Specific Inhibitor Of Nitric Oxide Formation Research Articles

Role of adenosine and nitric oxide in the hyperemic response to superficial and deep gastric mucosal injury and H+ back-diffusion in cats.

This study was undertaken to examine the role of adenosine and nitric oxide (NO) in the hyperemic response to H+ back-diffusion into superficially or deeply injured gastric mucosa, and the role of adenosine in mucosa when blood flow was reduced with indomethacin. Cat stomachs were exposed to 2 M NaCl for 10 min followed by luminal perfusion at pH 1. Gastric mucosal blood flow was determined by radioactive microspheres, portal vein blood flow by transit-time flowmetry, and H+ back-diffusion/secretion by pH-stat titration, and concentrations of histamine in aortic and portal vein blood were measured. In the antrum pretreatment with the adenosine blocker 8-phenyltheophylline (8-PT) or with NG-methyl-L-arginine (L-NMMA), a specific inhibitor of NO formation, had no effect on the hyperemic response or mucosal injury. However, pretreatment with 8-PT in addition to indomethacin produced extensive deep lesions in the antrum. In the corpus/fundus 8-PT had no effect on the hyperemic response and did not increase indomethacin-induced lesions. L-NMMA significantly reduced the hyperemic response in corpus/fundus. In areas with deep lesions very high blood flow was observed in the vital part of the mucosa below the necrotic tissue. This hyperemia was reduced by L-NMMA but not by 8-PT. Indomethacin increased the release of histamine during base-line conditions, whereas 8-PT reduced histamine release after damage. This study indicates that usually adenosine is not involved in the hyperemic response to mucosal damage, but it appears to have important protective functions in the antral mucosa under marginal circulatory conditions. NO is one of the mediators of the hyperemic response to mucosal injury in the corpus/fundus.

Impairment of pulmonary-artery endothelium-dependent relaxation in chronic obstructive lung disease is not due to dysfunction of endothelial cell membrane receptors nor to L-arginine deficiency.

1. Endothelium-dependent relaxation mediated by endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), is impaired in pulmonary arteries (PA) of hypoxic patients with chronic obstructive lung disease (COLD). To determine the mechanisms responsible for this impairment, we compared the response of rings of isolated PA from 12 COLD patients and 8 controls to the endothelium-dependent vasodilators acetylcholine (ACh), adenosine diphosphate (ADP), and the calcium ionophore, A23187. The response of PA rings to the endothelium-independent nitro-vasodilator sodium nitroprusside (SNP) was also studied in both groups. The PA rings had been pre-contracted by the alpha-adrenoceptor agonist phenylephrine (PE). 2. Endothelium-dependent relaxation was significantly reduced in PA rings from COLD patients as compared with controls when tested with ACh (37.8 +/- 8.8% vs 73.4 +/- 7.9%), ADP (38.4 +/- 6.7% vs 80 +/- 5.6%), and the calcium ionophore, A23187 (35.8 +/- 6.1% vs 87 +/- 6.6%). Relaxation with SNP was, however, significantly greater in PA rings from COLD patients (99.4 +/- 0.6% vs 90.3 +/- 3.1%), as was the contractile response to PE (1.91 +/- 0.21 g vs 1.33 +/- 0.15 g). Pretreatment with the specific inhibitor of NO formation, NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) significantly reduced the relaxation to ACh in all PA rings. This inhibition could be reversed by L-arginine (10(-3) M), the substrate for NO synthesis. Pretreatment with L-arginine alone, however, did not restore the impaired endothelium-dependent relaxation of PA rings from COLD patients. 3. We conclude that EDRF (NO) production is impaired in PA rings from COLD patients and that this impairment is neither due to endothelial receptors dysfunction nor a defect of L-arginine availability and/or transport. Our hypothesis is that the abnormality must lie within the biosynthesis pathway of NO from L-arginine, possibly involving the endothelial enzyme cell, NO synthase, the normal function of which might be altered by chronic hypoxia.

Renal failure increases gastric mucosal blood flow and acid secretion in rats: role of endothelium-derived nitric oxide.

