Evolution of In-Cylinder Diesel Engine Soot and Emission Characteristics Investigated with Online Aerosol Mass Spectrometry.

To design diesel engines with low environmental impact, it is important to link health and climate-relevant soot (black carbon) emission characteristics to specific combustion conditions. The in-cylinder evolution of soot properties over the combustion cycle and as a function of exhaust gas recirculation (EGR) was investigated in a modern heavy-duty diesel engine. A novel combination of a fast gas-sampling valve and a soot particle aerosol mass spectrometer (SP-AMS) enabled online measurements of the in-cylinder soot chemistry. The results show that EGR reduced the soot formation rate. However, the late cycle soot oxidation rate (soot removal) was reduced even more, and the net effect was increased soot emissions. EGR resulted in an accumulation of polycyclic aromatic hydrocarbons (PAHs) during combustion, and led to increased PAH emissions. We show that mass spectral and optical signatures of the in-cylinder soot and associated low volatility organics change dramatically from the soot formation dominated phase to the soot oxidation dominated phase. These signatures include a class of fullerene carbon clusters that we hypothesize represent less graphitized, C5-containing fullerenic (high tortuosity or curved) soot nanostructures arising from decreased combustion temperatures and increased premixing of air and fuel with EGR. Altered soot properties are of key importance when designing emission control strategies such as diesel particulate filters and when introducing novel biofuels.

Stroke and coronary heart disease in treated hypertension -- a prospective cohort study over three decades.

OBJECTIVE: To compare cardiovascular mortality and morbidity in middle-aged hypertensive men with initially nonhypertensive men derived from the same random population sample, and to study stroke morbidity in these men in relation to cardiovascular risk factors during 25-28 years of follow-up. DESIGN: Prospective, population-based observational study in men where the main intervention effort was directed towards treatment of hypertension in a special outpatient clinic. SUBJECTS AND METHODS: A total of 754 hypertensive men aged 47-55 years at screening were compared with 6740 men with normal blood pressure. The hypertensive men got stepped care treatment with either beta-blockers, thiazide diuretics, or combination treatment including vasodilating agents during the whole observational period. Data on cause-specific mortality and morbidity, and all cause mortality were obtained from patient files and the national registers on mortality and hospital admissions respectively. MAIN OUTCOME MEASURES: Baseline and change of cardiovascular risk factors during the first 15 years of follow-up and all cause mortality, and mortality and morbidity from stroke and coronary heart disease during 25-28 years. RESULTS: Treated hypertensive men had their blood pressure reduced with 21/15 mmHg during the first 5 years of the study and mean blood pressure levels were then rather constant. A minor reduction of serum cholesterol was also observed and a significant reduction in the prevalence of smoking. Treated hypertensive men suffered a substantial increased incidence of cardiovascular complications that escalated during the latter course of the study. Their total incidence of stroke was doubled; they had 50% more myocardial infarctions (MIs); mortality from coronary heart disease was doubled and all cause mortality was increased by a third, compared with nonhypertensive. In multiple regression analysis the incidence of stroke was significantly related to smoking and diabetes at entry and in time-dependent Cox's regression analysis it was significantly related only to smoking. There was no relationship observed between achieved systolic or diastolic blood pressure and the risk of stroke or MI nor was there any relationship between the change in blood pressure and such cardiovascular complications. CONCLUSION: In spite of a substantial reduction of their blood pressure, treated hypertensive middle-aged men had a highly increased risk of stroke, MI and mortality from coronary heart disease compared with nonhypertensive men of similar age. The increased risk of cardiovascular complications escalated during the latter course of the study.

Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B.

The N-methyl-D-aspartate (NMDA) receptors are glutamate-regulated ion channels that are critically involved in important physiological and pathological functions of the mammalian central nervous system. We have identified and characterized the gene encoding the human NMDA receptor subunit NR3A (GRIN3A), as well as the gene (GRIN3B) encoding an entirely novel subunit that we named NR3B, as it is most closely related to NR3A (57.4% identity). GRIN3A localizes to chromosome 9q34, in the region 13-34, and consists of nine coding exons. The deduced protein contains 1115 amino acids and shows 92.7% identity to rat NR3A. GRIN3B localizes to chromosome 19p13.3 and contains, as does the mouse NR3B gene (Grin3b), eight coding exons. The deduced proteins of human and mouse NR3B contain 901 and 900 amino acid residues, respectively (81.6% identity). In situ hybridization shows a widespread distribution of Grin3b mRNA in the brain of the adult rat.

