Reduction by indomethacin of furosemide effects in the rabbit

The effects of furosemide on urine flow, sodium and potassium excretion and on plasma renin activity (PRA) were studied in anesthetized rabbits with and without pretreatment with indomethacin 5 mg/kg. Furosemide caused a 10-fold increase in urine flow and in sodium excretion, and a 2-3 fold increase in PRA. Pretreatment with the prostaglandin synthesis inhibitor, indomethacin, reduced the effects of furosemide on diuresis and on electrolyte excretion by over 80% (p less than 0.01) and PRA did not increase over the initial level. The results suggest that the effects of furosemide on PRA and on urinary sodium excretion may be related to the intrarenal activation of the prostaglandin system.     

Free-radical scavengers, thiol-containing reagents and endothelium-dependent relaxation in isolated rat and human resistance arteries

1. Small arteries were isolated from either rat mesentery or human subcutaneous fat, and mounted in a myograph for the measurement of isometric force. 2. Superoxide dismutase, either in the presence or absence of catalase, relaxed noradrenaline-induced tone. This effect was abolished by removal of the endothelium or incubation with an inhibitor of NO synthase, N-omega-nitro-L-arginine methyl ester. Catalase alone had a negligible effect on noradrenaline-induced tone. 3. Captopril, an angiotensin-converting enzyme inhibitor and putative free-radical scavenger, did not relax pre-contracted isolated vessels. N-Acetylcysteine caused an endothelium-independent relaxation of rat vessels. Similar effects were observed in human vessels. 4. Acetylcholine induced a concentration-dependent relaxation of isolated resistance arteries, which was inhibited by removal of the endothelium or N-omega-nitro-L-arginine methyl ester, but unaffected by indomethacin. Preincubation with captopril, N-acetylcysteine or catalase alone did not alter the acetylcholine concentration-response relationship, but superoxide dismutase in combination with catalase enhanced responses to acetylcholine, causing a six-fold increase in potency. 5. Superoxide dismutase causes endothelium-dependent relaxation of resistance arteries and potentiates responses to acetylcholine. This action is probably due to the ability of the enzyme to scavenge superoxide anions which inhibit endothelium-dependent relaxation. 6. N-Acetylcysteine causes an endothelium-independent relaxation of resistance arteries which is probably unrelated to the putative ability of this compound to scavenge superoxide radicals and may reflect a direct action on vascular smooth muscle.     

Effects of dietary Spirulina maxima on endothelium dependent vasomotor responses of rat aortic rings

The aim of this study was to evaluate the effects of Spirulina maxima on vasomotor responses of aorta rings from male Wistar rats fed on a purified diet. For this purpose, the animals (weighing 200-240 g) were allocated randomly in two groups. One receiving purified control diet (A) and the other receiving purified diet containing 5% Spirulina (B). Purified diets were according to American Institute of Nutrition guidelines and adjusted to Spirulina protein content. All animals were fed (20 g/day/rat) during two weeks, receiving water ad libitum and 12 h. light-dark cycles. Spirulina maxima effects were evaluated by concentration-response (CR) curves of aorta rings with or without endothelium to phenylephrine (PE), both in presence and absence of indomethacin (Indom) or indomethacin plus L-NAME (Indom. + L-NAME), and to carbachol (CCh). Aorta rings with endothelium from group B showed, relative to corresponding rings from group A: 1) a significant decrease in the maximal tension developed in response to PE. 2) this decrease was reverted by Indom. 3) Indom. + L-NAME induced an additional increase in the contractile responses to PE. 4) a significant shift to the left of the CR curve to CCh. No significant differences were observed in the tension developed in response to PE in rings without endothelium from either group. These results suggest that Spirulina maxima may decrease vascular tone by increasing the synthesis and release of both a vasodilating cyclooxygenase-dependent product of arachidonic acid and nitric oxide, as well as by decreasing the synthesis and release of a vasoconstricting eicosanoid from the endothelial cells.     

