Role Of Endothelium-derived Nitric Oxide Research Articles

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 nitric oxide in mediating renal response to volume expansion.

The objective of the present study was to determine the role of endothelium-derived nitric oxide in mediating the renal response to extracellular volume expansion with isotonic saline (5% body weight). In anesthetized dogs (n = 7) and before volume expansion, nitric oxide synthesis was inhibited in the right kidney by continuous intrarenal infusion of NG-nitro-L-arginine-methyl ester (1 microgram/kg/min). Arterial pressure and renal hemodynamics of both kidneys did not change significantly either during nitric oxide synthesis inhibition or during 5% volume expansion. However, in response to extracellular volume expansion, increases in natriuresis, diuresis, and fractional excretion of lithium (an index of proximal sodium reabsorption) were inhibited in the right kidney by 27%, 28%, and 41%, respectively, when compared with the contralateral kidney. Increases of renal interstitial hydrostatic pressure during 5% volume expansion were not statistically different between both kidneys. In another group of dogs (n = 4), the administration of L-arginine (0.5 mg/kg/min) into the right renal artery prevented the renal effects induced by the nitric oxide synthesis inhibitor during volume expansion. The findings in this study suggest that nitric oxide production plays an important role in regulating the renal response to extracellular volume expansion. The proximal tubule seems to be involved in the reduced renal excretory response to volume expansion during nitric oxide synthesis inhibition.

Inhibition of synthesis of endothelium-derived nitric oxide in conscious dogs. Hemodynamic, renal, and hormonal effects.

The role of endothelium-derived nitric oxide (EDRF/NO) for control of systemic and regional vascular resistances and for regulation of neurohumoral systems was investigated by studying the effects of the inhibitor of EDRF/NO-synthesis NG-nitro-L-arginine (L-NNA; 5 mg/kg) in six conscious dogs. L-NNA increased mean arterial pressure by an increase in total peripheral resistance, increased renal vascular, and total pulmonary resistances and reflexly decreased heart rate and cardiac output. Renal plasma flow, urine flow, and urinary sodium excretion were reduced, glomerular filtration rate was not affected. These changes were reversed by additional treatment with L-arginine (150 mg/kg). Plasma concentrations of renin, norepinephrine, vasopressin, and atrial natriuretic peptide were not changed by L-NNA. Our conclusions were that basal release of EDRF/NO plays an important physiologic role for control of systemic and regional vascular resistances, thereby controlling blood pressure, organ blood flow, and function. Neurohumoral systems are not affected by the inhibition of EDRF/NO synthesis and do not contribute to the observed vasoconstriction.

N omega-nitro-L-arginine blocks the second phase but not the first phase of the endothelium-dependent relaxations induced by substance P in isolated rings of pig carotid artery.

Endothelium-dependent relaxations can be evoked by a variety of stimuli, among them substance P (SP), which is found in sensory nerve fibers supplying the adventitia-media junction of most muscular arteries. This study determined the role of endothelium-derived nitric oxide as a mediator of endothelium-dependent relaxations to SP in isolated rings of the pig carotid artery suspended in organ chambers for isometric tension recording. SP (10(-12)-10(-7) M) caused concentration-dependent relaxations of arteries precontracted with norepinephrine (10(-7) M). The relaxations were characterized by a partially transient relaxation (phase 1) and a sustained relaxation of the artery (phase 2). The inhibitor of nitric oxide formation, N omega-nitro-L-arginine (L-NNA) methyl ester caused a gradual increase in tension, the phase I response at 3 x 10(-10) to 3 x 10(-7) M SP was shifted to the right, but the maximal relaxation was comparable in the presence of L-NNA. However, the sustained relaxation after addition of substance P (phase II) was lost and tension in the presence of L-NNA returned to a level above that induced by L-NNA and norepinephrine (10(-9) M). These results suggest that the endothelium-dependent relaxations to SP, particularly the prolonged relaxation (phase II), are due to de novo synthesis of nitric oxide and hence fully abolished by a specific inhibitor.

Role of phospholamban in No/EDRF-induced relaxation in rat aorta

The role of endothelium-derived nitric oxide (NO) to cause smooth muscle phospholamban (PLB) phosphorylation was studied in the isolated perfused rat aorta precontracted with norepinephrine using a back-phosphorylation technique. NO-induced relaxation was associated with increased PLB-phosphorylation while norepinephrine as such was ineffective. Removal of endothelium significantly reduced PLB-phosphorylation in indomethacin treated vessels. Stimulation of NO-formation by ATP augmented PLB-phosphorylation in intact vessels but was ineffective in denuded aortas. The results indicate that PLB-phosphorylation of vascular smooth muscle plays an important role in mediating NO-dependent relaxation by enhancing Ca ++-uptake into sarcoplasmic reticulum.

Endothelium-Derived Nitric Oxide as a Mediator of Acetylcholine-Induced Coronary Vasodilation in Dogs

To investigate the role of endothelium-derived nitric oxide (NO) in regulation of the tonus of the coronary artery system in vivo, the effect of NG-mono-methyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of NO from L-arginine, on acetylcholine (ACh)-induced coronary vasodilation was examined in open-chest, anesthetized dogs. At baseline, the infusion of ACh and adenosine into the left circumflex coronary artery (LCX) increased the LCX blood flow. Continuous infusion of L-NMMA (2 mumol/min, for 20 min) into LCX significantly attenuated ACh-induced increase in the LCX flow: percentage increases in the LCX flow by ACh (10 and 100 ng/kg) before L-NMMA were 42.0 +/- 8.7 and 137.3 +/- 12.5%, respectively, whereas those after L-NMMA were 14.0 +/- 4.9 (p less than 0.02) and 88.9 +/- 10.9% (p less than 0.005), respectively. L-NMMA showed no effect on adenosine-induced increase in the LCX flow. After the L-NMMA infusion was terminated, the effect of ACh partially returned to the baseline level. In other dogs, L-arginine (3 mg/min, for 20 min) was administered just after the L-NMMA infusion, which completely reversed the inhibitory effect of L-NMMA on ACh-induced vasodilation. Endothelium-derived NO is a mediator of ACh-induced vasodilation of the coronary resistance vessels in dogs.