The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development.

Nodal proteins have crucial roles in mesendoderm formation and left-right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling.

Identification and characterization of a Drosophila nuclear proteasome regulator. A homolog of human 11 S REGgamma (PA28gamma ).

We report the cloning and characterization of a Drosophila proteasome 11 S REGgamma (PA28) homolog. The 28-kDa protein shows 47% identity to the human REGgamma and strongly enhances the trypsin-like activities of both Drosophila and mammalian 20 S proteasomes. Surprisingly, the Drosophila REG was found to inhibit the proteasome's chymotrypsin-like activity against the fluorogenic peptide succinyl-LLVY-7-amino-4-methylcoumarin. Immunocytological analysis reveals that the Drosophila REG is localized to the nucleus but is distributed throughout the cell when nuclear envelope breakdown occurs during mitosis. Through site-directed mutagenesis studies, we have identified a functional nuclear localization signal present in the homolog-specific insert region. The Drosophila PA28 NLS is similar to the oncogene c-Myc nuclear localization motif. Comparison between uninduced and innate immune induced Drosophila cells suggests that the REGgamma proteasome activator has a role independent of the invertebrate immune system. Our results support the idea that gamma class proteasome activators have an ancient conserved function within metazoans and were present prior to the emergence of the alpha and beta REG classes.

Candesartan cilexetil and renal hemodynamics in hypertensive patients.

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.

Decreased pulmonary levels of the anti-inflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics.

The Clara cell 16 kDa protein (CC16) maps to an atopy-associated region of chromosome 11 and has been ascribed an anti-inflammatory function. Using reverse-phase HPLC and Western blot analysis, we have evaluated the polypeptide pattern in bronchoalveolar lavage (BAL) fluid retrieved from asthmatics, before and after induction of airway inflammation by low-dose allergen inhalation challenge. A prominent decrease of CC16 was seen after induction of inflammation, and a further CC16 decrease was observed in lavage fluid where surfactant had been removed. Reduced levels of pulmonary CC16 may cause loss of anti-inflammatory activity in the airways and contribute to the development of airway inflammation in asthma.

Clara cell secretory protein. Levels in BAL fluid after smoking cessation.

STUDY OBJECTIVES: The bronchiolar Clara cell is a major target for tobacco smoke exposure. To improve our understanding of the putative regenerative/repair mechanism(s) in the bronchiolar epithelium, we measured the levels of the Clara cell secretory protein (CCSP) in BAL fluid in healthy volunteers following smoking cessation. DESIGN: BAL was performed before smoking cessation, and at 1, 3, 6, 9, and 15 months following smoking cessation, in eight healthy volunteers with a previous mean cigarette consumption of 19 pack-years. The levels of CCSP in BAL fluid were assessed in immunoblotting experiments using an antibody against human CCSP. RESULTS: Significantly (p < 0.05) higher levels of CCSP in BAL fluid were observed at 3, 6, and 9 months after smoking cessation, while the levels of CCSP in BAL fluid at 15 months after smoking cessation were the same as those before smoking cessation. CONCLUSIONS: Despite the long history of smoking among patients in the present study group, signs of early regeneration in the bronchiolar epithelium were noted, in that the levels of CCSP in BAL fluid were elevated at the indicated time points following smoking cessation. Furthermore, we propose that the insult to the bronchiolar epithelium made by cigarette smoking caused the levels of CCSP in the BAL fluid at 15 months after smoking cessation to return to the levels noted before smoking cessation. The present study suggests a role for CCSP as a marker for nonciliated bronchiolar cell function.

Experimental follow-up model for clinical frontal sinus obliteration with bioactive glass (S53P4).