Refractory ascites: definition, pathogenesis and treatment

Refractory ascites, that is ascites which cannot be mobilized by low sodium diet and maximal doses of diuretics (up to 400 mg spironolactone or potassium canrenoate and 160 mg furosemide per day), occurs in 5% of cirrhotic patients with ascites. The development of refractory ascites is mainly related to the progression of arterial vasodilation-mediated vascular underfilling and to the imbalance between reduced synthesis of renal vasodilating factors (especially renal prostaglandins) and extreme activation of vasoconstricting systems. Further features include increased sodium reabsorption in the proximal tubule and altered pharmacokinetics and pharmacodynamics of diuretics. In patients with impaired renal function (as is the case for most patients with refractory ascites), the marked reduction of renal perfusion and glomerular filtration rate, with the consequent decrease of filtered sodium load, becomes the main pathogenetic factor. The principal therapeutic options for refractory ascites include repeated paracentesis and implantation of the LeVeen shunt. Paracentesis is a rapid and safe procedure to remove ascites, but it does not correct sodium retention. Ascites recurrence, therefore, may occur after a brief interval. The LeVeen shunt allows for better long-term control of ascites, but severe complications may supervene, and shunt occlusion is common. Neither therapeutic procedure improves survival. Different experimental therapeutic procedures have been proposed. Administration of ornipressin corrects hyperdynamic circulation and improves renal function. Thromboxane synthase inhibitors, by reducing renal synthesis of thromboxane A2, potentiate the diuretic and natriuretic response to furosemide. More invasive procedures, including portosystemic shunt and transjugular intrahepatic stent, are rarely used in the treatment of refractory ascites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of indomethacin-induced inhibition of tubuloglomerular feedback by prostaglandin infusion

Experiments were performed in rats to study the effect of infusion of PGI2, PGE2, and PGF2 alpha on tubuloglomerular feedback responses (i.e. the change of SNGFR in response to a change of loop of Henle flow rate) in the presence and absence of simultaneous inhibition of endogenous PG synthesis with indomethacin. Infusion of PGI2 or PGE2 at rates that did not alter arterial blood pressure did not significantly modify the magnitude of feedback responses (PGI2 8.5 micrograms/hr, PGE2 85 micrograms/hr). Some inhibition of feedback responses was seen when PGI2 and PGE2 were administered at higher rates that were associated with a reduction of blood pressure (PGI2 20 micrograms/hr, PGE2 200 micrograms/hr). PGI2 (8.5 micrograms/hr) and PGE2 (85 micrograms/hr) largely prevented feedback inhibition induced by indomethacin. When given subsequent to indomethacin PGI2 and PGE2 restored feedback responsiveness almost to normal. In contrast, PGF2 alpha did not influence feedback inhibition caused by indomethacin. Infusion of PGI2 induced partial restoration of feedback responses in DOCA-salt treated animals in which the feedback system is virtually completely inactive. Our results indicate that availability of PGI2 or PGE2 is necessary for the normal operation of the tubuloglomerular feedback mechanism for control of nephron filtration rate.     

Influence of the estrous cycle on the norepinephrine-induced contraction of rat aorta: relationship to vascular prostanoids biosynthesis

Since ovarian sex steroids (estradiol and progesterone) may affect both blood pressure and prostanoids synthesis, and because prostaglandin-E2 (PGE2) and prostacyclin (PGI2) can modulate the vascular action of pressor hormones, we investigated the vascular reactivity to norepinephrine during the estrous cycle of the rat. In addition, we determined the vascular biosynthesis of PGE2 and 6-keto-PGF1 alpha (the stable metabolite of PGI2) at different stages of the estrous cycle. Cumulative dose-response curves were obtained by a stepwise increase in the concentration of norepinephrine. The contraction of thoracic aortic rings induced by norepinephrine did not change significantly between estrus, metestrus and diestrus. However, aortic rings obtained on proestrus showed a significant reduction in the maximal contraction (Emax) induced by norepinephrine (p < 0.001). In addition, we found significant increases in vascular synthesis of PGE2 and PGI2 on proestrus (p < 0.001). These results indicate that vascular reactivity and vascular prostanoids synthesis are influenced by the hormonal changes occurring during the estrous cycle of normal female rats. It is possible that prostanoids generated locally may play an important role in the regulation of vasomotor tone in the systemic vascular bed throughout the estrous cycle.     

