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Cites a study which determines whether bone loss or fractures are associated with the presence of aortic calcifications among a large cohort of French women. Observation of lower femoral T-score and BMD in women with calcifications; Positive association of markers of bone loss and a history of fractures with the presence of vascular calcifications; Likelihood of osteoprotegerin levels to be higher among persons with fractures but not in the presence of calcifications.

Background Medication review is time-consuming and not exhaustive in most French hospitals. We routinely use an innovative hybrid decision support system using Artificial Intelligence to prioritize medication review by scoring prescriptions by their risk of containing at least one drug related problem (DRP). Aim Our aim was to attest that the prescriptions with low risk of DRPs ruled out by the tool in everyday practice were effectively free of any DRPs with potentially severe clinical impact. Methods We conducted a randomized single-blinded study to compare the rate of pharmaceutical interventions (PI) between low and high-risk prescriptions defined by the tool's calculated score. Prescriptions were reviewed daily by a clinical pharmacist. Proportion of prescriptions with at least one severe DRP was calculated in both groups. Severe DRPs were characterized through a multidisciplinary approach. Results Four hundred and twenty (107 low score and 313 high score) prescriptions were analyzed. The percentage of prescriptions with severe DRPs was dramatically decreased in low score prescriptions (2.8% vs. 15.3% for high-risk; p = 0.0248). A significant difference was found (94% vs. 20%; p < 0.001) in the percentage of severe DRPs detected by the hybrid approach compared to a CDSS. During the study period, the hybrid tool allowed to rule out 55% of all prescriptions in our hospital.Conclusion This hybrid decision support tool has shown to be accurate to detect DRPs in daily practice. Despite some limitations, it offers the best possible solution to prioritized medication review, considering the shortage of clinical pharmacists in France and considerably improves the safety of patients' care., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Endothelial dysfunction, one of many causes of arterial changes in end-stage kidney disease (kidney failure), is a likely link between early vascular aging and the risk of thrombosis or bleeding in this condition. To evaluate this, we compared links between arterial stiffness and endothelial/coagulation factors in 55 patients receiving hemodialysis therapy and 57 age-/sex-matched control individuals. Arterial stiffness was assessed from carotid-femoral pulse wave velocity, and coagulation status from the endogenous thrombin generating potential. Markers of endothelial dysfunction (von Willebrand factor, tissue factor pathway inhibitor), neutrophil extracellular traps and tissue factor-positive extracellular vesicles were higher in patients with kidney failure. Prothrombin fragments 1 and 2, and D-dimer markers of in vivo coagulation activation were also higher. However, in vitro in the presence of platelets, endogenous thrombin generating potential was lower and its downregulation by activated protein C impaired. Antiplatelet drugs did not affect these parameters. In multiple regression analysis, prothrombin fragments 1 and 2, D-dimer, factor VIII and monocyte-derived tissue factor-positive extracellular vesicles correlated with higher carotid-femoral pulse wave velocity. In patients with kidney failure, in vivo hypercoagulability occurred with reduced thrombin generation in platelet-rich plasma, likely explaining the opposing thrombotic and bleeding tendencies in patients with kidney failure. Importantly, arteriosclerosis is more closely related to a prothrombotic state. Thus, coagulation changes plus arterial stiffness highlight a major therapeutic challenge for anticoagulant and antiplatelet drug use., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: To improve patient safety and clinical outcomes by reducing the risk of prescribing errors, we tested the accuracy of a hybrid clinical decision support system in prioritizing prescription checks., Materials and Methods: Data from electronic health records were collated over a period of 18 months. Inferred scores at a patient level (probability of a patient's set of active orders to require a pharmacist review) were calculated using a hybrid approach (machine learning and a rule-based expert system). A clinical pharmacist analyzed randomly selected prescription orders over a 2-week period to corroborate our findings. Predicted scores were compared with the pharmacist's review using the area under the receiving-operating characteristic curve and area under the precision-recall curve. These metrics were compared with existing tools: computerized alerts generated by a clinical decision support (CDS) system and a literature-based multicriteria query prioritization technique. Data from 10 716 individual patients (133 179 prescription orders) were used to train the algorithm on the basis of 25 features in a development dataset., Results: While the pharmacist analyzed 412 individual patients (3364 prescription orders) in an independent validation dataset, the areas under the receiving-operating characteristic and precision-recall curves of our digital system were 0.81 and 0.75, respectively, thus demonstrating greater accuracy than the CDS system (0.65 and 0.56, respectively) and multicriteria query techniques (0.68 and 0.56, respectively)., Discussion: Our innovative digital tool was notably more accurate than existing techniques (CDS system and multicriteria query) at intercepting potential prescription errors., Conclusions: By primarily targeting high-risk patients, this novel hybrid decision support system improved the accuracy and reliability of prescription checks in a hospital setting., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function., Methods: The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death. The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra)., Findings: From March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0·22 [95% CI 0·11-0·41; p<0·0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR 0·22 [95% CI 0·10-0·49]; p=0·0002). An increase in liver aminotransferases occurred in seven (13%) patients in the anakinra group and four (9%) patients in the historical group., Interpretation: Anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. Confirmation of efficacy will require controlled trials., Funding: Groupe Hospitalier Paris Saint-Joseph., (© 2020 Elsevier Ltd. All rights reserved.)