Mediatory Role of Endothelium-Derived Nitric Oxide in Renal Vasodilatory and Excretory Effects of Bradykinin

Intrarenal infusions of 5 ng/kg/min bradykinin (BK) in 5 mg/kg intravenous bolus meclofenamate-treated anesthetized dogs significantly increased renal blood flow, diuresis, natriuresis, and kaliuresis. All these effects were abolished by the simultaneous intrarenal infusion of a competitive inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (LNMMA). Furthermore, the intrarenal infusion of this inhibitor alone also produced a significant decrease in basal renal blood flow. The administration of L-arginine, a precursor of nitric oxide, prevented the inhibitory effect of LNMMA on the renal vasodilatory and excretory response to BK. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. It is concluded that the renal vasodilatory and excretory responses to intrarenal BK in meclofenamate-treated dogs are largely dependent on endothelium-derived nitric oxide.

Oxidized, but not native low density lipoproteins inhibit relaxations of porcine coronary arteries by a scavenger receptor dependent mechanism: Role of endothelium-derived nitric oxide

Oxidized, but not native low density lipoproteins inhibit relaxations of porcine coronary arteries by a scavenger receptor dependent mechanism: Role of endothelium-derived nitric oxide

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.

Role of endothelium‐derived nitric oxide in the regulation of tonus in large‐bore arterial resistance vessels, arterioles and veins in cat skeletal muscle

The role of endothelium-derived nitric oxide in the regulation of vascular resistance (tonus) in cat skeletal muscle was studied with the use of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide formation from L-arginine. The study was performed with a whole-organ technique which permits simultaneous, continuous and quantitative recordings of resistance reactions in the whole vascular bed (RT) and in its three consecutive sections: large-bore arterial resistance vessels (greater than 25 microns; Ra,prox), small arterioles (less than 25 microns; Ra,micro) and veins (Rv). NG-monomethyl-L-arginine (3-100 mg kg-1 tissue, i.a.) induced a dose-dependent increase in resistance that was preferentially, but not selectively, confined to the large-bore arterial resistance vessels. At a maximally effective dose (100 mg kg-1), the nitric oxide inhibitor caused a marked constriction, within 5 min, on average increasing RT by 99%, Ra,prox by 138%, Ra,micro by 18% and Rv by 23%. The constrictor response to NG-monomethyl-L-arginine was long-lasting but disappeared gradually over a period of about 1 h. However, it could be abruptly abolished by excess L-arginine (300 mg kg-1, i.a.). The vasodilator response (RT) to acetylcholine was significantly attenuated in the presence of NG-monomethyl-L-arginine compared with the control response. The results suggested that nitric oxide formation from L-arginine by the vascular endothelium plays a fundamental role in the regulation of vascular resistance (tone) in vivo, with its main site of action located in the large-bore arterial resistance vessels.

Role of endothelium-derived nitric oxide in the regulation of blood pressure.

The role of endothelium-derived nitric oxide in the regulation of blood pressure in the anesthetized rabbit was studied with N omega-monomethyl-L-arginine (L-NMMA), a specific inhibitor of its formation from L-arginine. L-NMMA (3-100 mg.kg-1), but not its D-enantiomer, induced a dose-dependent long-lasting (15-90 min) increase in mean systemic arterial blood pressure. L-NMMA (100 mg.kg-1) also inhibited significantly the hypotensive action of acetylcholine, without affecting that of glyceryl trinitrate. Both these actions of L-NMMA were reversed by L-arginine (300 mg.kg-1), but not by D-arginine (300 mg.kg-1), indomethacin (1 mg.kg-1), prazosin (0.3 mg.kg-1), or by vagotomy. The effects of L-NMMA in vivo were associated with a significant inhibition of the release of nitric oxide from perfused aortic segments ex vivo. This inhibition was reversed by infusing L-arginine through the aortic segments. These results indicate that nitric oxide formation from L-arginine by the vascular endothelium plays a role in the regulation of blood pressure and in the hypotensive actions of acetylcholine.

ENDOGENOUS NITRIC OXIDE INHIBITS HUMAN PLATELET ADHESION TO VASCULAR ENDOTHELIUM

The adhesion of human platelets to monolayers of bovine endothelial cells in culture was studied to determine the role of endothelium-derived nitric oxide in the regulation of platelet adhesion. The adhesion of unstimulated and thrombin-stimulated platelets, washed and labelled with indium-111, was lower in the presence than in the absence of bradykinin or exogenous nitric oxide. The inhibitory action of both bradykinin and nitric oxide was abolished by haemoglobin, but not by aspirin, and was potentiated by superoxide dismutase to a similar degree. It is suggested that the effect of bradykinin is mediated by the release of nitric oxide from the endothelial cells, and that nitric oxide release contributes to the non-adhesive properties of vascular endothelium.