Prostanoid production in umbilical vessels and its relation to glucose tolerance and umbilical artery flow resistance

OBJECTIVE: To study prostanoid synthesis in umbilical vessels relative to maternal glucose tolerance and umbilical artery blood flow resistance. STUDY DESIGN: Umbilical artery pulsatility index was determined by Doppler velocimetry in 21 women with diabetes or impaired glucose tolerance and 10 healthy women. Segments from the umbilical artery and vein were incubated and prostacyclin (PGI2) and thromboxane (TxA2) metabolites determined. Statistical analyses with the Mann-Whitney U test, Kruskal-Wallis test, Wilcoxon signed-ranks matched-pairs test, contingency table analysis, Fisher's exact test, and simple linear regression analysis were used and a two-tailed P value of < 0.05 considered statistically significant. RESULTS: No significant difference in PGI2 or TxA2 production was found in umbilical vessels between the women with diabetes/impaired glucose tolerance and controls, but the PGI2/TxA2 ratio in the vein was significantly lower in the diabetes/impaired glucose tolerance group. The umbilical artery pulsatility index was positively correlated to the PGI2/TxA2 ratio in cord vessel segments and to cord plasma TxA2 concentration. The cord plasma TxA2 concentration was significantly higher in cases with a high umbilical artery pulsatility index. The prostanoid production was not correlated to maternal HbA1c or cord plasma C-peptide concentrations. CONCLUSIONS: In association with diabetes, an increased 'peroxide vascular tone' and an enhanced 'endoperoxide shift' between platelets and vascular endothelium may explain the unexpected positive correlation found between the umbilical artery pulsatility index and the vascular PGI2/TxA2 synthesis ratio.     

The beta adrenoreceptor antagonist, nipradilol, preserves the endothelial nitric oxide response in atherosclerotic vessels of rabbit

We evaluated the effects of nipradilol, a beta-adrenoreceptor antagonist which contains a nitroxy residue, for vascular response in atherosclerosis of rabbits. Four groups of rabbits received different diets (standard diet; standard diet plus 10 mg/kg/day nipradilol; atherogenic diet [standard diet plus 1% cholesterol]; atherogenic diet plus 10 mg/kg/day nipradilol) for 9 weeks. Plasma lipids, blood pressure, vascular function, nitric oxide (NO), activity of NO synthase, cGMP, and histological atherosclerotic changes were evaluated. Neither the atherogenic diet nor nipradilol treatment affected significantly the animals' body weight, blood pressure, or heart rate. The atherogenic diet increased total cholesterol and triglycerides, which were not altered by nipradilol. The atherogenic diet diminished the acetylcholine-induced NO mediated relaxation. Nipradilol treatment restored this relaxation. Analyses using a NO-sensitive selective electrode showed that nipradilol released NO in the presence of cells and that NO release was greater in atherosclerotic aorta with than without nipradilol treatment. Nipradilol treatment increased the basal NO release as evaluated by the aortic tissue cyclic GMP (cGMP) levels in atherosclerotic vessel, and reduced the esterified cholesterol levels in atherosclerotic vessel. Conclusively, NO released by nipradilol may protect endothelium derived relaxation in atherosclerotic vessels, and may partially inhibit the accumulation of cholesterol in the atherosclerotic lesions.     

Effect of captopril cardioplegia on renin-angiotensin system, prostaglandins, free radicals and electrolytes in the isolated hypothermic ischemic and reperfusion rabbit hearts

The effect of captopril cardioplegia on ischemic and reperfusion myocardium after 3 hours of hypothermic (13 +/- 1 C) arrest and 35 minutes of reperfusion was studied in the isolated working rabbit heart. In comparison with the control group, captopril cardioplegia reduced the content of angiotensin II (381 +/- 56 vs 507 +/- 84 pg/g wt of the control group, P < 0.01) and MDA (50.0 +/- 9.2 vs 85.1 +/- 16.1 pmol/mg pr, P < 0.01) in the reperfusion myocardium; augmented the renin activity of ischemic (1050 +/- 353 vs 669 +/- 301 pg/g wt/h, P < 0.05) and reperfusion myocardium (1261 +/- 421 vs 498 +/- 353 pg/g wt/h, P < 0.01) increased the 6-K-PGF1 alpha/TXB2 ratio in the reperfusion myocardium (by 48.1% of the control group). Meanwhile, captopril cardioplegia could also decrease the content of calcium (0.027 +/- 0.015 vs 0.045 +/- 0.014 microM/mg pr, P < 0.05) and sodium (0.54 +/- 0.26 vs 0.82 +/- 0.15 microM/mg pr, P < 0.05) in the reperfusion myocardium, but had no effect on the potassium content. The results show that the protective effect of captopril on hypothermic myocardium may be related to the free radical scavenging action, inhibition of angiotensin II production, improvement of PGI2/TXA2 ratio and decrease of calcium and sodium overload in the myocardium.     

