Role of propolis on biochemical parameters in kidney and heart tissues against l-NAME induced oxidative injury in rats

Nitric oxide (NO), produced by endothelial NO synthase, is recognised as a central antiinflammatory and antiatherogenic principle in the vasculature. Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, may improve vascular function by enhancing NO bioavailability. In this article, we investigated antioxidant effects of propolis on biochemical parameters in kidney and heart tissues of acute NO synthase inhibited rats by Nω-nitro-l-arginine methyl ester (l-NAME). There was increase (p?l-NAME treatment groups when compared with control rats, but NO levels were decreased in both kidney and heart tissues. There were statistically significant changes (p?l-NAME?+?propolis treated rats as compared with l-NAME-treated group. In summary, propolis may influence endothelial NO production.     

Protective effect of Ferula gummosa hydroalcoholic extract against nitric oxide deficiency-induced oxidative stress and inflammation in rats renal tissues

Abstract

Nitric oxide (NO) synthase inhibition increases hypertension and causes renal injury. Ferula gummosa is used in Iranian traditional medicine for treatment of several diseases and has been reported to exert a potent anti-inflammatory and antioxidant action. The aim of this investigation was to evaluate the renoprotective effects of hydroalcoholic extract of Ferula gummosa (HEG) on Nω-nitro-l-arginine methyl ester (l-NAME)-induced oxidative stress and inflammation and explore the mechanisms that link NO deficiency with altered renal heat shock protein (HSP70). Rats were injected intraperitoneally with l-NAME (10?mg/kg) to induce renal injury. Simultaneously, HEG (90?mg/kg) was administered by gastric gavage to l-NAME-treated rats for 6 days/week during an 8-week period. Renal thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), HSP70, plasma NO and total antioxidant capacity (TAC) were evaluated. The administration of l-NAME significantly increased renal TBARS, TNF-α, IL-6, HSP70 levels and decreased renal SOD activity, that these changes were accompanied by the reduced plasma NO and TAC levels. HEG administration decreased TBARS, HSP70, TNF-α and IL-6 levels and increased SOD activity in the kidney tissues of l-NAME treated rats (p?<?0.05). Also, plasma TAC level and NO bioavailability have been elevated after administration of HEG (p?<?0.05). These findings support that NO deficiency induces renal stress oxidative and inflammation, which markedly increased renal HSP70 and HEG could protect kidney against these damaging effects via its anti-oxidative, anti-inflammatory action and modulate renal HSP70.     

Endogenous nitric oxide modulates small intestinal nutrient transit and activity in healthy adult humans

Objective. Nitric oxide (NO) mechanisms have been shown to modulate fasting small intestinal motility in humans, but a role in the regulation of human postprandial small intestinal motility has not been assessed. The aim of this study was to evaluate the effect of the NO synthase inhibitor NG-monomethyl-l-arginine (l-NMMA) on the regulation of small intestinal nutrient transit and postprandial small intestinal motility in healthy humans. Material and methods. Seven healthy male volunteers (18–27 years) underwent antroduodenal manometry recordings for 4 h on 2 occasions after intraduodenal instillation of a 500 KJ [120 Kcal] test meal. The meal was administered 15 min after the commencement of a 60-min intravenous infusion of l-NMMA (4 mg kg^?1 h^?1) or saline (0.9%). Studies were separated, performed in randomized order and >3 days apart. The frequency and amplitude of duodenal pressure waves together with time to return of fasting motility (phase III) was determined. On each day, small intestinal transit was measured using a lactulose breath test. Results. The test meal interrupted fasting small intestinal motility in all subjects. The time to recurrence of fasting motility following its postprandial disruption was similar (l-NMMA versus saline 1.6±0.2 h versus 1.9±0.1 h; p>0.05). Duodenocaecal transit was delayed by infusion of l-NMMA compared with saline (l-NMMA versus saline 92.1±3.9 min versus 66.4±6.4 min; p<0.005). Infusion of l-NMMA significantly increased the frequency (l-NMMA versus saline 50.4±6.6 versus 34.8±5.5 waves per 30 min; p<0.05) and amplitude (l-NMMA versus saline 20.4±1.5 versus 15.5±1.1 mmHg; p<0.01) of duodenal pressure waves. Conclusions. These data suggest that endogenous NO may play a role in the regulation of small intestinal nutrient transit by regulating small intestinal motility in healthy individuals.     

