Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In lightly-anesthetized dogs, ionic or non-ionic RCM (Iotalamato and iohexol, respectively) when injected by intracarotid route (i.c.), elicit a pain response comparable to that caused by bradykinin (BK) or capsaicin (CAP). This response, which is characterized by vocalization, hyperpnea, bradycardia and neck muscle contraction, was dose dependent and related to the osmolarity of the RCM. In the present study we observed that indomethacin did not interfere with CAP and RCM-induced pain at dose (2 mg/kg i.c.) that reduced BK-elicited responses. In contrast, Ruthenium Red (RR), in dose (1 mg/kg i.c.) that reduced CAP and/or RCM-induced effects did not affect BK-induced phenomena. We also verified that L-NAME (50 mg/kg i.c.) reduced the BK-, but not the CAP- and/or RCM-induced pain responses which suggests that an L-arginine-derived NO or related compound is involved in BK activation of perivascular nociceptors. Indeed, we found that i.c. injection of 20 mg of S-nitrosocysteine, a putative EDRF, caused BK-like responses. On the other hand, RCM and CAP appear to activate the same RR sensitive ionic channels of primary afferent endings. Therefore, RR-analogues could constitute a novel approach to minimizing or eventually abolishing the RCM side effects.
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PMID:Mechanism of pain induced by radiocontrast media. 128 41

We investigated the effect of aging on atrial natriuretic peptide (ANP)-induced relaxation and cyclic GMP (cGMP) formation in the rat thoracic aorta. In the aorta from young rats (4 weeks old), removal of the endothelium, and treatment with the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), the radical scavenger, hemoglobin (Hb), and the soluble guanylate cyclase inhibitor, methylene blue (MB), attenuated ANP-induced relaxation and considerably reduced ANP-stimulated cGMP formation. With increasing age of the rats, the ANP-induced relaxation and cGMP formation in endothelium-intact aorta decreased, and Hb, L-NAME and MB no longer inhibited the ANP-induced effects, irrespective of whether the endothelium was present or absent. In the arteries without endothelium, the age-associated reduction in ANP-induced relaxation was less than in arteries with endothelium. Aging also decreased the relaxation induced by the soluble guanylate cyclase activator, nitroprusside. Potentiation due to the cGMP-phosphodiesterase (cGMP-PDE) inhibitor, M&B 22948, of the ANP-induced relaxation was greater in aortas from old rats than in those from young rats, suggesting that the degradation of cGMP may be accelerated in old rats. These results suggest that the relaxant action of ANP on the thoracic aorta from young rats is in part modulated by endothelium-derived relaxing factor (EDRF/nitric oxide), which in turn activates soluble guanylate cyclase, thus elevating the cGMP level. Aging may decrease the ANP-induced relaxation and ANP-stimulated increase in cGMP level by decreasing the ability of endothelial cells to produce EDRF, by decreasing guanylate cyclase activity, and by enhancing cGMP-PDE activity.
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PMID:Possible mechanisms of age-associated reduction of vascular relaxation caused by atrial natriuretic peptide. 135 Sep 88