Because of the contradictory findings in clinical studies, and the complete lack of animal studies, the purpose of this investigation was to characterize the changes in gastric mucosal blood flow (GMBF) and acid secretion in an animal model of chronic renal failure. Rats with chronic renal failure induced by partial kidney infarction had a significantly higher basal GMBF and lower gastric vascular resistance than control rats. The gastric acid secretory and mucosal hyperemic response to pentagastrin were markedly enhanced in renal failure rats. Because endothelial-derived nitric oxide (NO) is an endogenous vasodilator that regulates gastric vascular tone, we hypothesized that NO mediates the gastric hyperemia of renal failure rats. The administration of N omega-nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of NO formation, produced a significantly greater decrease in GMBF in renal failure rats than in control rats, including a low dose inhibiting the basal hyperemia in renal failure rats but having no effect in control rats. It also attenuated pentagastrin-stimulated GMBF in both groups. In contrast, L-NAME produced a similar decrease in basal skeletal muscle blood flow in both renal failure and control rats. We conclude that in the renal failure rat 1) there is an increased basal GMBF and pentagastrin-stimulated acid output and GMBF, and 2) this gastric mucosal hyperemia is mediated by NO.

Role of endothelium-derived nitric oxide in the bleeding tendency of uremia.

Endothelium-derived relaxing factor, now identified as nitric oxide (NO), is a labile humoral agent formed by vascular endothelial cells from L-arginine. NO mediates the action of substances that induce endothelium-dependent relaxation and plays a role in regulating blood pressure. In this study we investigated whether NO is involved in the pathogenesis of the bleeding tendency associated with renal failure. Rats with extensive surgical ablation of renal mass develop renal insufficiency due to progressive glomerulosclerosis. Like uremic humans, rats with renal mass reduction and uremia have a bleeding tendency that manifests itself by a prolonged bleeding time. We found that N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation from L-arginine, completely normalized bleeding time when given to uremic rats. L-NMMA injection also increased ex vivo platelet adhesion but did not affect ex vivo platelet aggregation induced by adenosine diphosphate, arachidonic acid, and calcium ionophore A23187. The shortening effect of L-NMMA on bleeding time was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. It thus appears that NO is a mediator of the bleeding tendency of uremia.

Nitric oxid release may be involved in the microcirculatory response to acetylcholine

An image-splitter television microscope for measurement of microvascular dimension changes in the rat exteriorized mesentery was used to investigate the role of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) in the microcirculation. This was done by studying the effect of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation, on the responses induced by acetylcholine (an endothelium-dependent vasodilator agent) and sodium nitroprusside (an endothelium-independent vasodilator agent). The effect of acetylcholine on mesenteric A 2 arterioles was impaired by previous application of L- but not D-NMMA to the preparations whereas the vasodilator response to sodium nitroprusside was not altered. The effect of L-NMMA was slow to disappear, unless accelerated by a 3-fold molar excess of L- but not D-arginine. It is suggested that EDRF/NO might be involved in the vasodilator response to endothelium-dependent agents such as acetylcholine at the microcirculatory level and that L-arginine might be the physiological precursor of NO.

Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit.

1. The role of nitric oxide (NO) in the regulation of the vascular tone of the coronary circulation of the Langendorff-perfused rabbit heart was investigated. 2. NG-monomethyl-L-arginine (L-NMMA; 10-100 microM), a specific inhibitor of NO formation from L-arginine (L-Arg), but not its D-enantiomer (D-NMMA; 100 microM) produced a dose-related, sustained increase in the coronary perfusion pressure (CPP). In addition, L-NMMA inhibited the vasodilator responses of acetylcholine (ACh), unmasking in some instances its direct vasoconstrictor effect. These effects of L-NMMA were attenuated by L-Arg. 3. L-NMMA (10 and 30 microM), but not D-NMMA (30 microM), caused a long-lasting inhibition of NO formation which was reversed by L-Arg (30 and 100 microM), but not by D-Arg (100 microM). 4. This study indicates that the formation of NO from L-Arg in the coronary circulation of the rabbit plays a role both as a regulator of vascular tone and as a mediator of the vasodilatation induced by ACh.