Aldehyde dehydrogenase 2 partly mediates hypotensive effect of nitrite on l-NAME-induced hypertension in normoxic rat

Nitrite has become a topic of interest in the field of medical research because of its potential therapeutic role as an alternative source of nitric oxide (NO). While the bioconversion of nitrite to NO occurs via either nonenzymatic or enzymatic reduction under acidic or hypoxic conditions, little is known about its conversion to NO under normoxic conditions. Because of a recent report of aldehyde dehydrogenase 2 (ALDH2)-catalyzed glyceryl trinitrate (GTN) vasorelaxation by denitration of GTN to 1,2-glyceryl dinitrate (1,2-GDN) and nitrite, we therefore investigated a catalytic activity of ALDH2 for nitrite reduction and subsequent effect on N^ω-nitro-l-arginine methyl ester (l-NAME)-induced hypertension in normoxic rat. Male Sprague–Dawley rats treated with l-NAME in drinking water for 3 weeks developed hypertension with significantly reduced plasma levels of nitrite and nitrate. The intravenous injection of sodium nitrite lowered the arterial pressure in a dose-dependent manner (17, 50 and 150?μmol/kg). Pretreatment with ALDH2 inhibitors (cyanamide and chloral hydrate) partially inhibited the hypotensive responses to sodium nitrite. In addition, cyanamide significantly delayed the nitrite clearance from plasma and most of the organs examined during the experimental period. These results suggest that ALDH2 may be at least in part involved in nitrite-mediated hypotensive effects and nitrite catalysis in many organs of normoxic rats.     

Endothelial Dysfunction in the Human Umbilical Artery due to Preeclampsia Can Be Prevented by Sildenafil

Abstract

Objectives. We aimed to determine the effects of sildenafil in human umbilical artery preparation taken from preeclamptic or normal pregnant women, also to investigate underlying mechanisms in these effects. Study design. Eighteen pregnant women with preeclampsia and 18 healthy pregnant women were involved. Relaxation responses of sildenafil in presence and absence of nitric oxide (NO) synthase inhibitor, N-[omega]-nitro-l-arginine methyl ester (l-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), were compared between the preeclampsia group and control group. Results. Sildenafil-induced relaxation responses were significantly attenuated in the presence of preeclampsia, l-NAME or ODQ, but not totally abolished. Interestingly, except with ODQ incubation, in all set of experiments maximal relaxation response was achieved by sildenafil. Conclusion. These data indicate that sildenafil might effect vascular responsiveness of human umbilical artery through the involvement of NO/cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Further investigations are needed to clarify the exact mechanisms.     

Human blood platelets lack nitric oxide synthase activity

Reports on expression and functionality of nitric oxide synthase (NOS) activity in human blood platelets and erythrocytes are contradictory. We used a specific gas chromatography–mass spectrometry (GC–MS) method to detect NOS activity in human platelets. The method measures simultaneously [¹⁵N]nitrite and [¹⁵N]nitrate formed from oxidized ¹⁵N-labeled nitric oxide (¹⁵NO) upon its NOS-catalyzed formation from the substrate l-[guanidino-¹⁵N₂]-arginine. Using this GC–MS assay, we did not detect functional NOS in non-stimulated platelets and in intact platelets activated by various agonists (adenosine diphosphate, collagen, thrombin, or von Willebrand factor) or lysed platelets. l-[guanidino-nitro]-Arginine-inhibitable NOS activity was measured after addition of recombinant human endothelial NOS to lysed platelets. Previous and recent studies from our group challenge expression and functionality of NOS in human platelets and erythrocytes.     

