A Simple Questionnaire as a First-Step Tool to Detect Specific Frailty Profiles: The Lorraine Frailty-Profiling Screening Scale.

OBJECTIVES: To propose a simple frailty screening tool able to identify frailty profiles. DESIGN: Cross-sectional observational study. SETTING: Participants were recruited in 3 different clinical settings: a primary care outpatient clinic (RURAL population, N=591), a geriatric day clinic (DAY-CLINIC population, N=76) and healthy volunteers (URBAN population, N=147). PARTICIPANTS: A total of 817 older adults (>70 years old) living at home were included. INTERVENTION: A 9-item questionnaire (Lorraine Frailty Profiling Screening Scale, LoFProSS), constructed by an experts' working group, was administered to participants by health professionals. MEASUREMENTS: A Multiple Correspondence Analysis (MCA) followed by a hierarchical clustering of the results of the MCA performed in each population was conducted to identify participant profiles based on their answers to LoFProSS. A response pattern algorithm was resultantly identified in the RURAL (main) population and subsequently applied to the URBAN and DAY-CLINIC populations and, in these populations, the two classification methods were compared. Finally, clinically-relevant profiles were generated and compared for their ability to similarly classify subjects. RESULTS: The response pattern differed between the 3 sub-populations for all 9 items, revealing significant intergroup differences (1.2±1.4 positive responses for URBAN vs. 2.1±1.3 for RURAL vs. 3.1±2.1 for DAY-CLINIC, all p<0.05). Five clusters were highlighted in the main RURAL population: "non-frail", "hospitalizations", "physical problems", "social isolation" and "behavioral", with similar clusters highlighted in the remaining two populations. Identification of the response pattern algorithm in the RURAL population yielded a second classification approach, with 83% of tested participants classified in the same cluster using the 2 different approaches. Three clinically-relevant profiles ("non-frail" profile, "physical frailty and diseases" profile and "cognitive-psychological frailty" profile) were subsequently generated from the 5 clusters. A similar double classification approach as above was applied to these 3 profiles revealing a very high percentage (95.6%) of similar profile classifications using both methods. CONCLUSION: The present results demonstrate the ability of LoFProSS to highlight 3 frailty-related profiles, in a consistent manner, among different older populations living at home. Such scale could represent an added value as a simple frailty screening tool for accelerated and better-targeted investigations and interventions.

Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats.

BACKGROUND AND PURPOSE: Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its overactivity in obesity is thought to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesized that early MRA treatment may target obesity-related disorders and consequently delay the development of HF. EXPERIMENTAL APPROACH: Twenty spontaneously hypertensive HF dyslipidaemic obese SHHF(cp/cp) rats and 18 non-dyslipidaemic lean SHHF(+/+) controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA treatment [eplerenone (eple), 100 mg∙kg(-1) ∙day(-1) ] from 1.5 to 12.5 months of age. KEY RESULTS: Eleven months of eple treatment in obese rats (SHHF(cp/cp) eple) reduced the obesity-related metabolic disorders observed in untreated SHHF(cp/cp) rats by reducing weight gain, triglycerides and total cholesterol levels and by preserving adiponectinaemia. The MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating the eccentric cardiac hypertrophy observed in untreated SHHF(cp/cp) animals and preserving ejection fraction (70 ± 1 vs. 59 ± 1%). The MRA also improved survival independently of these pressure effects. CONCLUSION AND IMPLICATIONS: Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF(+/+) and SHHF(cp/cp) rats, whereas SHHF(cp/cp) rats further benefited from the MRA treatment through a reduction in their obesity and dyslipidaemia. These findings suggest that preventive MRA therapy may provide greater benefits in obese patients with additional risk factors of developing cardiovascular complications.

Influence of Thoracic Aortic Inflammation and Calcifications on Arterial Stiffness and Cardiac Function in Older Subjects.