Bioactive glass S53P4 (BG) is an osteoconductive allograft material. Since 1990, BG has been used in the obliteration of frontal sinuses in more than 30 consecutive patients. The patients have been monitored regularly with clinical examinations, computer tomography (CT) scans, laboratory tests and, in a few cases, biopsies have also been obtained. The material has been well tolerated and no loss of volume of obliteration material has been seen in the obliterated sinuses. However, in repeated CT monitoring and with Region of Interest (ROI) analysis, a decrease in the density of the obliteration material inside the frontal sinuses has been seen. In the present study, the clinical conditions after an obliteration operation were simulated and the behaviour of the BG in the obliterated area was observed. The aim was to study whether it is possible indirectly to estimate the resorption of a massive amount of BG with ROI analysis for monitoring the clinical success of the treatment. Thus two sizes of granules (0.63-0.8 mm and 0.8-1.0 mm) in eight separate BG amounts, weight 25 g, were tested in simulated body fluid (SBF) in standard conditions. The dissolution of silicon (Si) and phosphate (P) was detected with direct plasma atom emission spectroscopy (DCP-AES) monthly up to 6 months. The BG amounts were scanned with CT and the slices analysed using the ROI technique at 1, 3 and 6 months. The cumulative loss of Si and P in SBF was significant during the study (p < 0.0001) and it was stronger with smaller than with larger granules (p < 0.0001). This was shown correspondingly by the decrease of Hounsfield units (p < 0.0001) in ROI analysis. The method seems reliably to reveal the resorption of BG for clinical purposes.

C/EBPalpha and C/EBPdelta activate the clara cell secretory protein gene through interaction with two adjacent C/EBP-binding sites.

The Clara cell secretory protein (CCSP) gene is a cell-specific differentiation marker for the bronchiolar Clara cell. Previous studies suggest that CCAAT/enhancer binding protein (C/EBP)alpha is involved in controlling differentiation-dependent gene expression in the distal lung. In this study, immunofluorescence studies demonstrated high level expression of C/EBPdelta in the bronchiolar epithelium as well as lower levels of C/EBPalpha. Cotransfection studies in the lung epithelial cell line A549 showed that both C/EBPalpha and C/EBPdelta activate the murine CCSP gene and that a C/EBP-response element resides in the proximal CCSP promoter. C/EBPdelta exhibits an approximately 2-fold higher transactivation potential than does C/EBPalpha. DNase I footprint analyses revealed a footprint region located at -100 to -62 bp, corresponding to two C/EBP-binding sites. Mutation of either site resulted in abolished or strikingly reduced transactivation of the CCSP promoter by C/EBPalpha and C/EBPdelta, as well as impaired binding of both factors, indicating that the two C/EBP-binding sites form a compound response element. In electrophoretic mobility shift assays, it was shown that C/EBPalpha and C/EBPdelta can bind to both C/EBP sites, whereas in DNase I footprint analyses, the interaction of C/EBPalpha with the proximal site was weak. Furthermore, electrophoretic mobility shift assays demonstrated that C/EBPalpha and C/EBPdelta preferentially form heterodimers at both binding sites. Cotransfections with C/EBPalpha and C/EBPdelta together resulted in a superinduction of the CCSP promoter, indicating a regulatory role for the C/EBPalpha-C/EBPdelta heterodimers. Our findings demonstrate that C/EBPalpha and C/EBPdelta regulate the CCSP gene through a compound response element and suggest that these factors are important for the differentiation-dependent expression of CCSP.

Enhanced left ventricular endocardial border delineation with an intravenous injection of SonoVue, a new echocardiographic contrast agent: A European multicenter study.

The safety and efficacy of SonoVue (also referred to as BR1), a new contrast agent for delineating endocardial border of the left ventricle after intravenous administration, was assessed. Two hundred and eighteen patients with suspected coronary artery disease undergoing fundamental echocardiography for the assessment of left ventricle were enrolled in a prospective multicenter, single blind, cross-over study with random sequence allocation of four different doses of SonoVue. Endocardial border definition in the apical and parasternal views was scored as 0 = not visible, 1 = barely visible, and 2 = well visualized before and after contrast enhancement. Analysis was performed by two pairs of off-site observers. Safety of SonoVue was also assessed. Results of our study indicated that the mean improvements in the endocardial border visualization score were as follows: 3.1 +/- 7.8 (95% CI, 2.5 and 3.7) for 0.5 ml, 3.4 +/- 8.0 (95% CI, 2.8 and 4.0) for 1 ml, 3.4 +/- 7.9 (95% CI, 2.8 and 4.0) for 2 ml, and 3.7 +/- 8.0 (95% CI, 3.1 and 4.3) for 4 ml (P < 0.05 for all doses from baseline). Changes from baseline in endocardial visualization scores were also seen in the apical views (P < 0.05) and they were dose-dependent (P < 0.001). Similar enhancements of endocardial visualization scores were observed in the apical views in patients with suboptimal baseline echocardiographic images. Diagnostic confidence for assigning a score and image quality also were significantly better following contrast enhancement. No significant changes in the laboratory parameters and vital signs were noted following contrast enhancement, and the side effects were minimal. It was concluded that SonoVue is safe and effective in delineating endocardial border, including in patients with suboptimal baseline images.