The spontaneously hypertensive rat model with reduced NO synthesis (SHRLN) shares features with aging and hypertension in humans, among other a severe aortic stiffening. The present in vivo study aimed to compare thoracic (TA) and abdominal (AA) aortic stiffness in the SHRLN (treated 5 weeks with L-NAME), SHR, and normotensive Wistar Kyoto (WKY). Dynamic properties of TA and AA were measured in the same rats, using echotracking recording of aortic diameter coupled with blood pressure (BP). Measurements were performed first at operating BP and then after BP reduction in hypertensive rats, thus in isobaric conditions. Histological staining and immunohistochemistry were used for structural analysis at both sites. At operating pressure, BP and pulse pressure (PP) were higher in SHRLN compared with SHR. Stiffness index was also increased and distensibility decreased in both TA and AA in SHRLN. At WKY-matched blood pressure, isobaric AA parameters remained specifically altered in SHRLN, whereas TA recovered to values identical to WKYs. Collagen, fibronectin, α 5-selectin, and FAK were increased in SHRLN compared with SHR or WKY. Nevertheless, only the strong accumulations of fibronectin and collagen at the AA site in SHRLN were associated with intrinsic stiffening. In conclusion, we confirm that NO restriction associated with hypertension induces a severe pathological phenotype and shows that L-NAME induced stiffening is more pronounced in AA than in TA as a result of greater fibrosis.

Lacosamide, one of the last antiepileptic drugs marketed, can cause extension of PR interval. Precautions are recommended when used in elderly and with other drugs extending PR interval. Cases of severe third-degree atrioventricular block have been reported only in post-marketing case reports when used at high-doses and remain rare. We report the case of an 88-year-old woman treated with bisoprolol, who experienced a complete atrioventricular block after initiation of lacosamide for epilepsy associated with neurodegenerative disease. This dramatic event required a pacemaker implementation. Not being dose-dependent (initiation dosage used), it seemed partially explained by drug-drug interaction with bisoprolol.

