Selective versus non-selective suppression of nitric oxide synthase on regional hemodynamics in rats with or without LPS-induced endotoxemia

The late phase of severe septic shock is associated with reduced cardiac output (CO) and activation of the inducible isoform of nitric oxide synthase (NOS). This study examined the effects of 1400 W (N-3-aminomethylbenzyl-acetamidine), a new selective inhibitor of inducible NOS (iNOS), relative to those of NG-nitro-L-arginine (L-NNA, non-selective inhibitor of NOS) and the vehicle, on mean arterial pressure (MAP), CO, total peripheral resistance (TPR) and tissue blood flow (BF) in thiobutabarbital-anesthetized rats with lipopolysaccharide (LPS, 10 mg/kg, i.v.) induced endotoxemia. At 2.5 as well as 4h after injection of LPS, MAP, CO, and BF of the stomach, skeletal muscle and skin were decreased, but TPR was increased, BF to the heart and kidneys were also decreased at 4 h after injection of LPS. Treatment of endotoxemic rats with 1400W (3 mg/kg followed by 3 mg/kg/h, i.v.) at 2.5 h after endotoxin challenge prevented the late phase fall in MAP without exacerbating the decreases in CO and tissue BF. In contrast, treatment with L-NNA (8mg/kg followed by 3 mg/kg/h, i.v.) at 2.5 h did not prevent the decline in MAP in the LPS-treated rats. Furthermore, CO drastically decreased, TPR markedly increased, and BF to the heart, brain, intestine and skeletal muscle were decreased at 4 h relative to the readings in saline- or 1400 W-treated endotoxemic rats. Therefore, selective inhibition of iNOS by 1400 W restores MAP without compromising CO, but non-selective inhibition of NOS is detrimental at the late stage of septic shock.link_to_subscribed_fulltex

Augmented pulmonary vascular and venous constrictions to N G-nitro-L-arginine methyl ester in rats with monocrotaline-induced pulmonary hypertension

The hemodynamic effects of NG-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide (NO) synthase) were examined in thiobutabarbital-anesthetized control- rats and rats with monocrotaline-induced pulmonary hypertension. L-NAME (1-16 mg/kg i.v.) increased mean arterial pressure, systemic vascular resistance, venous resistance and pulmonary vascular resistance, and decreased cardiac output in both the control and pulmonary hypertensive rats. Relative to the controls, L-NAME (16 mg/kg) caused a smaller increase (≈50% of control) in mean arterial pressure in the pulmonary hypertensive rats, but greater increases in venous (≈200%) as well as pulmonary vascular (≈400%) resistances and a greater decrease in cardiac output (≈140%). The results show that NO is an important dilator within the arterial, venous and pulmonary circulation; its pulmonary and venous dilator roles are augmented in pulmonary hypertension. Copyright © 2003 S. Karger AG, Basel.link_to_subscribed_fulltex

Chronic 17β-estradiol augments relaxant role of basal nitric oxide in blood vessels from rats with heart failure

The effects of chronic 17β-estradiol on endothelium-dependent relaxation to acetylcholine (ACh) and contraction to N(G)-nitro-L-arginine methyl ester (L-NAME), and endothelium-independent relaxation to sodium nitroprusside (SNP) were examined on blood vessels from rats with chronic heart failure (CHF). Two groups of ovariectomized female (50-60 days) rats were implanted with pellets containing 17β-estradiol (25 μg/day) or vehicle, and given ligation of the left main coronary artery 1 week later. Another group of ovariectomized rats was implanted with vehicle pellets, and sham-operated. After 7 weeks, thoracic aortic rings, pulmonary artery rings, and portal vein strips were prepared for in vitro studies. Relative to sham- operated rats treated with the vehicle, vessels from vehicle-treated, coronary-ligated rats had similar relaxation to ACh and SNP but reduced response to L-NAME that was significant (P<0.05) for the aorta and portal vein but not pulmonary artery. Treatment of ligated rats with 17β-estradiol augmented responses to L-NAME in the aorta, pulmonary artery and portal vein to values above those in sham-operated rat. 17β-Estradiol did not affect relaxation of any vessels to SNP and increased maximum relaxation to ACh only in the portal vein. Hence, 17β-estradiol enhances the relaxant role of basal nitric oxide in CHF.link_to_subscribed_fulltex

The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes

We examined if myocardial depression at the acute phase of diabetes (3 weeks after injection of streptozotocin, 60 mg/kg i.v.) is due to activation of inducible nitric oxide synthase and production of peroxynitrite, and if treatment with N-acetylcysteine (1.2 g/day/kg for 3 weeks, antioxidant) improves cardiac function. Four groups of rats were used: control, N-acetylcysteine- treated control, diabetic and N-acetylcysteine-treated diabetic. Pentobarbital-anaesthetized diabetic rats, relative to the controls, had reduced left ventricular contractility to dobutamine (1-57 μg/min/kg). The diabetic rats also had increased myocardial levels of thiobarbituric acid reactive substances, immunostaining of inducible nitric oxide synthase and nitrotyrosine, and similar baseline 15-F2t-isoprostane. N-acetylcysteine did not affect responses in the control rats; but increased cardiac contractility to dobutamine, reduced myocardial immunostaining of inducible nitric oxide synthase and nitrotyrosine and level of 15-F2t-isoprostane, and increased cardiac contractility to dobutamine in the diabetic rats. Antioxidant supplementation in diabetes reduces oxidative stress and improves cardiac function. © 2005 Elsevier B.V. All rights reserved.link_to_subscribed_fulltex

Use of A-192621 and IRL-2500 to unmask the mesenteric and renal vasodilator role of endothelin ETB receptors

