Effect of angiotensin-converting enzyme inhibitor on renal function in ovarian hyperstimulation syndrome in the rabbit.

OBJECTIVE: To investigate renal function and whether captopril prevents alterations in the handling of sodium and water in the ovarian hyperstimulation syndrome (OHSS) in the rabbit. DESIGN: Experimental study SETTING: Physiology laboratory. ANIMAL(S): Six female New Zealand white rabbits were used as controls, and 13 were hyperstimulated with gonadotropins. INTERVENTION(S): Saline or captopril. MAIN OUTCOME MEASURE(S): Renal excretory and hemodynamic variables. RESULT(S): The 3% extracellular volume expansion in OHSS animals induced a significant elevation in mean arterial pressure by 27%, although increments in natriuresis and diuresis were similar to those observed in controls. The OHSS group had impaired pressure-natriuresis sensitivity compared with controls (0.36 +/- 0.07 microEq/min/g of Na excreted per mm Hg vs. 1.74 +/- 0.45 microEq/min/g of Na excreted per mm Hg; P<.05. Captopril significantly reduced mean arterial pressure (P<.05) and shifted the pressure-natriuresis response to the left by 0.85 +/- 0.17 microEq/min/g of Na excreted per mm Hg (P<.05). CONCLUSION(S): In OHSS in the rabbit model, pressure-natriuresis sensitivity is impaired. Angiotensin II may play a significant role in this phenomenon, since angiotensin-converting enzyme inhibition normalized the pressure-natriuresis relationship.

17beta-estradiol prevents oxidative stress and decreases blood pressure in ovariectomized rats.

In this study, we tested whether estrogen deficiency is associated with oxidative stress and decreased nitric oxide (NO) production, which could be responsible for an increased blood pressure in ovariectomized rats. Hemodynamic studies were performed on conscious, chronically instrumented rats. Chronic estrogen replacement on ovariectomized rats lowered blood pressure approximately 13 mmHg, from 119 +/- 3 mmHg in ovariectomized rats to 106 +/- 3 mmHg in ovariectomized-treated rats; it was also accompanied by an increase in cardiac index and vascular conductance, achieving hemodynamic values similar to those shown by sham-operated rats. N(G)-nitro-L-arginine methyl ester administration lowered significantly less the vascular conductance (0.14 +/- 0.01 vs. 0.22 +/- 0.03 and 0.26 +/- 0.01 ml. min(-1). mmHg(-1)/100 g; P < 0.05) in ovariectomized rats than in the sham-operated and estrogen-treated ovariectomized rats, respectively. Estrogen replacement prevented the lower plasma levels of nitrites/nitrates observed in ovariectomized rats. The lower plasma total antioxidant status and reduced thiol groups and the increase in plasma lipoperoxides presented in ovariectomized animals were reestablished with the estrogen treatment. These results show that estrogen administration decreases blood pressure and increases vascular conductance in ovariectomized rats. This effect may be related to an increase in NO synthesis and/or preventing oxidative stress, then improving endothelial function.

Plasma redox status relates to severity in critically ill patients.

OBJECTIVE: To determine the relation between plasma redox status and severity of illness for patients admitted to an intensive care unit (ICU). DESIGN: A prospective cohort study. SETTING: A mixed medical and surgical adult ICU with 12 beds. PATIENTS: A total of 73 consecutive patients admitted to the ICU. INTERVENTIONS: Venous blood samples were routinely obtained within 24 hrs of admission. MEASUREMENTS AND MAIN RESULTS: Plasma total antioxidant capacity and lipoperoxides were measured by spectrophotometric technique at admission to the ICU. The plasma ratio total antioxidant capacity (mM)/lipoperoxides (microM) was used as an index of plasma redox status. Plasma concentration of the markers of leukocyte activation myeloperoxidase (enzyme-linked immunosorbent assay) and polymorphonuclear-elastase (immunoactivation assay) were also measured at admission to the ICU. Analysis of correlation between plasma ratio total antioxidant capacity/lipoperoxides and APACHE III score showed a negative association (p < .001, Spearman correlation test). Myeloperoxidase and polymorphonuclear-elastase correlated positively with Acute Physiology and Chronic Health Evaluation III scores (r2 = 0.58; p < .001; and r2 = 0.05; p = .035; respectively). CONCLUSIONS: Plasma redox status relates to severity in critically ill patients. We propose that it would be reasonable to provide antioxidant therapy as part of routine management of patients admitted to a mixed ICU, regardless of the specific reason for ICU admission. Plasma redox status might become useful to evaluate the risk in critically ill patients.

Depletion of liver glutathione potentiates the oxidative stress and decreases nitric oxide synthesis in a rat endotoxin shock model.