Effect of Treadmill Exercise and Ferula gummosa on Myocardial HSP72, Vascular Function,and Antioxidant Defenses in Spontaneously Hypertensive Rats

This study evaluates the effect of treadmill exercise and Ferula gummosa (FG) on heat shock protein (HSP72), biomarkers related to vascular function, and oxidant/antioxidant system in the heart tissue of spontaneously hypertensive rats treated with N(ω)-nitro-l–arginine-methyl ester (l–NAME). Fifty adult male Wistar rats are randomly classified into five groups: treadmill exercise, FG, combination of treadmill exercise + FG, l–NAME, and saline. Treadmill exercise was performed between 25 and 64 minutes at the speed of 15–22 m per minute for 8 weeks and five sessions a week. The FG will be fed through gavage with 90 mg/kg dosage. Hypertension was induced by l–NAME (10 mg/kg) for 8 weeks and six sessions a week. Administration of l–NAME for 8 weeks caused significant increase in HSP72, angiotensin-converting enzyme (ACE), and protein carbonyl (PC), and significant decrease in glutathione peroxidase (GPx) and nitric oxide (NO) level, when compared with the saline group. In contrast, both treadmill exercise and/or FG protocols, in particular, the combined protocol, led to the improvement in HSP72 and balance in oxidant/antioxidant process and inhibited vascular dysfunction, when compared with the l–NAME group. Moreover, no significant differences were detected in the HSP72 level between rats in the treadmill exercise and FG groups. These results provide a rationale for an inhibitory role and a cardioprotective effect of lifestyle related to the health in the attenuation of hypertension-induced cardiotoxicity.     

Nitric oxide and prostaglandin as mediators in the pathogenesis of hyperkinetic circulatory state in a model of endotoxemia-induced portal hypertension

Aims

To evaluate the participation of nitric oxide (NO) and prostaglandin (PGI₂) on hyperdynamic state in endotoxemia-induced portal hypertension (EIP) induced by chronic endotoxemia.

Methods

The portal pressure (PP) and mean arterial pressure (MAP) were recorded, in vivo before and after administration of l-NAME (NOS inhibitor) and indomethacin (specific blocker of COX). The vasoactive responses to acetylcholine of thoracic rat aortic rings were studied in vitro before and after nitric oxide and cyclooxygenase blockade using multichannel organ bath. The mRNA expression for isoforms of (cyclooxygenase) COX and nitric oxide synthase (NOS) were analyzed using RT-PCR.

Results

Administration of both l-NAME and indomethacin in EIP rabbits significantly reduced (p < 0.05) the PP and reversed the MAP to normal as compared to sham-operated (SO) rabbits. There was impaired vasodilatory response to acetylcholine in EIP rabbits. l-NAME caused a significant reduction in acetylcholine-induced vasorelaxation in SO rabbits than EIP due to preexisting hyperemia in EIP. Indomethacin partially restored vasoresponsiveness to acetylcholine in EIP group. The mRNA expression of eNOS (endothelial NOS) and COX-1 (constitutive COX) were significantly higher in SO than EIP rabbits. iNOS (inducible NOS) and COX-2 (inducible COX) mRNA expression was seen only in EIP rabbits.

Conclusions

A significant component of acetylcholine-mediated vasorelaxation in EIP model is modulated by eNOS. There was increased production of contractile prostaglandin in EIP rabbits. iNOS and COX-2 play an important role in the hemodynamic abnormalities of PHT. This novel model of PHT produced by chronic splanchnic endotoxemia in rabbit, mimics impaired vasodilation and vasoreactivity akin to other models of PHT.     

Inhibition of calcium-dependent nitric oxide synthase causes ileitis and leukocytosis in guinea pigs