1. An isolated, buffer-perfused rabbit ear preparation was used to investigate the influence of NG-nitro-L-arginine methyl ester (L-NAME) on endothelium-dependent vasodiltation and modulation of vasoconstrictor responses and vascular conductance. 2. Acetylcholine (0.55 pmol-1.6 nmol) caused dose-related vasodilatation of preparations constricted by the combination of 5-hydroxytryptamine and histamine (both 1 microM), with an ED50 = 31.1 +/- 7.8 pmol and a maximum dilatation of 69.9 +/- 4.3%. In the presence of 10 microM L-NAME the dose-response for vasodilator effects was shifted significantly (P less than 0.001) to the right (ED50 = 3.07 +/- 1.18 nmol) and there was a significant (P less than 0.01) depression of the maximum response (Rmax = 44.3 +/- 4.0%). The higher concentration of 100 microM L-NAME completely abolished vasodilatation to acetylcholine. L-Arginine (10 mM) did not reverse the inhibitory actions of L-NAME at either concentration. 3. L-NAME 100 microM, augmented vascular tone induced by 1 microM 5-hydroxytryptamine and 1 microM histamine, thus altering the characteristics of both pressure/flow and conductance/flow relationships such that conductance was reduced at all flow rates. The augmentation of constrictor tone was reversed in a concentration-dependent manner by L-arginine (10 microM-10 mM) and the effect of L-NAME on the conductance/flow relationships was similarly reversed by 10 mM L-arginine. The augmentation of tone was endothelium-dependent as it did not occur following functional destruction of the endothelium by perfusion of the vascular bed with the detergent CHAPS (0.3%) for 150s. 4. In conclusion, L-NAME is a potent inhibitor of agonist-induced endothelium-dependent vasodilatation. L-NAME reduces vascular conductance in pharmacologically constricted preparations and this emphasizes the important role of EDRF in vascular regulation. The ability of L-arginine to reverse L-NAME-induced inhibition of basal EDRF activity but not L-NAME-induced inhibition of agonistinduced endothelium-dependent relaxations suggests that there is pharmacological heterogeneity in the mechanisms responsible for the conversion of L-arginine to EDRF.
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PMID:Differential effects of L-arginine on the inhibition by NG-nitro-L-arginine methyl ester of basal and agonist-stimulated EDRF activity. 179 35

To what extent endothelial autacoids like endothelium-derived relaxant factor/nitric oxide (EDRF/NO), in addition to neural-humoral factors, are involved in the regulation of myocardial perfusion, is presently not known. Therefore, we investigated in conscious, chronically instrumented dogs the effect of stereospecific inhibitors (NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine (L-NNA), NG-monomethylester-L-arginine (L-NAME] of nitric oxide-synthesis and -release on epicardial coronary tone (and coronary diameter) and myocardial perfusion. A hydraulic coronary cuff was used, to produce reactive hyperemia and to keep the myocardial perfusion constant over short periods. 40 mg/kg L-NNA i.v. caused a long-lasting increase in mean arterial blood pressure from 94 +/- 8 to 129 +/- 11 mmHg and a simultaneous decrease in coronary diameter by 2.8 +/- 0.3%. Heart rate dropped from 87 to 58 min-1, but the double product of heart rate and blood pressure dropped by only 8 +/- 2% (p = 0.05). The maximal coronary conductance during peak reactive hyperemia (after 20 s ischemia) indicating complete coronary dilation was diminished by 48% after L-NNA. The severe drop in resting myocardial perfusion and O2-supply, and nearly unchanged rate pressure product and thus myocardial metabolic rate following the inhibition of nitric oxide formation demonstrate a substantial contribution of EDRF/NO to the regulation of myocardial perfusion.
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PMID:Endothelium-mediated regulation of coronary tone. 195 18

We investigated the effect of hypoxia on acetylcholine (ACh) stimulated, endothelium-derived relaxing factor/nitric oxide (EDRF/NO)-dependent relaxation, and on basal tension in rat aortic rings. ACh (10(-9)-10(-6) M)-mediated relaxation at high [95%, Emax -76.2 +/- 4.5% of phenylephrine (PE)-induced constriction] and normal (20%, Emax -81.2 +/- 3.6%) O2 levels was inhibited by hypoxia (5%, Emax -36.2 +/- 7.2%); residual hypoxic relaxation was blocked by the K+ channel antagonist glibenclamide. To address whether O2 influenced EDRF/NO and K+ channel contributions to basal tone, the effect of stepwise reduction of available O2 (95, 20, 5, and 0%) was studied in intact and endothelial cell (EC)-denuded rings. The effects in these rings were compared with results of the same progressive reduction in O2 in the presence of the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) or glibenclamide (10(-4) M). EC-intact and EC-denuded rings constricted to 0.80 +/- 0.10 and 1.41 +/- 0.15 g, respectively. Reducing O2 to 20% had no significant effect on vascular tension, but 5% caused constriction (p < 0.05) in EC-intact rings (0.90 +/- 0.15 g). This hypoxic vasoconstriction was blocked by L-NAME, but not by glibenclamide, suggesting that hypoxic vasoconstriction was mediated by withdrawal of EDRF/NO. In contrast, EC-denuded rings showed a significant relaxant response at 5% O2. When O2 was then reduced further (95% N2/5% CO2), both EC-intact and EC-denuded rings relaxed, and this relaxation reached baseline tension (0.10 +/- 0.1 g).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of oxygen on endothelium-derived relaxing factor/nitric oxide and K(+)-dependent regulation of vascular tone. 752 42