BACKGROUND: Vascular aging is accompanied by gradual remodeling affecting both arterial and cardiac structure and mechanical properties. Hypertension is suggested to exert pro-inflammatory actions enhancing arterial stiffness. OBJECTIVE: To determine the influence of thoracic aortic inflammation and calcifications on arterial stiffness and cardiac function in hypertensive and normotensive older subjects. DESIGN: A prospective study. SETTING: An acute geriatrics ward of the University Hospital of Nancy in France. SUBJECTS: Thirty individuals ≥ 65 years were examined, including 15 hypertensive subjects and 15 controls well-matched for age and sex. MEASUREMENTS: Applanation tonometry was used to measure aortic pulse wave velocity (AoPWV) and carotid/brachial pulse pressure amplification (PPA). Left ventricular parameters were measured with magnetic resonance imaging. Local thoracic aortic inflammation and calcification were measured by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Biomarkers of low-grade inflammation were also quantified. RESULTS: AoPWV was higher in elderly hypertensive subjects comparatively to normotensive controls (15.5±5.3 vs. 11.9±2.5, p=0.046), and hypertensives had a higher calcification volume. In the overall population, calcifications of the thoracic descending aorta and inflammation of the ascending aorta accounted for respectively 18.1% (p=0.01) and 9.6% (p=0.07) of AoPWV variation. Individuals with high levels of calcifications and/or inflammation had higher AoPWV (p=0.003). Inflammation had a negative effect on PPA explaining 13.8% of its variation (p<0.05). CONCLUSION: This study highlights the importance of local ascending aortic inflammation as a potential major actor in the determination of PPA while calcifications and hypertension are more linked to AoPWV. Assessment of PPA in the very elderly could provide complementary information to improve diagnostic and therapeutic strategies targeting ascending aortic inflammation.

[The metabolic syndrome in hypertensive black population of South Algeria]. / Le syndrome métabolique chez les hypertendus de la population noire du sud algérien.

INTRODUCTION: The metabolic syndrome is a risk factor for cardiovascular diseases. It exposes to two main complications: cardiovascular diseases and type II diabetes. This risk is higher among women. It causes a high cardiovascular mortality. OBJECTIVES: Assess the prevalence of the metabolic syndrome (MS) among our black hypertensive population. Study of the distribution of the different criteria in the cluster. Search cardiovascular complications. MATERIALS AND METHODS: This longitudinal study that was carried out included one thousand five hundred and fifty subjects of both sexes from black and white populations aged 40 and older, living in the Algerian Sahara and reviewed after six years of decline. The control consisted of filling a questionnaire oriented on civil status, in addition to a clinical examination, including morphometry, measurement of blood pressure performed with validated electronic device (OMRON 705 CP). Also, a biological check-up was done (glycemy, HDL, cholesterol). A univariate and multivariate analysis have been carried out. All calculations and statistical analyzes are processed by the SPSS 17.0 and Epi Info6 software. RESULTS: The MS frequency is 20.8%, more frequent among women than among men, with a significant difference (28.4% versus 15.1%, P<0.001). We found out a difference between black and white populations in terms of obesity (37.6% versus 31.1%), hypertension (60.6% versus 55.0%), diabetes (25.2% versus 19.2%) or other metabolic syndrome criteria. The most frequent complications according to decreasing frequency are: hospitalization for cardiovascular diseases 8.9%, stroke 6.3%, heart failure 5.8%, myocardial infarction 3.6%. The mortality rate is 14.7% among the blacks and 11.3% among the whites without difference. The survival rate of the population is influenced by the MS and by a non-checked blood pressure by an antihypertensive treatment. CONCLUSION: The MS is highly prevailing among hypertensive black population, and significantly higher among women. The ranking of the cluster elements frequency shows clearly the specifities of our population. It is necessary to elaborate an adequate strategy to prevent such cardiovascular morbidity and mortality.

[Cardiovascular morbimortality after a follow-up of six years in black hypertensive in South Algeria]. / Morbimortalité cardiovasculaires en 6ans des hypertendus noirs du sud algérien.