Candesartan Cilexetil, 16 mg, Provides a Greater Antihypertensive Effect than Losartan, 50 mg, in Patients with Mild to Moderate Hypertension.

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker, which binds tightly to and dissociates slowly from the AT 1 -receptor. These binding characteristics underpin the long duration of action and antihypertensive efficacy of candesartan, and help to differentiate it from losartan, which was the first AT 1 -receptor blocker to be approved for the treatment of hypertension. This study compared the antihypertensive effect and tolerability of candesartan cilexetil, 8 or 16 mg once daily, with that of placebo and of losartan, 50 mg once daily, in patients with mild to moderate primary hypertension. The dose of 50 mg for losartan was chosen, as this is the dose usually recommended; higher doses do not seem to result in further reductions in blood pressure. Men and women, aged 20-80 years, with primary hypertension and a sitting diastolic blood pressure (DBP) of 95-114 mmHg at the end of a 4-week placebo run-in period, were randomized to once-daily, double-blind treatment with candesartan cilexetil, 8 mg ( n = 82), candesartan cilexetil, 16 mg ( n = 86), losartan, 50 mg ( n = 84), or placebo ( n = 85) for 8 weeks. Blood pressure was measured 6 and 24 h after dosing, i.e. at the times of peak and trough effects, respectively. Differences among treatments in changes in blood pressure from randomization to the end of the study were assessed by analysis of variance. Patients were defined as having responded to treatment if sitting DBP was 90 mmHg or below at week 8 or if sitting DBP had been reduced by more than 10 mmHg from baseline to week 8. The proportion of responders in each treatment group was 15% for placebo, 46% for losartan, 50 mg, 50% for candesartan cilexetil, 8 mg, and 57% for candesartan cilexetil, 16 mg. The reduction in sitting DBP at trough (the primary effect variable) was significantly greater in patients treated with candesartan cilexetil, 16 mg, than in patients treated with losartan, 50 mg (see Table). In addition, both doses of candesartan cilexetil had a trough-to-peak ratio of approximately 1.0, compared with 0.7 for losartan. Both candesartan cilexetil and losartan were well tolerated, with the incidence of adverse events similar to placebo in both treatment groups. Overall, the most common new-onset adverse events reported were headache and respiratory infection, both of which are common in this type of patient population. In conclusion, candesartan cilexetil, 8 or 16 mg once daily, is an effective and well-tolerated antihypertensive treatment, with a trough-to-peak ratio close to 1.0. Candesartan cilexetil, 16 mg once daily, produces a significantly greater reduction in blood pressure than losartan, 50 mg once daily.

Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin.

Human alveolar macrophages have exceptionally high capacity to convert cholesterol into 27-hydroxycholesterol and cholestenoic acid by the sterol 27-hydroxylase mechanism. It is shown here that the human lung has a higher content of 27-hydroxycholesterol relative to cholesterol than any other organ. In order to evaluate the importance of the sterol 27-hydroxylase mechanism for cholesterol homeostasis in the lung, the production of cholestenoic acid by human lung was investigated. Removal of one lung reduced the level of cholestenoic acid in the circulation by 48 +/- 4% (P < 0.005). The levels of cholestenoic acid in the pulmonary artery and in the pulmonary vein showed significant differences (P < 0.002) with higher levels in the pulmonary vein (108 +/- 16 and 104 +/- 16 ng/mL, respectively). This corresponds to a net flux of cholestenoic acid from the lung of about 14 mg/day, which is more than 80% of the reported removal of this oxysterol and its metabolites from the circulation by the liver per day. Bypassing the lung for 60 min led to a reduction in circulating cholestenoic acid (30%) that fits with a pulmonary origin when taking into account the half-life of cholestenoic acid. The level of circulating cholestenoic acid was found to be less in patients with different lung diseases. It is evident that most of the cholestenoic acid in the circulation is of pulmonary origin. The present results suggest that the sterol 27-hydroxylase in the lung is responsible for at least half of the total flux of 27-oxygenated cholesterol metabolites to the liver and that this enzyme system may be of importance for cholesterol homeostasis in the lung.