As nitric oxide reduces gut epithelial permeability, we designed a study to determine if chronic nitric oxide synthase inhibition predisposes the gut to inflammation. Nitric oxide synthase (NOS) inhibitors were administered in the drinking waterad libitum, for seven days: aminoguanidine (10 µg/ml), a selective inhibitor of the inducible form of nitric oxide synthase; andN ^G-nitro-l-arginine methyl ester (l-NAME, 1, 10, and 100 µg/ml), which inhibits both the constitutive and inducible forms. Control animals drank tap water only or water withd-NAME, the inactive enantiomer. After one week, circulating leukocyte count and tissue myeloperoxidase activity were measured.l-NAME (100 µg/ml), but notd-NAME or aminoguanidine, caused a twofold increase in a circulating leukocyte numbers. This increase in leukocyte numbers was time- and dose-dependent, but the differential count was unaltered. Tissue myeloperoxidase (MPO) activity as an index of granulocyte infiltration was comparable in all groups in the stomach, jejunum, colon, liver, lung, kidney, heart, and skeletal muscle. However, ileal MPO activity was elevated threefold in thel-NAME- (100 µg/ml) treated group (P<0.05). Results in thed-NAME and aminoguanidine groups were similar to controls.l-NAME administration resulted in a reduction in NOS activity ([¹⁴C]citrulline formation) in the ileum but not jejunum, whereas cGMP levels were elevated in both ileum and jejunum. We conclude that chronic inhibition of the constitutive form of nitric oxide synthase predisposes the ileum to inflammation and leads to a progressive leukocytosis.     

l-Leucine influx through Slc7a5 regulates inflammatory responses of human B cells via mammalian target of rapamycin complex 1 signaling

Abstract

Objectives: Increasing evidence has revealed the close correlation between immune cell functions and their intracellular metabolism. Mammalian target of rapamycin complex 1 (mTORC1) is the important metabolism-modulating signal that regulates cellular activities. In certain types of cell, it is known that mTORC1 activation depends on influx of l-leucine through an amino acid transporter, Slc7a5. In B cells, however, the expression and the role of Slc7a5 have never been investigated.

Methods: CD19⁺ B cells were obtained from peripheral blood of healthy adults and stimulated by a toll-like receptor 9 ligand, CpG oligodeoxynucleotides. The expression of Slc7a5 and l-leucine uptake were evaluated by RT-PCR, flow cytometry and radioisotope assay. Then the effect of Slc7a5 inhibition on mTORC1 activity, plasmablast differentiation and production of IgG and inflammatory cytokines were analyzed.

Results: CpG stimulation significantly induced the expression of Slc7a5 in B cells, resulting in l-leucine influx. Furthermore, inhibition of Slc7a5 abrogated mTORC1 activation, plasmablast differentiation, and production of IgG and inflammatory cytokines in CpG-stimulated B cells.

Conclusion: l-leucine influx through Slc7a5 critically regulates mTORC1 activity and the immunological responses of human B cells. Slc7a5-mTORC1 pathway may provide a novel therapeutic strategy for autoimmune diseases.     

Correlation of Exhaled Nitric Oxide Levels and Airway Inflammation Markers in Stable Asthmatic Patients

Monitoring of inflammation is an important factor in asthma management. The gold standard for measuring direct airway inflammation is bronchial biopsy specimens taken from proximal airways through a fiberoptic bronchoscope. As a noninvasive procedure, the use of exhaled nitric oxide (Fe_NO) for monitoring airway inflammation has been reported in many studies. The aim of this study was to evaluate the correlation of Fe_NO with direct measurements of airway inflammation in biopsy specimens and pulmonary function tests (PFT). Histopathologic features were observed on bronchial biopsy specimens obtained from nine stable mild-moderate asthmatics. Each subject had measurements of PFT, Fe_NO levels, blood eosinophil count, and bronchoscopy with bronchial biopsies and bronchoalveolar lavage. Five subjects with forced expiratory volume in 1 second >80% had methacholine challenge test. None of the subjects had prior anti-inflammatory therapy for asthma. No correlation was found between PFT, blood eosinophil count, and Fe_NO levels. There was a negative correlation between PC20 and Fe_NO. Though there was no correlation between bronchial biopsy eosinophil, monocyte and lymphocyte counts, and Fe_NO, we found a weak positive correlation between total inflammatory cell count in bronchial biopsies and Fe_NO levels. A negative significant correlation was found between Fe_NO levels and epithelial desquamation (p<0.05, r = ?0.7). These results suggest that, Fe_NO levels reflect the increased number of activated inflammatory cells in airways and the negative correlation with epithelial desquamation reflects the role of epithelium in NO syntheses. Fe_NO should not be interpreted as a specific inflammation marker for asthma.     

