HIV-infected patients' beliefs about their chronic co-treatments in comparison with their combined antiretroviral therapy.

OBJECTIVES: Thanks to the success of combination antiretroviral therapy (cART), HIV-infected patients can have almost a normal life expectancy. This has resulted in an aging HIV-infected population with other chronic comorbidities such as cardiovascular diseases, osteoporosis, and depression. Our hypothesis is that patients' perceptions of and attitudes towards their cART, which is perceived as crucial to their survival, differ from their beliefs about their co-treatments, and this may have an impact on their medication adherence. METHODS: We used the French version of the Beliefs about Medicine Questionnaire (BMQ-f) to measure the perceptions of patients about their co-treatments and the Beliefs about Medicine Questionnaire for Highly Active Antiretroviral Therapy (BMQ-HAART) to measure their beliefs about their cART in a representative sample (n = 150) of patients enrolled in the Swiss HIV Cohort Study (SHCS) and followed at the Infectious Disease Service at the University Hospital in Lausanne, Switzerland. The survey was administered to all eligible patients by the order of their scheduled appointments at the end of their medical visit. The BMQ comprises two subscores: Specific-Necessity (5 identical items in BMQ-f and BMQ-HAART) and Specific-Concerns (also 5 identical items in BMQ-f and BMQ-HAART). The subscores were standardized by dividing the score scale by the number of questions in the scale, resulting in a range of responses between 1 (low) and 5 (high). Self-reported medication adherence was measured using the SHCS Adherence Questionnaire (SHCS-AQ). Adherence was defined as not missing any dose or missing one dose of the treatment in the past 4 weeks. Sociodemographic variables were retrieved by reviewing the SHCS database. RESULTS: A response rate of 73% (109 of 150) was achieved. A total of 105 patients were included in the analysis: their median age was 56 [interquartile range (IQR) 51, 63] years and 74 were male (70%). Eighty-seven patients (83%) were adherent to cART and 75 (71%) were adherent to their co-treatments (P = 0.0001). The standardized mean responses for the BMQ Specific-Necessity subscores were 4.46 [standard deviation (SD): 0.58] and 2.86 (SD: 1.02) for cART and co-treatments, respectively (P < 0.0001). For Specific-Concerns, the standardized mean responses were 2.9 (SD: 1.02) for cART and 4.09 (SD: 1.02) (P < 0.0001) for co-treatments. cART and co-treatment concerns increased as the number of co-treatments increased (P = 0.03 and P < 0.0001, respectively). CONCLUSIONS: Patients had higher Necessity and lower Concerns scores for their cART in comparison with their co-treatments. A higher percentage of patients reported being adherent to cART compared with the co-treatments that they reported they were most likely to miss. Further research using a bigger sample size and more objective measures of adherence is needed to explore the association between adherence and patients' perceptions.

SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial.

BACKGROUND AND AIMS: Sodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes characterized by sodium retention leads to decreased tissue sodium content due to its pharmacological action. MATERIALS AND METHODS: In a prospective double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to either dapagliflozin 10 mg or placebo once daily for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analysed the sodium content in the skin and muscles of the lower leg by Na-MRI. RESULTS: Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11 mmHg, p = 0.010), and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024), 24-h ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline [24.1 ± 6.6 vs. 22.7 ± 6.4 A.U.(arbitrary unit) p = 0.013]. No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 A.U. p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline. CONCLUSION: SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in tissue sodium content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT02383238) retrospectively registered.

Switching from a two-tablet regimen of tenofovir/emtricitabine and efavirenz to a one-tablet regimen may affect patients' perceptions and drug management.