Endothelin-1 (ET-1) is known to cause a transient (1 h) pressor response. The former through the activation of ETB receptors, and the latter through the activation of ETA and ETB receptors. This study examines if ETB receptors mediate sustained mesenteric and renal dilation in anesthetized rats. Intravenous bolus ET-1 (0.8, 1.4, and 2 nmol/kg) and IRL-1620 (ETB agonist, 2, 5, and 10 nmol/kg) caused transient decrease followed by sustained increases in mean arterial pressure (MAP) that were accompanied by increases in total peripheral resistance (TPR), reductions in cardiac output (CO), and mesenteric and renal vasoconstriction. Pretreatment with FR-139317 (ETA antagonist, 1 mg/kg) attenuated the pressor and constrictor effects of ET-1 but did not alter responses to IRL-1620. IRL-2500 (ETB antagonist, 5 mg/kg) slightly inhibited the renal constrictor effect of IRL-1620, whereas A-192621 (ETB antagonist, 5 mg/kg) abolished all hemodynamic responses to IRL-1620. Both IRL-2500 and A-192621 markedly enhanced MAP, TPR, and mesenteric, and the renal constrictor effects of ET-1. Therefore, A-192621 was more effective than IRL-2500 in blocking IRL-1620-induced vasoconstriction, but both augmented constrictor responses to ET-1. The potentiation of ET-1-induced vasoconstriction by ETB receptor antagonists revealed a sustained vasodilator role of ETB receptors.link_to_subscribed_fulltex

Attenuated arterial and venous constriction in conscious rats with streptozotocin-induced diabetes

We examined if arterial or venous constriction is impaired in early diabetes. Dose-pressor and mean circulatory filling pressure (index of venous tone) response curves to noradrenaline and angiotensin II were constructed in four groups of conscious, instrumented, Wistar rats pretreated with streptozotocin (60 mg/kg i.v.) or vehicle at 2 weeks prior to the study. Rats with diabetes, relative to controls, had increased ED 50 (reduced potency) for the pressor (2.5-fold of control) and mean circulatory filling pressure (4.3-fold of control) response to noradrenaline, as well as reduced maximum pressor response (efficacy) to noradrenaline (diabetic, 74±8 mm Hg; control, 96±5 mm Hg). Diabetic rats also had reduced potency (ED 50, 5-fold of control) of the pressor response to angiotensin II; however, maximum pressor response and dose-mean circulatory filling pressure curve to angiotensin II were similar in both groups. Therefore, arterial and venous constrictions are impaired at an early phase of type I diabetes. © 2002 Elsevier Science B.V. All rights reserved.link_to_subscribed_fulltex

Independent Influence of Parental Myopia on Childhood Myopia in a Dose-related Manner in 2055 Trios: The Hong Kong Children Eye Study.

PURPOSE:To determine the effects on childhood myopia of parental myopia, parental education, children's outdoor time and children's near wok. DESIGN:Population-based cross-sectional study METHODS: A total of 6,155 subjects in 2,055 family trios. Cycloplegic auto-refraction was measured for children and non-cycloplegic auto-refraction for parents. Parental education, children's outdoor time and near work were collected by questionnaires. Children were categorized into ten groups based on parental myopia levels. Associations of the above factors with myopia were evaluated by regression analyses. The areas under the receiver operating characteristic curve (AUROC) for myopia were evaluated. RESULTS:Mild parental myopia did not increase childhood myopia's risk, but the risk was 11.22-folds when both parents were highly myopic. Higher parental education (Father: OR=1.08, P=0.046; Mother: OR=1.11, P=0.001) and more reading time of children were risk factors (OR=1.21, P=0.044). Reduced odds of myopia were associated with more time spent on outdoor activities (OR=0.78, P=0.017) and on electronic devices (OR=0.80, P=0.005). Notably, all these factors became insignificant after adjustment, except for parental myopia. Children with more severe parental myopia spent more time on reading, but less on electronic devices. Parental myopic status alone accounted for 11.82% of myopia variation in children. With age and parental myopia, the AUROC for myopia was 0.731. CONCLUSIONS:Among parental and environmental factors, parental myopia confers, in a dose-related manner, the strongest independent effect on childhood myopia. Therefore children with high risk of myopia can be identified for early prevention, based on parental myopia data

Different optineurin mutation pattern in primary open-angle glaucoma

PURPOSE. The optineurin gene (OPTN) is the second gene besides MYOC in which mutations have been identified to be associated with primary open-angle glaucoma (POAG). In this study, sequence alterations in the OPTN gene associated with POAG in Chinese subjects were investigated. METHODS. All the coding exons of OPTN were screened, including the intron-exon boundaries, for sequence alterations in a Chinese sample of 119 sporadic patients with POAG and 126 unrelated control subjects by polymerase chain reaction-conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS. Sixteen sequence changes were identified: 3 had been reported (T34T, M98K, and R545Q) and 13 were novel (T49T, E103D, V148V, P199P, T202T, H486R, IVS6-5T→C, IVS6-10G→A, IVS7+24G→A, IVS8+20G→A, IVS13+21C→G, IVS15+10G→, and IVS15-48C→A). Among them, only E103D, H486R, V148V, and IVS13+21C→G were found exclusively in patients with POAG, whereas P199P, T202T, and IVS8+20G→A were present only in control subjects. The genotype of IVS7+24G→A showed a significant association with POAG (P = 0.02, Fisher two-tailed exact test) and with and increased cup-to-disc ratio in these patients (P = 0.005, Mann-Whitney test). CONCLUSIONS. The findings in the current study enrich the evidence on the OPTN gene as a causative gene for POAG and suggest a different mutation pattern of OPTN in Chinese than in whites. The wide spectrum of putative mutations detected in this study suggests that both structural and functional disruptions in OPTN may contribute to the pathogenesis of glaucoma.link_to_subscribed_fulltex