Nitric Oxide and Hydrogen Sulfide Interact When Modulating Gastric Physiological Functions in Rodents

Aim

The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H₂S) donors and possible interactions between these two systems in modulating gastric function.

Methods

Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson’s reagent (H₂S donor), PAG + SNP, l-NAME, l-NAME + NaHS, or l-NAME + Lawesson’s reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated.

Results

SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson’s reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and l-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and l-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and l-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or l-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus.

Conclusion

NO and H₂S interact in gastric physiological functions, and this “cross-talk” is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.

     

Distribution of the activity of the angiotensin-converting enzyme in the rat aorta and changes in the activity with aging and by the action of l-NAME

The activity of the angiotensin-converting enzyme (ACE) of the inner surface (the endothelium surface) of rat aorta sections has been studied depending on their distance from the aortic arch, age of rats, and the duration of treatment of rats with the NO synthase inhibitor, N_ω-nitro-l-arginine (l-NAME). The activity of ACE of aorta sections was determined by measuring the hydrolysis of hippuryl-l-histidyl-l-leucine and was expressed as picomoles of Hip–His–Leu hydrolyzed per minute per square millimeter of the endothelium surface. It was found that the ACE activity considerably varies along the aorta of young rats. This variability decreases with increasing age of rats and by the action of l-NAME. The average ACE activity in the aorta increases with the age of rats and with increasing time of l-NAME treatment. Enalapril normalizes the distribution of the ACE activity along the aorta and decreases the average ACE activity. The changes in the distribution of the ACE activity along the aorta and in the average ACE activity in the aorta with increasing age of the rat and by the action of l-NAME may play a role in the development of atherosclerosis of vessels on aging and the inhibition of formation of nitric oxide.     

Nitric oxide production in rheumatoid arthritis

Abstract

Nitric oxide (NO), originally found as endothelium-derived relaxing factor (EDRF), is a free radical synthesized by NO synthases (NOS). Two isoforms exist in NOS, i.e. constitutive NOS (cNOS) and inducible NOS (iNOS). Inflammatory cytokines such as interleukin-1, interferon-γ, tumor necrosis factor-α induce iNOS expression in various cells including macrophages. Enhanced NO production is observed in arthritic conditions both in rodent models and human. The onset of arthritis in rodent models is significantly inhibited by the NOS inhibitor, N ^G-monomethyl-l-arginine. These data suggest a possible involvement of NO in the induction and/or maintenance of rheumatoid arthritis.     

Effect of telmisartan on VEGF-induced and VEGF-independent angiogenic responsiveness of coronary endothelial cells in normal and streptozotocin (STZ)-induced diabetic rats

Telmisartan possesses endothelial protective effects due to angiotensin II type 1 receptor antagonist, peroxisome proliferator-activated receptor γ (PPARγ) agonist and antioxidant action. Therefore, our objective was to study effect of telmisartan on angiogenic responsiveness of coronary endothelial cells (cECs) of normal and diabetic rats. Male Wistar rats were divided into six groups, normal rats, diabetic rats 30?d. (30 days after administration of STZ), diabetic rats 60?ds. (60 days after administration of STZ), telmisartan-treated normal rats (2?mg/kg, p.o., for 15 days before isolation of hearts), telmisartan-treated diabetic rats 30?ds, and telmisartan-treated diabetic rats 60?ds. Each group was further divided into two subgroups, sham rat hearts and ischemia-reperfused rat hearts. After isolation of cEC from each subgroup, angiogenic responsiveness and nitric oxide releasing properties were studied using chorioallantoic membrane (CAM) assay and Griess method, respectively. cEC of normal rats showed significant increase in angiogenic responsiveness in presence of vascular endothelial growth factor (VEGF) but not in absence of it. This activity was attenuated by pretreatment of cEC with l-NAME, wortmannin and chelerythrine. Diabetes and ischemia reperfusion injury suppressed angiogenic responsiveness of cEC. Telmisartan treatment showed significant increase in VEGF-induced angiogenic responsiveness and nitric oxide releasing properties of cECs of all subgroups as compared to their respective non-treated subgroups. These effects of telmisartan were significantly inhibited by pretreatment of cECs with l-NAME and wortmannin but not with chelerythrine. Our data suggest that telmisartan improves VEGF-induced coronary angiogenic activity in normal and diabetic rats via stimulation of PI3K/eNOS/NO pathway.     

Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway

Purpose

We examined the role of the phosphatidylinositol-3 kinase (PI3K)/nitric oxide (NO) signaling pathway in low-level vagus nerve stimulation (LLVNS)-mediated inhibition of atrial fibrillation (AF).

Methods

In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters to the superior and inferior pulmonary veins and atrial appendages. Rapid atrial pacing (RAP) was maintained for 6 h. Each hour, programmed stimulation was used to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 h, RAP was overlapped with right LLVNS (50 % below that which slows the sinus rate). In group 1 (n?=?7), LLVNS was the only intervention, whereas in groups 2 (n?=?6) and 3 (n?=?4), the NO synthase inhibitor N ^G-nitro-l-arginine methyl ester (l-NAME) and the PI3K inhibitor wortmannin, respectively, were injected in the right-sided ganglionated plexi (GP) during the last 3 h. The duration of acetylcholine-induced AF was determined at baseline and at 6 h. Voltage–sinus rate curves were constructed to assess GP function.

Results

LLVNS significantly decreased the acetylcholine-induced AF duration by 8.2?±?0.9 min (p?<?0.0001). Both l-NAME and wortmannin abrogated this effect. The cumulative WOV (the sum of the individual WOVs) decreased toward baseline with LLVNS (p?<?0.0001). l-NAME and wortmannin blunted this effect during the fifth (l-NAME only, p?<?0.05) and the sixth hour (l-NAME and wortmannin, p?<?0.05). LLVNS suppressed the ability of GP stimulation to slow the sinus rate, whereas l-NAME and wortmannin abolished this effect.

Conclusion

The anti-arrhythmic effects of LLVNS involve the PI3K/NO signaling pathway.     

Effects of Nebivolol on Aortic Compliance in Patients With Diabetes and Maximal Renin Angiotensin System Blockade: The EFFORT Study

The beneficial effects of nebivolol on arterial stiffness and endothelial dysfunction are well documented in untreated hypertensive patients and differ from nonvasodilatory β‐blockers. This study tests the hypothesis that the addition of nebivolol in predominantly African American patients with type 2 diabetes already receiving maximally tolerated doses of renin‐angiotensin system (RAS) blockers will further improve large artery compliance. Patients with type 2 diabetes and hypertension on maximal RAS blockade (n=70) were randomized to nebivolol or metoprolol succinate daily. Doses were titrated until systolic blood pressure (SBP) was <130 mm Hg. Radial artery applanation tonometry and pulse wave velocity (PWV) analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits at intervals during a 6‐month period. Both metoprolol succinate and nebivolol groups demonstrated reductions in brachial SBP (−8.2±4.3 mm Hg [P=.01] and −7.8±3.7 [P=.002], respectively) and aortic DBP (−2.4±1.8 [P=.039] and −4.0±2.9 mm Hg [P=.013], respectively). Aortic SBP decreased in the nebivolol group only (125.3±8 to 121.6±8.2, P=.025). There were no between group differences in aortic SBP, DBP, augmentation index, or PWV reduction. A significant increase in hemoglobin A_1c was observed only in the metoprolol group. In patients with well‐controlled type 2 diabetes and hypertension treated with maximally tolerated RAS blockade, nebivolol does not offer significant reductions in aortic BP over metoprolol succinate but maintains a stable metabolic profile.