INTRODUCTION: Arterial hypertension is a major public health problem not only internationally, but also in our country, and it is the major risk factor for cardiovascular diseases. In south Algeria, the black population is nearly half the population of the oases of the Algerian Sahara. THE OBJECTIVES OF THE STUDY: The objectives of the study are to analyze the long-term fate of the black hypertensive subjects in Algerian oases in southern Algeria, in terms of morbidity and mortality, comparing the morphometric profile and cardiovascular complications with the white population of the same oases. MATERIALS AND METHODS: One thousand four hundred and twenty-five subjects of both sexes were included (811 blacks and 614 white subjects), aged 40 and older, living in the Algerian Sahara and were reviewed after six years of decline. The control consisted of filling a questionnaire oriented on civil status, target organ damage, the number of hospitalizations and mortality. All calculations and statistical analyzes are processed by the SPSS 17.0 and Epi Info6 software. RESULTS: Mean age for the black population and the white population was 60.3±11.1 and 58.6±10.6years, respectively. The incidence of hypertension was 50 % among blacks. The main complications observed were: stroke in 3.8 %, heart failure in 3.1 %, myocardial infarction in 1.7 %, hospitalizations related to cardiovascular complications of the black population was around 4.4 %, mortality 5.4 %. CONCLUSION: These data on hypertension black subjects emphasize the importance of a policy of adequate local health issues raised, both in terms of the management of hypertension, as in investment in local medical research.

Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum.

OBJECTIVE: Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease. APPROACH AND RESULTS: Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability. CONCLUSIONS: Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.

Telomere length in vascular tissues from patients with atherosclerotic disease.

OBJECTIVES: The present study was aimed at evaluating telomere length in blood and in different vascular tissues with or without atheroma, in 3 groups of subjects: a group of atherosclerotic subjects who underwent surgery (Atherosclerosis-Surgery), a second group of subjects with asymptomatic atherosclerotic carotid plaques but who did not undergo cardiovascular surgery (Atherosclerosis-No surgery), and a third group of subjects without atherosclerotic disease (Controls). The main objective was to determine if there is in vivo regulation of telomere length in situ by atherosclerotic lesions. METHODS: A total of 84 subjects (mean age 69 ± 8 years) were studied. Blood and arterial tissue telomere lengths were determined by Southern blotting. Personal medical history (diabetes, hypertension, cardiovascular disease, dyslipidemia), family medical history, drug intake, and lifestyle were evaluated in the entire population through the use of a questionnaire. RESULTS AND CONCLUSION: Arterial segments which did not develop atherosclerosis such as the saphenous vein and internal mammary artery, had longer telomere length than aortic segments. On the other hand, telomere length was shorter in aortic tissues which presented atherosclerotic lesions compared to corresponding tissues without atherosclerotic lesions. These results also suggest tissue regulation of telomere size by local factors likely related to oxidative stress responses.

Effect of urban waste compost application on soil near-saturated hydraulic conductivity.

Compost application tends to increase soil fertility and is likely to modify soil hydrodynamic properties by acting on soil structural porosity. Two composts, a municipal solid waste compost (MSW) and a co-compost of green wastes and sewage sludge (SGW), have been applied every other year for 6 yr to cultivated plots located on a silt loam soil in the Parisian Basin, France. Four soil zones were defined in the topsoil after plowing: the plowpan located at the base of the plowed layer, compacted (Delta) or noncompacted (Gamma) zones located within the plowed layer, and interfurrows created by plowing and containing a large quantity of crop residues together with the recently-applied compost. To assess the effect of compost application on the near-saturated soil hydraulic conductivity, infiltration rates were measured using a tension disc infiltrometer at three water pressure potentials -0.6, -0.2, and -0.05 kPa in the various zones of the soil profile. Compost addition decreased K((sat)) in the interfurrows after plowing by almost one order of magnitude with average values of 5.6 x 10(-5) m.s(-1) in the MSW plot and 4.1 x 10(-5) m.s(-1) in the SGW plot, against 2.2 x 10(-4) m.s(-1) in the control plot. This effect had disappeared 6 mo after plowing when the average K((sat)) in the control plot had decreased to 1.9 x 10(-5) m.s(-1) while that in the compost-amended plots remained stable.