Background Clinical pharmacists' involvement has improved patients' care, by suggesting therapeutic optimizations. However, budget restrictions require a prioritization of these activities to focus resources on patients more at risk of medication errors. Objective The aim of our study was to identify variables influencing the formulation of pharmaceutical to improve medication review efficiency. Setting This study was conducted in medical wards of a 643-acute beds hospital in Paris, France. Methods All hospital medical prescriptions of all patients admitted within four medical wards (cardiology, rheumatology, neurology, vascular medicine) were analyzed. The study was conducted in each ward for 2 weeks, during 4 weeks. For each patient, variables prospectively collected were: age, gender, weight, emergency admission, number of high-alert medications and of total drugs prescribed, care unit, serum creatinine. Number of pharmaceutical interventions (PIs) and their type were reported. Main outcome measures Variables influencing the number of pharmaceutical interventions during medication review were identified using simple and multiple linear regressions. Results A total of 2328 drug prescriptions (303 patients, mean age 70.6 years-old) were analyzed. Mean number of hospital drug prescriptions was 7.9. A total of 318 PIs were formulated. Most frequent PIs were drug omission (n = 88, 27.7%), overdosing (n = 69, 21.7%), and underdosing (n = 51, 16.0%). Among variables studied, age, serum creatinine level, number of high-alert medications prescribed and total number of drugs prescribed were significantly associated with the formulation of pharmaceutical interventions (adjusted R 2  = 0.34). Conclusions This study identified variables (age, serum creatinine level, number of high-alert medication, number of prescribed drugs) that may help institutions/pharmacists target their reviews towards patients most likely to require pharmacist interventions.

In many individuals, blood pressure varies between clinic visits conducted days, weeks, or months apart. This visit-to-visit variability (VVV) of blood pressure has been recently related with an increased risk of coronary heart disease, stroke, and mortality, independently of mean blood pressure. As for other chronical diseases, patients' adherence to hypertensive therapies remains low and partial adherence to antihypertensive treatment may constitute a source of VVV, as suggested by recent studies. This data should lead to a new clinical approach for hypertension care, based on patients' real adherence to treatment. Therapeutic strategies should include patients' adherence. In this context, the role of community pharmacists for patients' follow-up of hypertension should be reinforced, as they represent efficient and easily accessible health professionals.

Central artery stiffening is recognized as a cardiovascular risk. The effects of hypertension and aging have been shown in human and animal models but the effect of salt is still controversial. We studied the effect of a high-salt diet on aortic stiffness in salt-sensitive spontaneously hypersensitive stroke-prone rats (SHRSP). Distensibility, distension, and β-stiffness were measured at thoracic and abdominal aortic sites in the same rats, using echotracking recording of the aortic diameter coupled with blood pressure (BP), in SHRSP-salt (5% salted diet, 5 weeks), SHRSP, and normotensive Wistar-Kyoto (WKY) rats. Hemodynamic parameters were measured at BP matched to that of WKY. Histological staining and immunohistochemistry were used for structural analysis. Hemodynamic isobaric parameters in SHRSP did not differ from WKY and only those from the abdominal aorta of SHRSP-salt presented decreased distensibility and increased stiffness compared with WKY and SHRSP. The abdominal and thoracic aortas presented similar thickening, increased fibrosis, and remodeling with no change in collagen content. SHRSP-salt presented a specific increased elastin disarray at the abdominal aorta level but a decrease in elastin content in the thoracic aorta. This study demonstrates the pro-stiffening effect of salt in addition to hypertension; it shows that only the abdominal aorta presents a specific pressure-independent stiffening, in which elastin disarray is likely a key mechanism., (The Author(s). Published by S. Karger AG, Basel.)