Endothelial prostaglandin and nitric oxide synthesis in atherogenesis and thrombosis

Human arterial thrombotic disorders are triggered by many agents, with participation of platelets and monocytes, blood coagulation factors and vascular cells. Platelet hyperaggregability appears to be an important risk factor for these disorders. Vascular endothelium possesses several properties to defend against vascular insults and thrombotic atherosclerotic lesions. Two molecules, prostacyclin (PGI2) and nitric oxide (NO), are of particular importance. The rate-limiting step of PGI2 synthesis is cyclooxygenase (COX). Constitutive and upregulated constitutive COX (COX-1) expression and inducible COX (COX-2) expression are important in PGI2 production required for the physiologic and pathologic defense of blood vessels and blood fluidity. NO synthesis is catalyzed by endothelial nitric oxide synthase (eNOS), which can be stimulated by lipid mediators. Virus or non-virus mediated transfer of COX-1 and eNOS are accompanied by augmented PGI2 and NO synthesis, respectively. In animal angioplasty models, it has been shown that transfer of these two genes has a dramatic antithrombotic and anti-intimal hyperplastic effect. Transfers of these two enzymes may have potential therapeutic uses.     

The effect of indomethacin and other anti-inflammatory drugs on the renin-angiotensin system

The administration of two different doses of indomethacin, 9 and 18 mg/kg, to two different groups of rabbits was followed 6 h later by a significant decrease in plasma renin activity, and these levels were not increased by hemorrhage. The administration of 2 mg/kg of indomethacin did not alter the basal levels of plasma renin activity, but it was effective in diminishing the peripheral increase of renin produced by hemorrhage. Similar effects were obtained in other groups of rabbits treated with 9 mg/kg of meclofenamate or 18 mg or aspirin. The lowering effect of indomethacin on plasma renin activity is not specifically related to hemorrhage because it also prevented the increase in plasma renin activity elicited by 5 mg/kg of furosemide. Further studies showed that indomethacin did not exert any significant effect in vivo on the plasma level of renin substrate or on the generation of angiotensin from normal plasma by exogenous renin. And indomethacin did not interfere with the binding capacity of anti-angiotensin I for angiotensin I in the radioimmunoassay reaction or with the in vitro formation of angiotensin from hog renin-nephrectomized rabbit plasma reaction. The results thus indicate that the lowering effect of indomethacin on plasma renin activity is due to the interference with renal renin release. That this effect may be related to the blockade of prostaglandin synthesis is suggested by the similar effect exhibited by other blockers of prostaglandin synthesis.     

Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure

Long-term administration of prostacyclin (PGI2) improves the hemodynamic state, symptoms, and survival in patients with primary pulmonary hypertension, but it increases mortality in patients with heart failure despite obvious hemodynamic benefits when it is given acutely. We evaluated the mechanisms of action of PGI2 in patients with heart failure and secondary pulmonary hypertension. Nineteen patients with end-stage heart failure and pulmonary hypertension, all candidates for heart transplantation, underwent right- and left sided cardiac catheterization with micromanometer-tipped catheters and were tested for PGI2 at incremental doses. PGI2 infusion significantly improved pulmonary hemodynamics with a 47% reduction in pulmonary vascular resistance (p=0.0003) and a doubling of pulmonary artery compliance (p <0.0001), reflecting improvement in pulmonary vascular tone. The dose of PGI2 necessary to reach this hemodynamic effect correlated significantly to the baseline severity of pulmonary artery compliance (r=0.54, p=0.01). Furthermore, PGI2 produced a significant positive inotropic effect (contractile element maximum velocity increased from 1.10+/-0.09 to 1.33+/-0.13 circ/s, p <0.009). The hemodynamic effects of PGI2 infusion were independent of the plasma and urinary levels of endogen prostaglandins. Thus, PGI2 at therapeutic doses exerts a positive inotropic effect in patients with heart failure, which may explain the increased mortality rate observed with the long-term use of PGI2 in this type of patient. The spectacular acute benefits on right ventricular afterload, however, may be useful in unstable patients with heart failure and secondary pulmonary hypertension or in transplanted patients with acute right ventricular failure of the donor heart.     