Nebivolol, a highly selective β₁‐antagonist, has different chemical and mechanistic properties than previously developed β‐blockers. Compared with conventional β₁‐selective adrenergic receptor antagonists such as metoprolol succinate, nebivolol exerts additional vasodilatory properties by stimulating endothelial cell nitric oxide (NO) production¹, ² mediated by β₃‐receptor activation³ and interaction with the estrogen receptor.⁴ Nebivolol decreases oxidative stress in primary hypertension and increases NO bioavailability through upregulation of endothelial NO synthase (eNOS) and reduction of circulating asymmetric dimethylarginine (ADMA).⁵, ⁶ Nebivolol administration also restores NO bioavailability in endothelial cells obtained from African Americans who have an impaired release of NO to conventional stimuli.⁷ Central pressure is also more closely associated with cardiovascular (CV) outcomes relative to brachial blood pressure (BP).⁸ Increases in pulse wave velocity (PWV) indicating stiffer vessels are associated with increases in CV risk and chronic kidney disease (CKD) progression.⁹, ¹⁰, ¹¹ Data from the Conduit Artery Function Evaluation (CAFE) trial¹² show that agents that reduce central aortic as well as peripheral pressures are associated with a lower CV risk profile compared with agents that lower only peripheral pressures. Traditional β‐blockers, eg, atenolol or metoprolol, while reducing CV risk in people with coronary disease do not affect aortic stiffness compared with blockers of the renin‐angiotensin system (RAS). Vascular compliance studies comparing traditional β‐blockers with newer vasodilating β‐blockers in patients with type 2 diabetes on maximally dosed background RAS blockade have not been performed. Given that patients with diabetes have increased pulse wave velocities compared with age‐matched patients without diabetes¹³ and that African Americans have about a 50% lower response to stimuli of NO, the present study was designed to examine the effect of nebivolol therapy compared with metoprolol succinate therapy on peripheral and aortic arterial pressure as well as aortic compliance. The null hypothesis tested states that there will be no benefit on aortic compliance with nebivolol compared with metoprolol in the presence of maximally tolerated RAS therapy in a predominantly African American population with type 2 diabetes.     

Analysis of the levels of endotoxin and β-d-glucan in the synovial fluid of hemodialysis patients

Abstract

We analyzed the levels of endotoxin and β-d-glucan, which possibly induce cytokine production, in the synovial fluid of patients on long-term hemodialysis and compared the results to those in patients with osteoarthritis and rheumatoid arthritis. We studied 42 knees in 42 hemodialysis patients, 21 in 21 osteoarthritis patients, and 26 in 26 rheumatoid arthritis patients. The mean ages were 60.7, 63.2, and 59.7 years, respectively. The duration of hemodialysis in the long-term hemodialysis group averaged 14.0 years. The concentrations of endotoxin and β-d-glucan in the synovial fluid of these three groups were measured. The concentration of endotoxin was the same in the three groups. However, the concentration of β-d-glucan was significantly higher in long-term hemodialysis patients. This finding suggests that β-d-glucan may have some relation to the pathogenesis of the synovitis which exists in the hydrarthrosis of long-term hemodialysis patients.     

Evaluation of Pneumocystis pneumonia infection risk factors in patients with connective tissue disease

Abstract

We conducted a retrospective, clinical evaluation of connective tissue disease (CTD) patients who were tested for either sputum or bronchoalveolar lavage fluid Pneumocystis polymerase chain reaction (PC-PCR) and analyzed the risk factors that cause Pneumocystis pneumonia (PCP) susceptibility and fatality. PC-PCR was performed on 66 CTD patients who presented with symptoms, data, or radiological findings strongly suggesting respiratory infection. Patients with higher oral corticosteroid doses, use of oral methotrexate (MTX), bilateral lung findings, positive β-d-glucan, and no prophylaxis use were more susceptible to PCP. They had significantly low immunoglobulin G and significantly high β-d-glucan and lactate dehydrogenase. Survivors and nonsurvivors of PCP were also evaluated. Poor prognoses were observed with older age, elevated β-d-glucan, rheumatoid arthritis (RA) patients using MTX, hypoxemia, bilateral lung findings, and mechanical ventilation use. Nonsurvivors had significantly lower lymphocytes, oxygen saturation, and significantly higher β-d-glucan. In RA, poor prognoses were seen with those taking MTX. Disease duration, underlying pulmonary complications, and oral corticosteroid doses did not lead to poor prognoses in RA. Because PCP in CTD leads to abrupt onset of symptoms with poor survival rates, early diagnosis and initiation of treatment are critical, and it is essential for clinicians to recognize risk factors that predispose patients to PCP and its mortality.