Endothelial cell nitric oxide synthase (ECNOS) is a membrane-associated enzyme that generates endothelium-derived relaxing factor/nitric oxide (EDRF/NO) from L-arginine. We have suggested, from the cloning of the bovine ECNOS cDNA, that the presence of an N-myristoylation consensus sequence may impart its membrane localization since cytosolic forms of NOS do not contain such domains. To test the hypothesis that N-myristoylation is necessary for particulate ECNOS, we performed site-directed mutagenesis of the myristic acid acceptor site, Gly-2, and changed the glycine codon to alanine by a single nucleotide substitution. Expression of wild-type ECNOS in COS cells resulted in greater than 95% of the enzymatic activity in crude membrane fractions (as measured by the conversion of [3H]L-arginine to [3H]L-citrulline). In contrast, expression of the Gly-2 to Ala-2 mutant (G2A) demonstrated 8% ECNOS activity in membranes and 92% in the cytosol. The back mutation (from Ala-2 to Gly-2, A2G) restored ECNOS activity to the particulate fraction as seen with the wild type. Both wild-type membrane ECNOS and cytosolic G2A ECNOS activities were dependent on NADPH and calcium and were inhibited to the same extent by NG-monomethyl L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME). Moreover, kinetic analysis of these enzymes revealed similar Kms for L-arginine (2-4 microM, n = 3), demonstrating that the mutation did not affect ECNOS function. Thus, N-myristoylation is necessary for the membrane localization of ECNOS and may be of special significance for the basal or flow-induced production of NO by the endothelium.
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PMID:Mutation of N-myristoylation site converts endothelial cell nitric oxide synthase from a membrane to a cytosolic protein. 768 Feb 89

Marked neointima formation occurs after balloon injury to the intima of rat arteries. Angiotensin II has been implicated as a growth factor in this process, since angiotensin converting enzyme (ACE) inhibitors block neointima formation after injury. However, ACE is an important kininase, and its inhibitors may act in part by a kinin-mediated mechanism. Kinins are also known to stimulate synthesis of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) and prostacyclin, both of which have antigrowth effects. To determine whether the effect of ACE inhibitors on neointima formation is due to blockade of angiotensin II synthesis alone and/or inhibition of kinin inactivation, we followed two approaches. First, we compared the inhibition of neointima formation induced by the AT1-type angiotensin II receptor antagonist losartan with that caused by the ACE inhibitor ramipril. We also studied whether a kinin receptor antagonist, Hoe 140, blocks the effect of two different ACE inhibitors, ramipril and enalapril, on neointima formation. In addition, we studied whether the effect of ramipril is blocked by an NO synthesis inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME). Although both ramipril and losartan significantly reduced neointima formation, ramipril had a more marked effect (p < 0.05 for ramipril versus losartan). The kinin antagonist Hoe 140 reduced the inhibitory effect of ramipril and enalapril by 73% and 62%, respectively. The remaining effect of the ACE inhibitors was now similar to that of losartan. Inhibition of neointima formation by ramipril was also blocked by the NO synthesis inhibitor L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. 768 31