The effect of dopamine and PGI2 on indomethacin and alcohol-induced gastric lesions in rats of various ages in relation to gastric vascular permeability and HCl secretion

Gastric lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied in rats after a 24 hour fast. The size of gastric lesions was correlated with gastric HCl secretion and with gastric vascular permeability (determined from the Evan's blue concentration in the gastric tissue after its i.v. administration). These parameters were also studied in rats pretreated with either PGI2 (5 micrograms.kg-1) or dopamine (0.5 mg.kg-1). It was found that in 12-months old rats the gastric lesions were significantly higher compared with the 3-month old group. PGI2 and dopamine significantly decreased gastric lesions in the 3-month rats but not in 12-month old rats. Both indomethacin and ethanol increased gastric vascular permeability in both age groups. It was observed that the decrease of gastric lesions after pretreatment with PGI2 and dopamine in the 3-month old rats was followed with decreased gastric vascular permeability and HCl secretion. On the other hand the increased susceptibility of the gastric mucosa due to indomethacin in the 12-month old rats was followed by a decrease of HCl secretion. PGI2 or dopamine had any effect on the 12-month old rats. These results show that susceptibility of gastric mucosa to PGI2 and dopamine is dependent on age. (Fig. 3, Ref. 31.)     

Aorto-intestinal fistula as a possible cause of endoscopically undetermined gastrointestinal hemorrhage

Elastin peptides are present in human blood. As elastin receptors exist on several cell types, especially endothelial cells, this investigation was carried out to study the effect of elastin peptides on vascular tone. For this purpose, rat aortic rings were mounted in an organ bath for isometric tension measurements. Elastin peptides (kappa-elastin) were added in the concentration range of 0.1 ng/ml to 1 microgram/ml, concentrations similar to those found in the circulating blood. In rat aortic rings, precontracted or not with noradrenaline (10(-6) M), elastin peptides induced an endothelium-dependent vasodilation. The pretreatment of aortic rings with N-omega-nitro-L-arginine methyl ester (10(-5) M), an inhibitor of nitric oxide (NO) production, or with indomethacin (10(-5) M), an inhibitor of cyclooxygenase, prevented elastin peptide-induced vasodilation. These findings suggest that elastin peptides act through the synthesis of prostanoids, leading to the production of NO. Moreover, this relaxant effect of elastin peptides was decreased or inhibited when aortic rings were treated with lactose (10(-5) to 10(-2) M) or laminin (10(-6) to 10(-4) mg/ml) whereas lactose or laminin was unable to inhibit acetylcholine-induced vasodilation. These findings suggest that the inhibitory effects of lactose and laminin are specific for elastin peptide receptors and are in agreement with previous studies on these receptors. As there is evidence of the degradation of elastin in several vascular diseases, the concept that elastin peptides may contribute to the control of vascular tone is discussed.     

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin J (Ang I), and tetradecapeptide (TDP) renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 microM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 microM) significantly reduced (80-90%) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95%) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition.     

Involvement of thromboxane A2 in the mediation of the contractile effect induced by inhibition of nitric oxide synthesis in isolated rat middle cerebral arteries

Inhibition of nitric oxide (NO) synthesis induces vasoconstriction and reduction of the blood flow in the brain, indicating that basal release of NO provides a resting vasorelaxant tone in the cerebral circulation. In the present study, the contractile effect of the NO synthase blocker NG-nitro-L-arginine (100 mumol/L) in isolated rat middle cerebral arteries was attenuated markedly in the presence of the cyclooxygenase inhibitor indomethacin (5 mumol/L), the thromboxane A2 synthase inhibitor ridogrel (10 mumol/L), or the thromboxane receptor antagonist ICI 192605 (100 mumol/L). These results indicate that removal of the endogenous NO stimulates the release of thromboxane A2 in cerebral vessels and basal NO production regulates the resting cerebrovascular tone, at least in part, by suppressing thromboxane A2.     