Rationale, Aims, and Objectives: Intravenous (IV) to oral (PO) drug switch is a challenge for tertiary care institutions for several reasons: catheter-related infections, patient's pain and discomfort or higher costs, and overuse of IV drugs considered as an irrational use of medicines. The objective was to evaluate yearly acetaminophen and proton-pump inhibiters' (PPIs) IV/PO ratios from 2011 to 2015 and to determine their correlation with all drugs IV/PO ratios and their relevance as drug tracers. A secondary objective was to estimate costs savings associated with a IV to PO switch improvement., Methods: Data on IV and PO consumptions and impact on costs were presented to physicians yearly, followed by the development of a computerized tool and pharmaceutical validation of prescriptions. Intravenous and PO drug consumptions were extracted yearly for all drugs, acetaminophen, and PPIs from 2011-01-01 to 2015-12-31. Acetaminophen and PPIs' IV/PO ratios were compared to IV/PO consumptions for all drugs. Costs savings associated with this switch were calculated yearly by multiplying the difference in average cost per dose by the total number of doses delivered (fixed purchase prices, euros) for both routes., Results: All drugs IV/PO ratio decreased every year to achieve a 16.3% reduction between 2011 and 2015. Acetaminophen and PPIs also decreased respectively by 35.5% and 16.5%. Same tendency of decrease of ratios year by year was noted for all drugs, PPIs, and acetaminophen. Savings for both acetaminophen and PPIs IV/PO switch were over 98 000€ for 5 years., Conclusions: This study demonstrated that acetaminophen IV/PO ratio, easily produced in routine, was a relevant tracer to follow IV/PO switch improvement as it was correlated with all drugs IV/PO ratio. Direct cost savings associated with IV/PO switch improvements were consequent and illustrate well the impact of our approach on the efficiency of therapeutics' management., (© 2017 John Wiley & Sons, Ltd.)

Background: Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear. Our objectives were to determine the temporal evolution of both BPV and pulse wave velocity (PWV), a surrogate measure of arterial stiffness, using an animal model of remodeling-dependent aortic stiffening., Method: We thus, developed a new telemetric technique allowing continuous measurement of PWV in conscious, unrestrained rats. Studies were performed in spontaneously hypertensive rats (SHR) treated for 2 weeks with N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (SHR-LN). BPV was evaluated conventionally or with a new device composed of two pressure transducers in two different sets of rats. This allowed a continuous monitoring of telemetered PWV, systolic (SPV), diastolic (DPV), and pulse pressure variability (PPV). Aortic structure was then characterized by immunohistochemical analysis., Results: SPV, DPV, and PPV were increased in SHR-LN, when calculated by 24-h SD or using average real variability a parameter used to assess short-term variability in man. We observed rapid and simultaneous increases in BP, SPV, and PWV. Interestingly, PPV was the most increased parameter resulting mainly from different time course of SPV and DPV. Structural alterations of the aortic wall were observed, with a eutrophic inward remodeling and accumulation of fibronectin and its two main receptors (α5 and αv integrins)., Conclusion: This offers unequivocal evidence of a significant relationship between PWV, BPV, and arterial structure.

Background: Meta-analyses of antihypertensive therapy suggest that, independently of blood pressure (BP) level, stroke prevention is influenced mainly by calcium-entry blockers (CEB) and cardiac risk prevention by angiotensin-converting enzyme inhibitors (ACEIs). The possibility that central systolic and pulse pressure (PP) reduction differs between the two drug classes for the same mean BP (MBP) has never been explored. Our aim was to compare carotid PP at the same MBP obtained with the CEB, amlodipine, and the ACEI, trandolapril, in spontaneously hypertensive rats (SHR), and to evaluate the resulting changes of fibronectin (Fn) and its integrin alpha5beta1 receptor on central PP and arterial stiffness., Methods: Amlodipine and trandolapril were administered chronically to achieve the same MBP. Carotid arterial systolic BP (SBP) and PP, diameter and incremental elastic modulus (E(inc)) were determined using echo Doppler techniques, and complemented with vascular histomorphometry, and Fn and alpha5beta1-integrin immunolabeling., Results: Both drugs produced the same MBP, carotid wall thickness, and stress. Trandolapril reduced PP and E(inc) significantly more than amlodipine, while both agents comparably lowered EIIIA-Fn. Total Fn and alpha-subunit were lowered significantly by trandolapril, but unaffected by amlodipine, indicating that ACEI alone contributed to both diminished carotid stiffness and decrease of the Fn-integrin complex., Conclusions: Results showed that amlodipine and trandolapril have different effects on carotid mechanical properties for comparable MBP reduction. Changes in Fn-integrin complex not only modify consistently ACEI mechanotransduction but also are associated with selective central PP reduction. Whether this property has consequences on cardiovascular (CV) risk remains to be investigated.