Effects of lean and fat mass on bone mineral density and arterial stiffness in elderly men.

SUMMARY: The role of body composition on arterial stiffness and osteoporosis remains unclear, especially in the elderly male population. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest bone mineral density. INTRODUCTION: The aim of this study was to evaluate the influence of fat and lean mass on both arterial stiffness and bone mass density (BMD) in elderly men. METHODS: This study was performed in 169 French males over 60 years old. Aortic stiffness was assessed by carotid/femoral pulse wave velocity (PWV). BMD and body composition were determined with a dual-energy X-ray absorptiometry device in the lumbar spine L1-L4, femoral neck, and total body. RESULTS: Lean mass was positively correlated with the three T scores accounting for 11.6%, 26.6%, and 12.2% of the variability in the lumbar spine L1-L4, femoral neck, and total body BMD T scores, respectively. Fat mass had no effect on BMD. However, fat mass was positively correlated with aortic PWV, accounting for 9.8% of its variability. Lean mass was not a determinant of PWV. Hypertension, diabetes, and dyslipidemia were associated with higher PWV but had no effect on BMD. CONCLUSIONS: In males from a general population over 60 years of age, bone and arterial aging are differently influenced by lean and fat mass. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest BMD.

Effects of valsartan on mechanical properties of the carotid artery in spontaneously hypertensive rats under high-salt diet.

The aim of this investigation was to evaluate the influence of a high-salt diet (HSD) on the effects of valsartan, an angiotensin II type 1 (AT(1)) receptor antagonist, on carotid arterial stiffness and structure in spontaneous hypertensive rats (SHR). Carotid arterial stiffness was studied in SHR receiving a HSD or a normal-salt diet (NSD) from the 10th to 20th week of age. Within each of the 2 groups, the animals received treatment with either placebo or valsartan (30 mg. kg(-1). d(-1)) administered on the 4th to 20th week of age. Arterial pressure, wall stress, incremental elastic modulus (Einc), medial cross-sectional area, and EIIIA fibronectin isoform were significantly increased in placebo-HSD rats compared with placebo-NSD rats with no change in the ratio of collagen to elastin. Valsartan reduced mean arterial pressure in both NSD and HSD rats but reduced pulse pressure only in NSD rats. In NSD rats, valsartan reduced Einc and medial cross-sectional area. In HSD, valsartan increased Einc and did not modify medial cross-sectional area and fibronectin. In valsartan-treated rats, the ratio of collagen to elastin was greater in HSD than in NSD rats. In conclusion, the effects of AT(1) blockade are greatly influenced by salt intake in SHR. Despite a reduction in mean arterial pressure in HSD rats, AT(1) blockade was not able to prevent the effects of a HSD on pulse pressure, carotid artery stiffness, and hypertrophy.

Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives.

BACKGROUND: The polymorphism of several candidate genes has been studied in relation to essential hypertension and cardiovascular complications. Target organ damage in essential hypertension is a complex disorder influenced by multiple genetic and environmental factors. The possible contribution of endothelin gene variants to target organ damage in hypertension in humans has not been studied in depth. PROCEDURE: We assessed the influence of genetic variants of components of the endothelin system ETAR -231A/G, 1363C/T, ETBR 30G/A and endothelin-1 (ET-1) 138insertion/deletion (I/D) on aortic stiffness, left ventricular geometric, and radial artery parameters in 528 never-treated hypertensive subjects of European origin. The study population included 314 men and 214 women with a mean age of 48+/-0.5 years (+/-SEM). In samples of patients, aortic stiffness was assessed with carotid-femoral pulse wave velocity (PWV). Radial artery thickness was measured with an echotracking angiometer and left ventricular geometric parameter with standard echographic procedures. RESULTS: The main results showed that the ETAR-231A/G (P = .022) and the ETBR 30G/A (P = .026) receptor gene variants influenced PWV level in women. The -231G and 30G alleles were associated with a codominant increase in PWV, explaining 18.6% of its variability (P = .005). In men, the ETBR 30G/A receptor gene variant was also related to the level of radial artery parameters (P = .02). No association between the 138I/D polymorphism of the ET-1 gene and left ventricular and radial artery parameters was observed in either men or women. CONCLUSIONS: These results indicate that the influence of endothelin system genes can be detected first on arterial parameters.

Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects.

OBJECTIVES: Arterial stiffness is associated with excess morbidity and mortality, independently of other cardiovascular risk factors. Age is the main determinant responsible for arterial wall changes leading to arterial stiffening. Environmental and genetic factors may however influence the magnitude of the effects of age on large artery stiffness. DESIGN AND METHODS: The present study assessed whether or not the relationship between age and aortic stiffness was influenced by genetic variants of angiotensinogen (AGT 174T/M, 235M/T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 1166A/C, -153A/G) and aldosterone synthase (CYP11B2 -344T/C). This study was realized in 441 untreated hypertensive subjects of European origin (aged 18-74 years). Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS: Carriers of the angiotensin II type 1 receptor -153G allele showed a steeper age/PWV relationship than the AT1 -153AA subjects. The effect of the AT1 -153A/G polymorphism on aortic stiffness became apparent after the age of 55 years. In subjects with the AT1 1166C allele, the relationship age/PWV is shifted upward, indicating higher values of aortic stiffness at any age compared to the AT1 1166AA patients. Carriers of both the AT1 1166C and -153G alleles presented the additive effects of these 2 genotypes on aortic stiffness. Angiotensinogen, ACE and CYP11B2 genotypes did not influence the effects of age on PWV. CONCLUSIONS: AT1 receptor genotypes could influence arterial ageing in hypertensive subjects. These results also show that the association between genotypes and arterial stiffness may manifest itself later in life.

Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity.

Chronological age is the primary determinant of stiffness of central arteries. Increased stiffness is an independent indicator of cardiovascular risk. The aim of this study was to determine whether telomere length, a possible index of biological aging, provides a better account than chronological age for variation in arterial stiffness, evaluated by measuring pulse pressure and aortic pulse wave velocity. The study population included 193 French subjects (120 men, 73 women), with a mean age of 56+/-11 years, who were not on any antihypertensive medications. Telomere length was evaluated in white blood cells by measuring the mean length of the terminal restriction fragments. Age-adjusted telomere length was longer in women than in men (8.67+/-0.09 versus 8.37+/-0.07 kb; P=0.016). In both genders, telomere length was inversely correlated with age (P<0.01). Multivariate analysis showed that in men, but not in women, telomere length significantly contributed to pulse pressure and pulse wave velocity variations. In conclusion, telomere length provides an additional account to chronological age of variations in both pulse pressure and pulse wave velocity among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and pulse wave velocity, which are indices of large artery stiffness. The longer telomere length in women suggests that for a given chronological age, biological aging of men is more advanced than that of women.

Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats.