Osmotic regulation of the Na+/myo-inositol cotransporter and postinduction normalization

BACKGROUND: The mechanisms underlying the vascular effects of propofol are not fully understood. Vasopressin, a potent vasoactive peptide, stimulates the arachidonate cascade and the synthesis of prostacyclin (PGI2; the main metabolite of the cascade in vascular smooth muscle cells). Arachidonic acid (AA) release by phospholipases is the rate-limiting step in the cascade. We investigated the mechanisms underlying vasopressin-induced AA release and the effect of propofol on PGI2 synthesis in a rat aortic smooth muscle cell line: A10 cells. METHODS: In cultured A10 cells pretreated with propofol, the stimulation by vasopressin of AA release and PGI2 synthesis was evaluated by measuring [3H]AA and 6-keto PGF1alpha, respectively, in the culture medium. The effects of propofol on vasopressin-induced activation of phosphoinositide-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D were evaluated by measuring inositol phosphate formation and choline formation, respectively. RESULTS: A phospholipase C inhibitor and a phosphatidic acid phosphohydrolase inhibitor both attenuated vasopressin-induced AA release and PGI2 synthesis, as did a phospholipase A2 inhibitor. Propofol inhibited vasopressin-induced activation of phosphoinositide-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D, but this effect of propofol was significant only at supraclinical concentration (0.1 mM). Propofol reduced vasopressin-induced PGI2 synthesis. The inhibitory effect was observed at concentrations (10 microM-0.1 mM) higher than those used clinically. CONCLUSIONS: Propofol suppresses the arachidonate cascade caused by vasopressin at least partly by inhibiting phosphoinositide-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D, resulting in the inhibition of PGI2 synthesis. Propofol-mediated inhibition of vasopressin-stimulated synthesis of PGI2 may reduce the vasorelaxation by propofol.     

Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury

In a rat model of glomerular immune injury induced by administration of anti-glomerular basement membrane antibody and resembling human rapidly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosanoids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2 and PGI2, but had no effect on that of thromboxane A2 (TxA2). The syntheses of 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and leukotriene B4 (LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effect of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4 synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that of COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL, or indomethacin proteinuria worsened. In those given the 5-lipoxygenase inhibitor there was no change in urine protein excretion. These observations point to regulatory interactions between the arachidonic acid and the L-arginine: NO pathways in glomerulonephritis. These interactions are of importance in considering antiinflammatory strategies based on inhibition of iNOS or of specific eicosanoids.     

Early effects of acute gamma-radiation on vascular arterial tone

1. To determine the acute effects of irradiation on the functionality of vessel, rat aortic rings were mounted in an organ bath for isometric tension measurements and irradiated (60Co, 1 Gy min(-1), 15 min). 2. Irradiation, which is without effect on non-contracted or endothelium-denuded vessels, led to an immediate and reversible increase in vascular tone on (-)-phenylephrine (1 microM)-precontracted aortic rings. The tension reached a plateau about 5 min after the beginning of irradiation. 3. The maximal radiation-induced contraction occurred on aortic rings relaxed by acetylcholine (ACh) (1 microM). In this condition, the addition of catalase (1000 u ml(-1)), which reduces hydrogen peroxide, and DMSO (0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level while superoxide dismutase (SOD) (100 u ml(-1)), a superoxide anion scavenger, reduced the observed contraction. A similar result was obtained in the presence of indomethacin (10 microM), a cyclo-oxygenase blocker. 4. Pretreatment of rings with the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (10-100 microM) inhibited the radiation-induced contraction. 5. This effect was dose rate-dependent and even occurred for a very low dose rate (0.06 Gy min(-1)). 6. The present results indicate that gamma-radiation induces an instantaneous vascular tone increase that is endothelium and dose rate-dependent. This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly reduced by SOD and (iii) inhibited by L-NAME, suggesting a major involvement of complexes between NO and superoxide anion.