synthesis affects angiotensin II (Ang II) receptor gene expression and aldosterone secretion. The aim of this study was to investigate the effect of NO inhibition on the expression of Ang II receptors in the adrenal gland and on aldosterone secretion in rats. Wistar King A rats received normal water, L-NAME alone (1 mg/mL in the drinking water), or L-NAME and the alpha1-adrenergic receptor blocker bunazosin (0.1 mg/mL in the drinking water) for 1 week. After 1 week of treatment with L-NAME, systolic blood pressure, plasma aldosterone concentration (PAC), and mRNA level and number of Ang II type 1 receptor (AT1-R) were increased. Plasma renin activity, serum angiotensin-converting enzyme activity, and the number of AT2-R were unchanged. Although addition of bunazosin to L-NAME restored systolic blood pressure to the control level, PAC and AT1-R numbers remained significantly higher than those of control level. These results suggest that the increased AT1-R number and PAC induced by the inhibition of NO synthesis were independent of blood pressure and systemic renin-angiotensin system. Therefore, hypertension and myocardial fibrosis induced by NO blockade may be due in part to an elevation of PAC caused by increased AT1-R in the adrenal gland.
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PMID:Regulation of angiotensin II receptor expression by nitric oxide in rat adrenal gland. 974 Jun 21

Chronic blockade of NO production induces hypertension and early occlusive and fibrotic end-stage organ damage owing to vascular lesions in the brain, kidney, and heart. In this study, we evaluated the inflammatory phenotypic changes induced in the arterial wall by chronic N(G)-nitro-L-arginine methyl ester (L-NAME) administration and the effect of an angiotensin II receptor (AT1) antagonist, irbesartan, on these changes. For this purpose, 2 groups of rats received L-NAME in the drinking water (50 mg x kg(-1) x d(-1)) for 2 months. One group received no other treatment and the other was treated with irbesartan (10 mg x kg(-1) x d(-1)). A third group (controls) received neither L-NAME nor irbesartan. After 8 weeks, plasma, aortas, and left ventricles were sampled from all 3 groups. Expression of inducible NO synthase (iNOS) was evaluated at both the mRNA (quantitative reverse transcription-polymerase chain reaction) and the protein (Western blot and immunohistochemistry) level in the aorta. Expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was evaluated by reverse transcription-polymerase chain reaction, Western immunoblotting, and immunohistochemistry; inflammatory cell infiltration by immunohistochemistry; and fibrosis by Sirius red staining. Chronic L-NAME administration induced the expression of iNOS in the aorta, which was localized in smooth muscle cells as shown by immunohistochemistry and NADPH diaphorase activity. ICAM-1 and VCAM-1 expression was also increased in aortas of L-NAME-treated rats. These phenotypic changes of the vascular wall were associated with inflammatory cell infiltration and fibrosis in the heart. All of these pathological phenomena were prevented by the angiotensin II antagonist irbesartan. The proinflammatory phenotypic changes of the vascular wall induced by blockade of NOS activity could be involved in the interaction between endothelial dysfunction and the development of arteriosclerosis.
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PMID:Chronic blockade of NO synthase activity induces a proinflammatory phenotype in the arterial wall: prevention by angiotensin II antagonism. 974 29

It has been shown that nitric oxide (NO) may regulate angiotensin II (Ang II) receptors in vitro. To determine whether the chronic inhibition of NO synthesis upregulates cardiac Ang II receptors in a rat model, we evaluated the in vivo effect of Nomega-nitro-L-arginine methyl ester (L-NAME) on several Ang II receptors and on the expression of AT1 receptor mRNA in heart tissue. The chronic administration of L-NAME to normal rats increased the arterial blood pressure. The number of AT1 and AT2 receptors was increased, with no change in affinity, during the first week of L-NAME administration but returned to control levels after 4 weeks of treatment. The AT1 receptor mRNA was changed parallel to AT1 receptor number. Inflammatory changes (monocyte infiltration and myofibroblast formation) in perivascular areas surrounding coronary vessels and myocardial interstitial spaces were observed during the first week. The immunohistochemistry revealed that myofibroblasts expressed AT1 receptor. AT1 receptor blockade or cotreatment with L-arginine, but not cotreatment with hydralazine, prevented the L-NAME-induced increase in Ang II receptors and inflammatory changes. In conclusion, rat cardiac Ang II receptors are upregulated at an early phase of chronic inhibition of NO synthesis. This may contribute to cardiovascular inflammatory changes in an early phase and to remodeling at the later phase, which occurs after inhibition of NO synthesis.
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PMID:Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats. 975 45

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