We investigated the responses of canine coronary rings to endothelium-derived relaxing factor-nitric oxide- (EDRF-NO) dependent agonists and NO synthase (NOS) inhibitors 3 h after endotoxic shock was induced in dogs by lipopolysaccharide infusion (LPS; 2 mg/kg). EDRF-NO-dependent relaxation to thrombin [control maximum response produced after administration of thrombin (Emax) was -85.2 +/- 7.0% of the constrictor response produced by the thromboxane analogue U-46619], acetylcholine (control Emax -88.4 +/- 3.4%), or bradykinin (control Emax -80.5 +/- 2.2%) was not inhibited by LPS (Emax thrombin -75.9 +/- 9.5%; Emax acetylcholine -90.2 +/- 2.4%; Emax bradykinin -91.6 +/- 3.4%). The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (10(-6)-3 x 10(-4) M) caused constriction of rings with endothelium (Emax 36.3 +/- 5.6%), an effect that was greater after LPS (Emax 59.2 +/- 4.1%; P < 0.05). D-NMMA had no effect in control, but it increased tension after LPS (Emax 20.8 +/- 9.7%). Contrary to expectations, L- and D-NMMA relaxed endothelium-denuded rings (-30.4 +/- 8.7% L-NMMA; -45.1 +/- 11.7% D-NMMA; P < 0.05). However, neither agent caused relaxation after in vivo LPS (10.2 +/- 3.4% L-NMMA; 8.9 +/- 5.2% D-NMMA). N omega-nitro-L-arginine-methylester (L-NAME) and nitro-L-arginine (10(-6)-3 x 10(-4) M) increased tension (Emax 82.3 +/- 23.9 and 73.1 +/- 8.8%, respectively) but only when endothelium was present, and the increases were no greater in LPS-treated groups than in controls (with LPS: Emax L-NAME 87.3 +/- 16.5%; Emax nitro-L-arginine 65.7 +/- 3.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of NG-substituted arginines on coronary vascular function after endotoxin. 769 Jul 46

This study was done to investigate the mechanisms that underly the changes of renal renin gene expression upon hypoperfusion of one kidney. To this end the left renal arteries of male Sprague-Dawley rats were clipped with 0.2 mm silver clips and renal renin mRNA levels were assayed by RNase protection during the first ten days after clipping. Unilateral reduction of renal blood flow led to transient maximal fivefold increases of renin mRNA levels in the clipped kidneys and to sustained suppression of renin gene expression to 20% of the control value in the contralateral intact kidneys. Inhibition of prostaglandin (PG) formation by meclofenamate or EDRF synthesis by L-NAME markedly attenuated the increase of renin mRNA levels in response to clipping, and a combination of PG/EDRF inhibition almost abolished the increase of renin mRNA levels. Inhibition of PG/EDRF formation did not change the suppression of renin mRNA levels in the contralateral intact kidneys. Neither did renal denervation nor inhibition of macula densa function by furosemide prevent the suppression of renin gene expression in response to unilateral renal artery clipping. Only converting enzyme inhibition by ramipril and blockade of Ang II-AT1 receptors by losartan attenuated the decrease of renin mRNA levels in the contralaterals to clipped kidneys. These findings suggest that intact PG and EDRF synthesis represent stimulatory signals for renin gene expression that are required for the elevation of renin mRNA levels upon unilateral renal hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Control of renin gene expression in 2 kidney-1 clip rats. 770

The effects of 3,4-DHAP on hypoxic vasoconstriction response in pulmonary (PA) and basilar arterial (BA) rings of rabbits and their mechanism were compared in vitro. 3,4-DHAP in different concentration (2.64 x 10(-4), 7.92 x 10(-4), 2.376 x 10(-3) mol/L) decreased the basal tone of PA rings by 32.39 +/- 9.4 mg, 68.96 +/- 26.54 mg and 145.60 +/- 58.07 mg respectively, while the tension of the BA rings was decreased by 13.80 +/- 5.08 mg, 17.18 +/- 3.36 mg and 25.00 +/- 4.02 mg respectively. In PA rings it also decreased the percentage increase in tension induced by hypoxia (TIH%) from the control value 48.82 +/- 5.75% to 10.02 +/- 3.62%, 2.14 +/- 0.96%, and 0.00% respectively, while in BA rings from 27.27 +/- 5.78% to 11.23 +/- 2.71%, 7.49 +/- 1.62%, and 1.45 +/- 1.13% respectively. The effects of 3, 4-DHAP on TIH% were partially blocked by indomethacin 10 M and L-NAME 10 M. The results showed that 3, 4-DHAP can decrease the hypoxic pulmonary and basilar vasoconstriction in vitro, which can be partially inhibited by cyclooxygenase inhibitor and NO/EDRF inhibitor.
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PMID:Effects of 3,4-dihydroxyacetophenone on hypoxic vasoconstriction in isolated pulmonary and basilar arterial rings. 776 Apr 41


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