OBJECTIVES: Because the synthesis of aldosterone is mainly modulated by angiotensin II through type I receptor stimulation and because converting enzyme inhibition (CEI) does not modify aortic extracellular matrix in old normotensive rats, the aim of the present study was to determine whether inhibition of aldosterone formation was able to prevent aortic fibrosis in old Sprague-Dawley normotensive rats. BACKGROUND: We have previously shown that long-term aldosterone antagonism prevents the age-related increase in aortic collagen accumulation in young spontaneously hypertensive rats, independent of blood pressure changes. In contrast, we reported that the positive effects of CEI in the prevention of aortic collagen accumulation were related to the inhibition of angiotensin II actions on angiotensin II type I receptors. METHODS: For this purpose, we studied the histomorphometric and stiffness (echo-tracking technique) changes of an eight-week treatment with the aldosterone antagonist spironolactone by comparison with placebo. RESULTS: At the end of treatment, spironolactone in conscious animals did not change intra-arterial blood pressure, aortic and carotid wall thickness, and cardiac weight. Cardiac collagen density and, to a lesser extent, carotid collagen and elastin densities and contents were significantly decreased in association with an increase of carotid distensibility. CONCLUSIONS: These results show that in old normotensive rats, spironolactone can markedly prevent cardiac and, to a lesser extent, arterial fibrosis and improve arterial stiffness, despite a lack of hypotensive effect.

Pharmacokinetics, metabolism and excretion of megazol in a Trypanosoma brucei gambiense primate model of human African trypanosomiasis. Preliminary study.

The pharmacokinetics of megazol (2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol, CAS 19622-55-0) was investigated after a 100 mg/kg oral administration to six primates infected with Trypanosoma brucei gambiense. The plasma levels of megazol were between 0.2 microgram/ml and 46 micrograms/ml 24 h after dosing in all animals. In animals with prolonged infection, megazol absorption was accelerated (Tmax was 4 h compared with 8 h, for day 53 and day 39 post inoculation) but the amount absorbed was not modified. The megazol concentrations in the cerebrospinal fluid represented between 5.5% and 10.6% of the plasma levels at the same times. Unchanged megazol was eliminated predominantly via the kidneys: 46-96% of the ingested dose was recovered in the urine, compared with 0-5% in the faeces. Furthermore, this urinary elimination of megazol was altered in animals with prolonged infections. In the urine, 4 unknown metabolites were observed, unchanged megazol was characterized by LC-MS/MS. This study indicates that megazol crosses the blood-brain barrier after oral administration. Prolonged infections affect the absorption of megazol and its urinary elimination.

M1/MUC5AC mucin released by human airways in vitro.

A series of monoclonal antibodies which bind to a mucin known as M1 (anti-M1 MAbs) have also been shown to detect the product of the human gene MUC5AC. The aim of this investigation was to determine the concentration of the M1 mucin in the surface epithelium of human bronchial preparations by means of immunohistochemistry and in the bronchial fluid derived from human airways by means of an immunoradiometric assay. Human bronchial ring preparations from the resection material of 20 patients were challenged with methacholine, leukotriene D4, or anti-immunoglobulin E. Experiments were performed in preparations with an intact epithelium as well as in tissues in which the epithelium had been mechanically removed. The anti-M1 MAbs stained the goblet cells in the epithelium intensely and there was also light and less uniform staining in the submucosa. The M1/MUC5AC mucin in the fluids secreted by the bronchial preparations was not modified during either the experimental protocol or stimulation with the different secretagogues. However, in preparations in which the epithelium had been removed, there was a significant reduction in the amount of M1/MUC5AC mucin detected. These data suggest that the M1/MUC5AC mucin detected in the biological fluids produced by human airways in vitro may be released constantly, and principally from the goblet cells in the epithelial layer.

Arterial structural changes with verapamil in spontaneously hypertensive rats.

Reducing pulse pressure might be more powerful than reducing mean arterial pressure to obtain regression of vascular hypertrophy. However, this hypothesis has never been investigated in the conduit arteries of intact hypertensive animals. A group of 4-week-old spontaneously hypertensive rats (SHR) was treated with the calcium-entry blocker verapamil (50 mg/kg) for 16 weeks and compared with untreated SHR and control Wistar Kyoto (WKY) normotensive rats of the same age. At the end of the experiment, intraarterial thoracic aorta blood pressure was measured both in the conscious and anesthetized animals. Carotid artery diameter and stiffness (echo-tracking techniques) and aortic histomorphometry were determined in parallel. With verapamil, pulse pressure, but not mean arterial pressure, was significantly decreased but did not reach the normotensive values. Carotid internal diameter, medial thickness, and collagen content were significantly reduced by comparison with SHR and did not differ from the values of the WKY group. A significant positive and independent correlation was observed between pulse pressure and medial thickness in the overall population. The study shows that, in SHR chronically treated with verapamil, structural changes may be completely prevented without any change in mean arterial pressure. The parallel change in pulse pressure might suggest that mechanosensitive elements within the vascular wall may be selectively sensitive to the dynamic aspects of physical forces and are able to convert frequency and amplitude information into cellular responses that lead to vascular remodeling.