OBJECTIVES: Simplification of antiretroviral therapy enhances a patient's adherence but a new formulation could also lead to new adverse events and changes in daily routine. This study compared medication adherence, tolerance and satisfaction among subjects switching from a two-tablet tenofovir/emtricitabine/efavirenz regimen to a one-tablet regimen. METHODS: Clinical and sociodemographic data were collected and three surveys were administered at month 0 (=switch), and then 1 and 4-6 months after the switch: the Beliefs about Medicines Questionnaire, the HIV-symptom index questionnaire, the Short HIV Treatment Satisfaction Questionnaire, the Swiss HIV Cohort Study (SHCS) two-item adherence questionnaire, and a questionnaire on daily combination antiretroviral therapy (cART) management. Medication adherence of a subgroup of subjects was routinely monitored using an electronic device (MEMS(™) ). RESULTS: Eighty-eight subjects gave informed consent to participate in the study. The subjects' back-switch rate was 7% (six of 88). Subjects who did not back-switch preferred the one-tablet regimen (median = 2; IQR = 1.3-2.5; on a -3 to 3 scale), but no change in adherence was found (10 of 46 nonadherent subjects; P = 1.00). The perception of treatment necessity score decreased (P = 0.004), the efavirenz blood level increased (14%; P = 0.04), and association/dissociation of cART with food intake evolved (P = 0.01) after the switch. Subjects listed equivalent numbers of symptoms during the three visits. CONCLUSIONS: The one-tablet regimen was preferred but the number of back-switches was not negligible. The perception of treatment necessity score decreased with the simplification of the regimen from a two-tablet to a one-tablet formulation, which could negatively impact adherence. Switching is a sensitive time in a patient's treatment life and professionals should pay particular attention to patient's perceptions of treatment during such a transition.

Description of bovine major histocompatibility complex class IIa haplotypes using parthenogenetic embryo-derived cells.

In this study, we report an approach to characterize individual BoLA haplotypes using cells from parthenogenetic bovine embryos derived from slaughterhouse ovaries. Eight of the 15 parthenogenetic embryos so obtained had not undergone meiotic recombination on the BoLA region and were suitable to describe BoLA haplotypes. Detailed analysis of the BoLA class IIa region identified seven different class IIa haplotypes, including six not previously described and two new alleles of BoLA-DQA and one BoLA-DQB. Our method provided reliable sources of homozygous DNA to describe BoLA haplotypes.

Photoelectron spin-polarization control in the topological insulator Bi2Se3.

We study the manipulation of the spin polarization of photoemitted electrons in Bi2Se3 by spin- and angle-resolved photoemission spectroscopy. General rules are established that enable controlling the photoelectron spin-polarization. We demonstrate the ± 100% reversal of a single component of the measured spin-polarization vector upon the rotation of light polarization, as well as full three-dimensional manipulation by varying experimental configuration and photon energy. While a material-specific density-functional theory analysis is needed for the quantitative description, a minimal yet fully generalized two-atomic-layer model qualitatively accounts for the spin response based on the interplay of optical selection rules, photoelectron interference, and topological surface-state complex structure. It follows that photoelectron spin-polarization control is generically achievable in systems with a layer-dependent, entangled spin-orbital texture.

Rosuvastatin improves pulse wave reflection by restoring endothelial function.

One of the major indicators of intact endothelial function is basal nitric oxide (NO) activity. Further, it seems to be likely that statin therapy exerts beneficial effects on vascular function, at least in part via an improvement of NO bioavailability. In the present double-blind crossover study 29 hypercholesterolemic patients were randomly assigned to receive rosuvastatin and placebo for 42days. Pulse wave analysis was assessed after 30min of rest (baseline) and after infusion of N(G)-monomethyl-l-arginine (l-NMMA) at the end of 42days treatment period. The magnitude of the increase in central augmentation index (cAIx) in response to inhibition of NO synthase (NOS) by l-NMMA is indicative of basal NO activity. CAIx was significantly lower (18.3±10 versus 21.9±12%, p=0.027) with rosuvastatin compared to placebo. There was no increment of cAIx in response to l-NMMA in placebo group. In contrast, cAIx increased significantly in response to l-NMMA (20.5±11 versus 25.7±10mm Hg, p=0.001) in rosuvastatin group. The percentage of increase of cAIx tended to be more pronounced after treatment with rosuvastatin compared to placebo (53.7±92 versus 14.1±36%, p=0.087). Pulse pressure amplification (PPA) improved (1.31±0.2 versus 1.26±0.2%, p=0.016) after rosuvastatin compared to placebo. Regression analyses revealed that both LDL-cholesterol and CRP-levels are independent determinants of basal NO activity improvement, which itself is an independent determinant of vascular function, expressed by an improvement of pulse wave reflection and PPA. In this placebo controlled study, treatment with rosuvastatin improved vascular and endothelial function. Determinants for improved NO production in patients with hypercholesterolemia were the achieved levels of LDL-cholesterol and CRP. Overall, in patients without CV disease, rosuvastatin exerted beneficially effect on vascular dysfunction, one of the earliest manifestation of atherosclerosis.