Epidemiological studies have established a significant association between two major health problems, osteoporosis and atheroma, which is independent from age, gender, and other cardiovascular risk factors. Bone loss and the development of calcific deposits within vessel walls occur concomitantly. Proteins formerly thought to be specific of bone have been identified in atheroma lesions; and associations linking vertebral and proximal femoral fractures to aortic calcifications have been reported. Bone loss may be a marker for the risk of stroke and cardiovascular death. Bone loss may occur as a consequence of ischemia related to vascular disease. Despite numerous published studies, the mechanism underlying the osteoporosis-atheroma association remains controversial. Factors that perpetuate the debate include the often retrospective design of the studies, small sample sizes, and known limitations of absorptiometry as a tool for measuring osteoporosis severity. We reviewed the available clinical, epidemiological, and animal data on the mechanisms underlying the association between osteoporosis and atheroma. The possible effect of osteoporosis medications on the blood vessel wall is discussed. These issues remain a matter of debate, indicating a need for vast prospective studies to look for a causal link between osteoporosis and atheroma. The results of these studies may lead to new treatment strategies.

Methadone (MTD) maintenance treatment is a recognized method to reduce illicit opiate abuse. Because of the difficulties of collecting 24-hour urines routinely, the monitoring of MTD compliance is currently done with random urinary screening. However, monitoring of MTD compliance by random urinary screening lacks accuracy because of its highly variable pharmacokinetics, leading to false positive or negative results. This study's objective was to identify factors influencing the reliability of urinary screening of methadone for MTD compliance monitoring in a field setting involving usual care for opiate-dependent patients. In a cross-sectional population-based study, 1981 urine samples obtained from 68 patients in parallel with drug dose, gender, and weight were analyzed by MTD enzyme immunoassay (EMIT). Urinary pH was measured, and positive threshold was determined experimentally by box-plot analysis. Multivariate determinants of MTD excretion were established with stepwise multiple regression analysis. On this basis, adjusted values for MTD excretion were proposed and verified with an (S)-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) assay from independent urine samples that were negative or doubtful by the MTD assay. MTD excretion was higher in men, decreased with increased urinary pH, and increased with daily dosage of MTD; these factors explain 32% of the total variance of urinary MTD. Adjustment on these 3 variables (urinary pH, sex, daily dosage) improved the prediction of compliance to MTD treatment. Threshold was stable across pH values and in agreement with EDDP results. The influence of simple variables such as gender, urinary pH, and daily dosage on urinary MTD excretion could be put in evidence and accounted for. Adjusted values of urinary MTD are more reliable than the raw values for monitoring compliance to MTD treatment.

Increased large artery stiffness is believed to be a cardiovascular risk factor independent from mean arterial pressure. The mechanical properties of large arteries depend not only on the amounts of their main constituents (elastin, collagen, and smooth muscle cells) but also on the spatial organization and mechanical interactions among these components. These interactions may be mediated by extracellular matrix adhesion proteins and their membrane receptors or integrins. From a mechanical viewpoint, a key element may be the dense plaque, which is composed of cytoskeletal proteins linked to matrix proteins via membrane integrin receptors. Integrin expression in normal and diseased blood vessels is currently the focus of active research. In humans, hypertension-related arterial hypertrophy is not associated with an increase in intrinsic arterial wall stiffness. Aortic fibronectin expression is increased in spontaneously hypertensive rats (SHRs). By increasing cell-matrix anchoring, fibronectin may contribute to protect arterial wall components from the increased mechanical loads associated with hypertension. In atherosclerosis, the increase in cell-matrix anchoring plays a key role in preventing atheroma plaque rupture. To determine the exact role of adhesion molecules in arterial stiffness, there is a need for studies involving use of specific anti-integrin agents and of transgenic animal models.