Pharmacokinetics, metabolism and excretion of megazol, a new potent trypanocidal drug in animals.

The pharmacokinetics of megazol (CAS 19622-55-0) was investigated after intraperitoneal and oral administration of the drug (80 mg/kg) to mice. The plasma levels were significantly higher after oral administration of drug than after intraperitoneal route (33.8 micrograms/ml compared with 19.0 micrograms/ml for Cmax, 158714 micrograms.h/l compared with 96057 micrograms.h/l for AUC). When suramin (CAS 145-63-1) was administered 24 h before oral administration of megazol, megazol absorption was accelerated (2 h compared with 4 h for Tmax) but the amount absorbed was lower (19.9 micrograms/ml compared with 33.8 micrograms/ml for Cmax and 95547 micrograms.h/l vs 158714 micrograms.h/l for AUC). In the infected mice previously treated with suramin, all estimated pharmacokinetic parameters of plasma megazol were significantly modified, in particularly an increase in the apparent volume of distribution (5.6 l/kg compared with 0.9 l/kg) with a prolongation of the elimination half-life (3 h compared with 0.7 h) of megazol. Excretion of the total radioactivity of megazol was also evaluated after oral administration of 3H-megazol to rats. Total radioactivity was eliminated predominantly via the urinary route (80%) vs. 10.5% in the faeces, 9.5% remaining in the body 8 days after dosing. When unlabelled megazol was orally administered to rats with absence or presence of suramin, megazol recovered in urine and faeces 72 h dosing was: 55.7%/2% vs 20.6%/1.6%, respectively. In the urine, unchanged megazol was present as characterized by LC-MS/MS as well as 4 unknown metabolites. This study indicates that suramin significantly affects the pharmacokinetics of megazol and its elimination.

Prostanoid receptors involved in the relaxation of human bronchial preparations.

1. Iloprost and cicaprost (IP-receptor agonists) induced relaxations in the histamine- (50 microM) contracted human bronchial preparations (pD2 values, 6.63+/-0.12 and 6.86+/-0.08; Emax values, 90+/-04 and 65+/-08% of the papaverine response for iloprost (n=6) and cicaprost (n=3), respectively). 2. Prostaglandin E2 (PGE2) and misoprostol (EP-receptor agonist) relaxed the histamine-contracted human bronchial preparations (pD2 values, 7.13+/-0.07 and 6.33+/-0.28; Emax values, 67+/-04 and 57+/-08% of the papaverine response for PGE2 (n=14) and misoprostol (n=4), respectively). In addition, both relaxations were inhibited by AH6809 (DP/EP1/EP2-receptor antagonist; 3 microM; n=5-6). 3. The PGE2-induced relaxations of human bronchial preparations were not modified by treatment with AH23848B (TP/EP4-receptor antagonist; 30 microM; n=4). 4. The contracted human bronchial preparations were significantly relaxed by prostaglandin D2 (PGD2) or by BW245C a DP-receptor agonist. However, these responses did not exceed 40% of the relaxation induced by papaverine. In addition, the relaxations induced by PGD2 were significantly inhibited by treatment with a DP-receptor antagonist BWA868C (0.1 microM; n=3). 5. These data suggest that the relaxation of human isolated bronchial preparations induced by prostanoids involved IP-, EP2- and to a lesser extent DP-receptors but not EP4-receptor.