OBJECTIVE: To verify the effects of liver glutathione depletion on redox status and nitric oxide system in a rat endotoxic shock model. DESIGN: Prospective, randomized, controlled study on rats. SETTING: A cardiocirculatory research laboratory. SUBJECTS: A total of 28 Sprague-Dawley male rats (200-250 g body weight) were divided into four experimental groups. INTERVENTIONS: Arterial blood, liver, and lung samples were taken from each animal under sodium pentobarbital (40 mg/kg i.p.) anesthesia 4 hrs after lipopolysaccharide (LPS group: 5 mg/kg i.p.; n = 7) or vehicle (control group: isotonic NaCl sterile solution i.p.; n = 7) treatments. Phorone (250 mg/kg i.p.) was injected to deplete glutathione in another two experimental groups of rats 30 mins before LPS (phorone+LPS group; n = 7) or vehicle (phorone group; n = 7) treatments, and 4 hrs later the same samples as in LPS and control groups were taken under anesthesia. MEASUREMENTS AND MAIN RESULTS: Compared with the control group, the LPS group presented higher plasma concentration of end products of nitric oxide metabolism nitrites/nitrates, higher lung activity of inducible nitric oxide synthase, and oxidative stress defined by increased plasma concentration of the lipid peroxides malonaldehyde and 4-hydroxynonenal, and decreased plasma total antioxidant capacity. Treatment with phorone depleted liver glutathione (80% to 90%). In the liver glutathione-depleted animals, the oxidative stress induced by LPS was potentiated and blunted the increases in inducible nitric oxide synthase and plasma nitrites/nitrates. CONCLUSION: These results show that depletion of the liver glutathione increases the oxidative stress and decreases nitric oxide synthesis of LPS-induced shock in rats.

Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes.

OBJECTIVE: To assess the association of hot flushes during postmenopause with oxidative stress and to determine whether hormone replacement therapy (HRT) affects the plasma redox status of postmenopausal women. METHODS: We conducted a prospective clinical study of 49 postmenopausal women who have (n = 29) or do not have (n = 20) hot flushes. Twelve of the postmenopausal women with hot flushes and six without were treated with HRT (estradiol patches and medroxyprogesterone acetate) for 4 months. Plasma level of estradiol, total antioxidant status, reduced sulfhydryl groups, lipoperoxides, total cholesterol, and triglycerides were measured at 4-month intervals in both groups, before and after treatment. RESULTS: Postmenopausal women who have hot flushes, had lower total basal antioxidant status in plasma (.9 +/-.01 compared with 1.14 +/-.01 mmol/L), lower concentration of reduced sulfhydryl groups (145 +/- 4 compared with 200 +/- 3 micromol/L), and higher concentration of lipoperoxides (2.88 +/-.04 compared with 2.61 +/-.04 micromol/L) than women without hot flushes. After HRT, total antioxidant status and reduced sulfhydryl groups increased, and lipoperoxides decreased similarly in both groups. Hormone replacement therapy decreased the frequency of hot flushes per day from 11.2 +/- 0.8 to 1.4 +/- 0.3. CONCLUSION: Hot flushes in postmenopausal women were associated with the oxidative process. Hormone replacement therapy decreases oxidative stress and the number of episodes of hot flushes. Because oxidative stress is associated with a high risk for cardiovascular diseases, HRT might protect women with hot flushes.

Role of angiotensin II in modulating the hemodynamic effects of nitric oxide synthesis inhibition.

This study examined the role of ANG II in modulating the increase of hematocrit and vascular permeability that follows nitric oxide (NO) synthesis blockade, that are contributing to the decrease in cardiac index (CI) in conscious, chronically catheterized rats. Pretreatment with losartan attenuated the N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced increase in total peripheral resistance by 26% and also blunted the fall in CI (28%) and stroke volume. L-NAME produced an increase in hematocrit (4.5%) and in (125)I-labeled albumin content in the heart and small intestine in untreated rats, but the increase was prevented in rats pretreated with losartan. Furthermore, L-NAME induced a transient increase of plasma protein concentration and tissue intestinal blood flow, which was abolished in rats given losartan. The results of the present study indicate that the systemic hemodynamic responses, the fall in plasma volume, and the increase in albumin escape observed after inhibition of NO synthesis are in part the consequence of unmasking the actions of endogenous ANG II. These data suggest a physiological role for NO by restraint of the vascular actions of the renin-angiotensin system.

Effect of N-acetylcysteine on vascular endothelium function in aorta from oophorectomized rats.

1. Experiments were performed to examine and to compare vascular endothelial function in aortic rings from oophorectomized and from ovary-intact rats and to test the effect of thiol compound as N-acetylcysteine on endothelial function. 2. In precontracted aortic rings from oophorectomized and intact rats, vascular endothelial function was evaluated by measuring changes in isometric force in response to cumulative doses of superoxide dismutase, acetylcholine and sodium nitroprusside. 3. In studies designed to assess the tone-related release of nitric oxide from aortic rings moderately precontracted with phenylephrine, superoxide dismutase produced a lower concentration-related relaxant response in aortic rings from oophorectomized rats than from ovary intact rats. 4. Acetylcholine caused a concentration- and endothelium-dependent relaxation of less magnitude in aortic rings from oophorectomized animals compared with those from ovary-intact rats. Addition of N-omega-nitro-L-arginine methyl ester eliminated the relaxation induced by both superoxide dismutase and acetylcholine. 5. No differences between groups were noticed in the concentration-relaxation curve induced by sodium nitroprusside. 6. Preincubation with N-acetylcysteine normalized the depressed vasorelaxant response to acetylcholine in the aortic rings from oophorectomized rats, whereas the concentration-response curve for acetylcholine in aortic rings from ovary-intact rats did not alter. 7. These results suggest that the absence of ovary estrogens is associated with a vascular endothelium dysfunction that can be reverted by addition of N-acetylcysteine, a thiol-containing compound with a free radical scavenger effect.

Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion.

BACKGROUND: Renal ischemia is produced during orthotopic liver transplantation when the inferior vena cava is clamped above the renal veins (inferior vena cava occlusion [IVCO]), and it often leads to postoperative renal failure. Although free radicals and nitric oxide (NO) have been implicated in the pathogenesis of ischemic renal failure, the effect of free radical scavengers in this model is unknown. METHODS: The effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, on the acute renal failure that follows IVCO were evaluated in pentobarbital-anesthetized dogs. The effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester (NAME) was also studied. Renal vascular endothelial function was tested by infusing acetylcholine (Ach) into the renal artery before the ischemia and during reperfusion. RESULTS: Renal failure developed during IVCO and persisted during reperfusion in all groups. However, in NAC-pretreated dogs, the glomerular filtration rate recovered progressively, reaching 31% of basal preischemic values 150 min after reperfusion. During reperfusion, fractional excretion of sodium increased above preischemic values only in the control group, which indicates a beneficial effect of NAC and NAME on the tubular dysfunction observed during reperfusion. The renal response to Ach was abolished in control dogs and in animals given NAME during reperfusion, which indicates endothelial dysfunction. However, in NAC-pretreated dogs, the renal response to Ach was preserved during reperfusion. CONCLUSIONS: These results demonstrate that NAC ameliorates the renal failure and renal endothelial dysfunction induced by IVCO. This protective effect was abolished by NAME, which suggests that NO is involved in the beneficial effects of NAC. These data also suggest that the use of NAC could be beneficial in ameliorating the acute renal failure observed after orthotopic liver transplantation.

Role of nitric oxide on the central hemodynamic response to acute volume expansion in the pregnant rat.

OBJECTIVES: Our hypothesis was that during pregnancy nitric oxide acts as mediator in the hemodynamic response to volume expansion. STUDY DESIGN: The study was performed on 12 rats on days 19 to 20 of pregnancy. Six rats were injected intravenously with hexamethonium bromide plus the inhibitor of nitric oxide synthase L-nitro-arginine methyl ester. For a control group, six rats were injected with hexamethonium bromide plus the L-nitro-arginine methyl ester vehicle. A volume expansion (1.2% body weight) was performed in both groups by intravenous infusion of bovine albumin (6%) solution. RESULTS: In the control group volume expansion induced a hyperdynamic circulation characterized by increased cardiac output, decreased total vascular resistance, and no change in arterial pressure; however, in the study group volume expansion induced a pressor response without hyperdynamic circulation. CONCLUSION: During pregnancy volume expansion induces a hyperdynamic circulatory state possibly mediated by nitric oxide release. A defect in the release of nitric oxide may be responsible for an inadequate hemodynamic response to volume expansion.

Hemodynamic effect of 17 beta-estradiol in absence of NO in ovariectomized rats: role of angiotensin II.

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.

The NS2 polypeptide of parvovirus MVM is required for capsid assembly in murine cells.

Mutants of minute virus of mice (MVM) which express truncated forms of the NS2 polypeptide are known to exhibit a host range defect, replicating productively in transformed human cells but not in cells from their normal murine host. To explore this deficiency we generated viruses with translation termination codons at various positions in the second exon of NS2. In human cells these mutants were viable, but showed a late defect in progeny virion release which put them at a selective disadvantage compared to the wildtype. In murine cells, however, duplex viral DNA amplification was reduced to 5% of wildtype levels and single-strand DNA synthesis was undetectable. These deficiencies could not be attributed to a failure to initiate infection or to a generalized defect in viral gene expression, since the viral replicator protein NS1 was expressed to normal or elevated levels early in infection. In contrast, truncated NS2 gene products failed to accumulate, so that each mutant exhibited a similar NS2-null phenotype. Expression of the capsid polypeptides VP1 and VP2 and their subsequent assembly into intact particles were examined in detail. Synchronized infected cell populations labeled under pulse-chase conditions were analyzed by differential immunoprecipitation of native or denatured extracts using antibodies which discriminated between intact particles and isolated polypeptide chains. These analyses showed that at early times in infection, capsid protein synthesis and stability were normal, but particle assembly was impaired. Unassembled VP proteins were retained in the cell for several hours, but as the unprocessed material accumulated, capsid protein synthesis progressively diminished, so that at later times relatively few VP molecules were synthesized. Thus in NS2-null infections of mouse cells there is a major primary defect in the folding or assembly processes required for effective capsid production.