The objective of the present study was to determine the viscoelastic properties of the common carotid artery in 35 patients with aortic aneurysm before surgery (AAA) (age 71 years, range 61-84), in comparison with 48 patients with essential hypertension (HT: 50 years, range 24-88) and 44 normotensive subjects (NT: 44 years, range 23-85). The second objective was to establish the relations between common carotid artery (CCA) viscoelastic properties and histologic lesions observed on AAA segments, obtained after surgery. CCA diameter was larger and distensibility smaller in AAA patients than in HT and NT. Distensibility of the aortic aneurysm was smaller than that of upstream 'normal' aorta, itself being smaller than control aortas. AAA wall lesions were extensive, associating adventitial and medial fibrosis, elastolysis, smooth muscle rarefaction, neovascularization, inflammation and plaques. The grade of these lesions was not correlated with the mechanical properties of the aorta and CCA; however, they could explain their qualitative alterations. AAA is characterized by severe stiffening and dilatation of large arteries distant from the aneurysm location. Whether this pattern of arterial phenotype is explained by the increase in stiff material (collagen) and the rarefaction of distensible material (smooth muscle and elastin) remains to be determined.

Recent studies have shown that large-artery wall remodeling per se does not reduce distensibility in hypertension, indicating qualitative or quantitative changes in arterial components. The aim of the study was to determine in 1-year-old spontaneously hypertensive rats (SHRs) the changes in the elastic properties of large arteries, as assessed by the incremental elastic modulus (E(inc)), and the changes in the extracellular matrix, including fibronectin (FN) and alpha5beta1-integrin. The relationship between E(inc) and circumferential wall stress was calculated from in vivo pulsatile changes in blood pressure and arterial diameter by using a high-resolution echo-tracking system at the site of the abdominal aorta and in vitro medial cross-sectional area. E(inc)-stress curves and FN and integrin alpha5-subunit contents were determined for each animal. Mean stress and E(inc) were higher in SHRs than in Wistar rats. However, in a common range of stress, E(inc)-stress curves for SHRs were superimposable on those for Wistar rats, indicating that wall materials in both strains have equivalent mechanical behavior. Immunohistochemistry indicated that total FN, EIIIA FN isoform, and alpha5-integrin increased in the SHRs aortas without changes in elastin and collagen densities. Total FN was also increased in SHRs as determined by Western blot analysis. No differences in FN and alpha5-subunit mRNAs were detected between SHRs and Wistar rats. These results indicate that the aortic wall material of SHRs and Wistar rats have equivalent mechanical properties, although in SHRs it is subjected to a higher level of stress. By increasing cell-matrix attachment sites, FN may participate in the mechanical adaptation of both cellular and matrix components in SHRs.

Arterial wall viscosity (AWV) is a potential source of energy dissipation in circulation. That arteries, which are known to be markedly viscous in vitro, have lower viscosity in vivo has been suggested but not demonstrated under similar pressure conditions. Endothelium, which may modulate AWV through smooth muscle tone, could contribute to the low level of viscosity in vivo. Our objectives were first to compare AWV of the rat abdominal aorta, in vivo and in vitro, with similar pulse-pressure waves, and second, to determine whether endothelial function influences AWV in vivo and in vitro. The diameter of the abdominal aorta and distending pressure were measured in vivo and in vitro with a high-resolution echotracking system and a micromanometer, respectively. AWV was calculated as the area of the pressure-volume curve hysteresis. After in vivo examination, the arterial segments were isolated in vitro and submitted to resynthesized pressure waves identical to those recorded in vivo. Deendothelialization was performed in vivo by balloon rubbing; then arteries were examined either in vivo or in vitro. AWV was markedly lower in vivo than in vitro (6.6 +/- 0.7 versus 22.7 +/- 3.7 J.m-1.10(-5), respectively; P < .001). After deendothelialization, a sustained 40% increased AWV was observed during a 15-minute follow-up (P < .01). In vitro, deendothelialized arteries have a 64% higher AWV than segments with endothelium (P < .01). Our results indicate that the physiological effective viscosity, measured in vivo in intact animals, is threefold lower than the intrinsic viscosity of the arterial wall, measured in vitro. Endothelium removal determines a sustained increase in AWV, either in vivo or in vitro. These results suggest that active mechanisms compensate for intrinsic viscosity under physiological conditions. One of these energy-saving mechanisms might be dependent on normal endothelial function.

