Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension.

Adrenomedullin (AM) and intermedin (IMD; adrenomedulln-2) are vasodilator peptides related to calcitonin gene-related peptide (CGRP). The actions of these peptides are mediated by the calcitonin receptor-like receptor (CLR) in association with one of three receptor activity-modifying proteins. CGRP is selective for CLR/receptor activity modifying protein (RAMP)1, AM for CLR/RAMP2 and -3, and IMD acts at both CGRP and AM receptors. In a model of pressure overload induced by inhibition of nitric-oxide synthase, up-regulation of AM was observed previously in cardiomyocytes demonstrating a hypertrophic phenotype. The current objective was to examine the effects of blood pressure reduction on cardiomyocyte expression of AM and IMD and their receptor components. Nomega-nitro-L-arginine methyl ester (L-NAME) (35 mg/kg/day) was administered to rats for 8 weeks, with or without concurrent administration of hydralazine (50 mg/kg/day) and hydrochlorothiazide (7.5 mg/kg/day). In left ventricular cardiomyocytes from L-NAME-treated rats, increases (-fold) in mRNA expression were 1.6 (preproAM), 8.4 (preproIMD), 3.4 (CLR), 4.1 (RAMP1), 2.8 (RAMP2), and 4.4 (RAMP3). Hydralazine/hydrochlorothiazide normalized systolic blood pressure (BP) and abolished mRNA up-regulation of hypertrophic markers sk-alpha-actin and BNP and of preproAM, CLR, RAMP2, and RAMP3 but did not normalize cardiomyocyte width nor preproIMD or RAMP1 mRNA expression. The robust increase in IMD expression indicates an important role for this peptide in the cardiac pathology of this model but, unlike AM, IMD is not associated with pressure overload upon the myocardium. The concordance of IMD and RAMP1 up-regulation indicates a CGRP-type receptor action; considering also a lack of response to BP reduction, IMD may, like CGRP, have an anti-ischemic function.

The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease

BACKGROUND: Hypertension and cognitive impairment are prevalent in older people. It is known that hypertension is a direct risk factor for vascular dementia and recent studies have suggested hypertension also impacts upon prevalence of Alzheimer's disease. The question is therefore whether treatment of hypertension lowers the rate of cognitive decline. OBJECTIVES: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. SEARCH STRATEGY: The trials were identified through a search of CDCIG's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL on 27 April 2005. SELECTION CRITERIA: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life. MAIN RESULTS: Three trials including 12,091 hypertensive subjects were identified. Average age was 72.8 years. Participants were recruited from industrialised countries. Mean blood pressure at entry across the studies was 170/84 mmHg. All trials instituted a stepped care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic or an angiotensin receptor blocker. The combined result of the three trials reporting incidence of dementia indicated no significant difference between treatment and placebo (Odds Ratio (OR) = 0.89, 95% CI 0.69, 1.16). Blood pressure reduction resulted in a 11% relative risk reduction of dementia in patients with no prior cerebrovascular disease but this effect was not statistically significant (p = 0.38) and there was considerable heterogeneity between the trials. The combined results from the two trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.10, 95% CI -0.03, 0.23). Both systolic and diastolic blood pressure levels were reduced significantly in the two trials assessing this outcome (WMD = -7.53, 95% CI -8.28, -6.77 for systolic blood pressure, WMD = -3.87, 95% CI -4.25, -3.50 for diastolic blood pressure).Two trials reported adverse effects requiring discontinuation of treatment and the combined results indicated a significant benefit from placebo (OR = 1.18, 95% CI 1.06, 1.30). When analysed separately, however, more patients on placebo in SCOPE were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the three studies. There was difficulty with the control group in this review as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen. AUTHORS' CONCLUSIONS: There was no convincing evidence from the trials identified that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients given active treatment. This introduced bias. More robust results may be obtained by analysing one year data to reduce differential drop-out or by conducting a meta-analysis using individual patient data.

Differential effects of an anti-oxidant intervention on cardiomyocyte expression of adrenomedullin and intermedin and their receptor components in chronic nitric oxide deficiency

Background: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial oxidative stress and hypertrophic remodeling. Up-regulation of the cardiomyocyte adrenomedullin (AM) / intermedin (IMD) receptor signaling cascade is also apparent in NO-deficient cardiomyocytes: augmented expression of AM and receptor activity modifying proteins RAMP2 and RAMP3 is prevented by blood pressure normalization while that of RAMP1 and intermedin (IMD) is not, indicating that the latter is regulated by a pressure-independent mechanism. Aims: to verify the ability of an anti-oxidant intervention to normalize cardiomyocyte oxidant status and to investigate the influence of such an intervention on expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes. Methods: NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 35mg/kg/day) was given to rats for 8 weeks, with/without con-current administration of antioxidants (Vitamin C (25mg/kg/day) and Tempol (25mg/kg/day)). Results: In left ventricular cardiomyocytes isolated from L-NAME treated rats, increased oxidative stress was indicated by augmented (3.6 fold) membrane protein oxidation, enhanced expression of catalytic and regulatory subunits of pro-oxidant NADPH oxidases (NOX1, NOX2) and compensatory increases in expression of anti-oxidant glutathione peroxidase and Cu/Zn superoxide dismutases (SOD1, SOD3). Vitamin C plus Tempol did not reduce systolic blood pressure but normalized augmented plasma levels of IMD, but not of AM, and in cardiomyocytes: (i) abolished increased membrane protein oxidation; (ii) normalized augmented expression of prepro-IMD and RAMP1, but not prepro-AM, RAMP2 and RAMP3; (iii) attenuated (by 42%) increased width and normalized expression of hypertrophic markers, skeletal-�-actin and prepro-endothelin-1 similarly to blood pressure normalization but in contrast to blood pressure normalization did not attenuate augmented brain natriuretic peptide (BNP) expression. Conclusion: normalization specifically of augmented IMD/RAMP1 expression in NO-deficient cardiomyocytes by antioxidant intervention in the absence of blood pressure reduction indicates that these genes are likely to be induced directly by myocardial oxidative stress. Although oxidative stress contributed to cardiomyocyte hypertrophy, induction of IMD and RAMP1 is unlikely to be secondary to cardiomyocyte hypertrophy.