In vivo modulation of glucocorticoid receptor mRNA by inhaled fluticasone propionate in bronchial mucosa and blood lymphocytes in subjects with mild asthma.

BACKGROUND: In vivo regulation of the glucocorticoid receptor (GR) by glucocorticoids provides a means of modulating sensitivity of targeted cells. OBJECTIVE: We sought to determine the in vivo modulation of GR mRNA expression by fluticasone propionate (FP) in subjects with mild asthma. METHODS: Ten atopic asthmatic subjects were treated with FP 250 microg twice daily for 4 weeks. Before and after treatment, the patients underwent fiberoptic bronchoscopy with endobronchial biopsy and sampling of venous blood for measurements of GR mRNA levels. A solution hybridization assay was used for quantitative analysis of GR mRNA. In addition, a 24-hour urinary cortisol excretion and an adrenocorticotropic hormone test before and after treatment with FP were performed. RESULTS: A high interindividual variation in GR mRNA expression was seen. However, we detected a significant reduction of the GR mRNA levels in the endobronchial biopsy specimens after FP treatment (36.6 +/- 23.1 and 25.0 +/- 10.9 amol GR mRNA/microg RNA, respectively; P <.01). In the peripheral blood lymphocytes an even more striking downregulation of the GR by its cognate ligand was documented (30.3 +/- 26.5 and 8.8 +/- 5 amol GR mRNA/microg RNA, respectively; P <.001), possibly reflecting differences in glucocorticoid sensitivity between tissues. A small but significant reduction of the 24-hour urinary cortisol excretion was observed (233 +/- 109 and 157 +/- 66 nmol/L, respectively; P <.01), whereas the feedback regulation of glucocorticoid synthesis by means of the hypothalamic-pituitary-adrenal axis as assessed by the adrenocorticotropic hormone test remained normal after treatment with FP. CONCLUSION: The results in this study confirm the potency of the inhaled corticosteroid FP and provide evidence for a considerable tissue-specific interindividual variation in the expression of the GR.

Improved efficacy with maintained tolerability in the treatment of primary hypertension. Comparison between the felodipine-metoprolol combination tablet and monotherapy with enalapril. Swedish Multicentre Group.

In this multicentre, double-blind, parallel-group study, 120 out-patients with mild to moderate primary hypertension were randomised, after a 4-week single-blind placebo run-in period, to a combination tablet of felodipine-metoprolol 5/50 mg (Logimax, Mobloc, Astra) once daily or enalapril 10 mg once daily. If blood pressure (BP) remained suboptimally controlled after 4 weeks (supine diastolic BP >90 mm Hg 24-h post dose), the dose was doubled for a further 4 weeks. After 8 weeks felodipine-metoprolol reduced supine BP significantly more than enalapril (19.7/12.0 mmHg and 11.1/7.2 mm Hg, respectively). The mean differences in change in BP between treatments were 8.6/4.8 mm Hg in favour of felodipine-metoprolol (P = 0.001/P <0.001). A statistically significant difference to the advantage of felodipine-metoprolol was also seen in standing BP. Even though the dose was increased in a larger proportion of patients in the enalapril group (61%) than in the felodipine-metoprolol group (40%), fewer enalapril-treated patients achieved adequate BP control (41% vs 63% on felodipine-metoprolol, P <0.05). Both treatments were well tolerated. Three patients treated with felodipine-metoprolol and four with enalapril discontinued treatment due to adverse events. A similar number of patients reported adverse events in each treatment group. In conclusion, a combination tablet of felodipine-metoprolol 5/50-10/100 mg once daily reduced BP more effectively than enalapril 10-20 mg once daily 24 h post dose. The result was expected, but a more important observation was that both treatments were tolerated to a similar degree. Obviously, a considerable BP reduction may be well tolerated, as was the main purpose to demonstrate in this study.