Nitric oxide (NO) has been shown to be a ubiquitous intercellular autacoid in the heart and, in cultured rat ventricular myocytes, to decrease the contractile responsiveness to isoproterenol (ISO). The aim of the present study was to investigate whether exogenous (sodium nitroprusside, SNP) or endogenous nitric oxide generated from L-arginine modulated the response to ISO in cultured chick embryo ventricular myocytes. SNP 1 microM or L-arginine 1 mM had no effect on baseline contractile function. Superfusion with ISO 100 nM significantly increased myocyte amplitude of shortening to 1.31 +/- 0.06 (ratio to baseline amplitude). Initial superfusion with SNP 1 microM or L-arginine 1 mM attenuated the response to ISO to 0.89 +/- 0.05 and 1.09 +/- 0.07 respectively (P < 0.05). Potassium ferrocyanide which is not a NO donor and D-arginine the inactive substrate of NO synthase did not attenuate the response to ISO. Myocyte cGMP content was significantly increased by incubation with SNP 1 microM (31.65 +/- 3 fmol/well) but not by L-arginine 1 mM (11.1 +/- 0.3 fmol/well) as compared to myocytes incubated in control medium (11 +/- 0.9 fmol/well). Preincubation with SNP 1 microM or L-arginine 1 mM significantly attenuated the ISO mediated-increase in cAMP content from 4.33 +/- 0.2 pmol/well (ISO 100 nM alone) to 1.48 +/- 0.36 fmol/well and 1.72 +/- 0.21 pmol/well respectively. Potassium ferrocyanide and D-arginine had no effect on myocyte cGMP or cAMP content. Chick embryo myocytes have measurable and LNMMA-inhibited NO synthase activity as measured by the conversion of [3H] L-arginine to [3H] L-citrulline. In conclusion, these results demonstrate that in cultured chick embryo ventricular myocytes both exogenous and endogenous NO elevate cGMP. This may account for the inhibition of beta-adrenergic agonist-stimulated increases in cAMP and amplitude of shortening via an unidentified intracellular negative coupling.

We have previously shown that rat atrial natriuretic peptide (ANP) reduces the contractility of cultured, spontaneously beating chick embryo ventricular cells, an effect opposite to that of endothelin-1. Endothelin-1 has been described as a secretagogue for natriuretic peptides in vitro and in vivo. Natriuretic peptides can inhibit endothelin-1 secretion from cultured endothelial cells, suggesting a negative feedback mechanism between endothelial cells and cardiomyocytes. The aim of this study was to determine whether ANP attenuated the endothelin-1-induced increase in myocyte contractility. Using a video-microscopy system we studied the contractility of isolated cultured chick ventricular myocytes in response to endothelin-1, chicken natriuretic peptide (ChNP), and both. We also used Northern blot analysis to study the time course of ChNP expression in response to endothelin-1. Endothelin-1 (10(-8) M) increased chick cardiomyocyte contractility by 20-25% between 5 and 15 min (P < 0.05). Although ChNP (3 x 10(-7) M) did not significantly change the amplitude of contraction in basal conditions, it prevented the endothelin-1-induced increase in contractility (P < 0.05) when perfused prior to endothelin-1, and reversed it when perfused 5 min after endothelin-1 exposure (P < 0.05). Endothelin-1 significantly increased the accumulation of ChNP mRNA in chick ventricular myocytes as early as the 30 min after exposure (P < 0.05), with a maximal effect after 2 h of stimulation (P < 0.01); no effect was observed after 4 h. These data support an interaction between endothelin-1 and natriuretic peptides as autocrine/paracrine factors regulating the contractile function of chick cardiac myocytes, as well as their antagonistic effects on cardiac cell contractility. The early and transient expression of ChNP mRNA in response to endothelin-1 may be involved in this interaction.