Eradication of marine biofilms by atmospheric pressure non-thermal plasma: A potential approach to control biofouling?

Although the antimicrobial activity of atmospheric pressure non-thermal plasmas, including its capacity to eradicate microbial biofilms, has been gaining an ever increasing interest for different medical applications, its potential utilisation in the control of biofouling and biodeterioration has, to date, received no attention. In this study, the ability of atmospheric pressure plasma to eradicate biofilms of four biofouling bacterial species, frequently encountered in marine environments, was investigated. Biofilms were grown on both polystyrene and stainless steel surfaces before being exposed to the plasma source. Viability and biomass of biofilms were evaluated using colony count method and differential Live/Dead fluorescence staining followed by confocal laser scanning microscopy. Rapid and complete eradication of all biofilms under study was achieved after plasma exposures ranging from 60 to 120 s. Confocal microscopy examination showed that plasma treatment has mediated not only cell killing but also varying degrees of physical removal of biofilms. Further investigation and tailored development of atmospheric pressure non-thermal plasma sources for this particular application could provide an additional powerful and effective weapon in the current anti-biofouling armamentarium.

Microscopic Examination of Biofilm Destruction by Atmospheric Pressure Plasma

Objective: The aim of this study is to examine microscopically the destruction of bacterial biofilms mediated by atmospheric pressure non-thermal plasma (APNTP) at cellular level as well as at the level of biofilm structure as a whole. Methods: 3-day old bacterial biofilms were grown on polycarbonate coupons in a dual channel flow cell and were treated with an in-housed designed atmospheric pressure non-thermal plasma jet for up to 4 minutes of exposure before being examined by both confocal laser scanning microscopy (CLSM), preceded by Live/Dead bacterial viability staining, and scanning electron microscopy (SEM). Results: Differential live/dead staining followed by confocal microscopy examination revealed that biofilm eradication by APNTP was mediated by varying levels of both cell killing and physical removal. Relative extent of each mechanism was dependent on plasma operating conditions, bacterial species, growth conditions and biofilm thickness. On the other hand, SEM examination of plasma-exposed biofilms revealed a series of morphological changes exhibited by biofilm cells ranging from increased roughness of cell surface to complete cell lysis. Conclusions: Interesting mechanistic insights have been revealed by microscopic examination of plasma-treated bacterial biofilms that, when coupled with more specific biochemical studies, will not only contribute significantly to our understanding of the mechanism of plasma mediated biofilm destruction but also will help in better application-guided development of this novel anti-biofilm approach.

Determinants of postoperative corneal edema and impact on goldmann intraocular pressure.

PURPOSE: Recent studies report that increased corneal edema because of contact lens wear under closed lids is associated with elevated Goldmann intraocular pressure (GAT IOP). We sought to assess whether the impact of postoperative corneal edema on GAT IOP would be similar and to determine the differential effect of different amounts of edema. METHODS: The setting is a tertiary level cataract clinic in Shantou, China. Pre- and postoperative (day 1) GAT IOP, central corneal thickness (CCT), corneal hysteresis, corneal resistance factor, and radius of corneal curvature were measured for consecutive patients undergoing phacoemulsification surgery by 2 experienced surgeons. Corneal edema was calculated as the percentage increase in CCT. RESULTS: Among 136 subjects (mean age, 62.5 ± 15.4 years; 53.7% women), the mean increase in CCT was 10.3% postoperatively. Greater corneal edema was associated with lower GAT IOP in unadjusted analyses (P < 0.03) and in linear regression models (P < 0.01). In the model, higher corneal resistance factor (P < 0.001), lower corneal hysteresis (P < 0.001), and steeper radius of corneal curvature (P < 0.001) were associated with higher GAT IOP. Among subjects with edema < the median, edema was associated with lower GAT IOP (P = 0.004), whereas among those with edema ≥ the median, edema was not associated with GAT IOP. An increase in CCT of 7% was associated with an 8 mm Hg underestimation of GAT IOP in our models. CONCLUSIONS: The effect of postoperative edema on GAT IOP seems to be the opposite of contact lens-induced edema. The magnitude of the effect is potentially relevant to patient management.