Candesartan cilexetil in hypertension: effects of six weeks' treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system.

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg x ml(-1) x L x min (CI: 0.3; 2.3). The baroreceptor sensitivity was not influenced, but a change in the set-point was noted. Plasma renin activity and angiotensin II concentrations were increased, while the aldosterone concentration was significantly reduced. Plasma catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with candesartan cilexetil 16 mg o.d. induced systemic and forearm vasodilatation and a reduction in blood pressure without compromising cardiac performance. The plasma concentration of aldosterone was reduced.

Acute effects of candesartan cilexetil (the new angiotensin II antagonist) on systemic and renal haemodynamics in hypertensive patients.

OBJECTIVES: This study was performed to assess the acute effects of the new angiotensin II antagonist, candesartan cilexetil, on systemic and renal haemodynamics in patients with sustained essential hypertension [diastolic blood pressure (DBP) 95-114 mmHg]. METHODS: After 4 weeks of placebo treatment, systemic and renal haemodynamics were investigated in 17 patients with a mean age of 62 years and a mean systolic and diastolic blood pressure of 170/98 mmHg, just before (baseline) and for 4 h after administration of a single oral dose of candesartan cilexetil, 16 mg. Plasma concentrations of candesartan (the active compound formed from the pro-drug candesartan cilexetil), angiotensin II (Ang II), as well as plasma renin activity (PRA), were measured before and after dosing. RESULTS: At 2, 3 h and 4 h after dosing with candesartan cilexetil, systolic blood pressure (SBP) and DBP, as well as mean arterial pressure (MAP), were significantly lower than at baseline. The mean reduction in MAP 4 h after dosing was 8.8 mmHg (-6.5%). This effect was due to a fall in total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and cardiac output (CO) were virtually unchanged. After 4 h there was a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg x ml(-1) x min (-16%), resulting in an increased renal plasma flow of 64.9 ml x min(-1) (14%). The glomerular filtration rate was increased by 7.75 ml x min(-1) (8%), and the filtration fraction (FF) was not significantly changed. There was no apparent relationship between the changes observed in systemic and renal haemodynamic variables and plasma concentrations of candesartan. Plasma renin activity increased over the study period, but in general the patients had low PRA. Changes in plasma concentrations of angiotensin II were inconsistent between patients. CONCLUSION: A single oral tablet of candesartan cilexetil, 16 mg, induced systemic and renal arterial vasodilatation and blood pressure reduction, without compromising renal perfusion or filtration or affecting cardiac performance. Plasma renin activity which was low in general, increased over the study period, but changes in plasma concentrations of angiotensin II were inconsistent.

Tolerability of a modern antihypertensive agent: candesartan cilexetil.

Tolerability and not efficacy is the limiting factor for long-term successful antihypertensive treatment. Since the discontinuation rate of first line antihypertensives may be as high as 50-60% over six months, it is important to develop new agents with an improved efficacy/tolerability ratio. Candesartan cilexetil is particularly promising in this respect. Candesartan is a potent and selective angiotensin II type 1 (AT1) receptor blocker that binds selectively and tightly (insumontable binding) to the receptor. Candesartan is not associated with any increased risk of cough or angiodema. It is an orally effective vasodilator that does not cause reflex tachycardia or first dose hypotension or orthostatic hypotension. In the dose range from 4-16 mg, once daily candesartan cilexetil is not associated with any dose-dependent adverse events and it is equally well tolerated in men and women and by older (> 65 years) and younger (< 65 years) patients. Furthermore, the drug has no adverse effect on glucose homeostasis or plasma lipid profile. In a double-blind comparison with losartan 50 mg od, candesartan cilexetil 16 mg once daily was significantly more effective in lowering the diastolic blood pressure at the end of the 24 h dose interval but was equally well tolerated. In meta-analyses of clinical trials, candesartan cilexetil showed a tolerability profile comparable to that of placebo therapy.