Polymorphism and gene organization of water buffalo MHC-DQB genes show homology to the BoLA DQB region.

In cattle (Bos taurus), there is evidence of more than 50 alleles of BoLA-DQB (bovine lymphocyte antigen DQB) that are distributed across at least five DQB loci, making this region one of the most complex in the BoLA gene family. In this study, DQB alleles were analysed for the water buffalo (Bubalus bubalis), another economically important bovine species. Twelve alleles for Bubu-DQB (Bubalis bubalis DQB) were determined by nucleotide sequence analysis. A phylogenetic analysis revealed numerous trans-species polymorphisms, with alleles from water buffalo assigned to at least three different loci (BoLA-DQB1, BoLA-DQB3 and BoLA-DQB4) that are also found in cattle. These presumptive loci were analysed for patterns of synonymous (d(S)) and non-synonymous (d(N)) substitution. Like BoLA-DQB1, Bubu-DQB1 was observed to be under strong positive selection for polymorphism. We conclude that water buffalo and cattle share the current arrangement of their DQB region because of their common ancestry.

[Therapeutic adherence to oral cancer therapy and interdisciplinary management]. / Adhésion thérapeutique aux traitements oncologiques oraux et prise en charge interdisciplinaire.

Medication adherence is a well-known risk factor in internal medicine. However in oncology this dimension is emerging due to the increasing number of oral formulations. First results in the oral oncology literature suggest that patients' ability to cope with medical prescription decreases with time. This might preclude patients from reaching clinical outcomes. Factors impacting on medication adherence to oral oncology treatments have not been yet extensively described neither strategies to address them and support patient's needs. Oncologists and pharmacists in our University outpatient settings performed a pilot study which aimed at measuring and facilitating adherence to oral oncology treatments and at understanding determinants of patient's adherence. The ultimate purpose of such a patient-centered and interdisciplinary collaboration would be to promote patient self-management and complement the standard medical follow-up.

DNA sequencing of 13 cytokine gene fragments of Aotus infulatus and Saimiri sciureus, two non-human primate models for malaria.

Aotus and Saimiri are non-human primate models recommended by the World Health Organization for experimental studies in malaria, especially for vaccine pre-clinical trials. However, research using these primates is hindered by the lack of specific reagents to evaluate immune responses to infection or vaccination. As a step toward developing molecular tools for cytokine expression studies in these species, primer pairs for 18 cytokine gene fragments were designed based on human DNA sequences and used to amplify the corresponding genes in Aotus infulatus and Saimiri sciureus genomic DNA samples. IFNγ, TNFα, LTA, IL2, IL3, IL4, IL5, IL6, IL10, IL12, IL13, CSF2 and TGFß2 gene fragments were amplified and sequenced. Primer pairs for IL8, IL17, IL18, IL27 and MIF failed to generate amplification products. When compared to the available corresponding human and non-human primate sequences, most--except IL3 and IL4--showed identity degrees above 90%. Small variations in sequence can help to explain the failure to amplify certain genes or the amplification only at lower annealing temperatures as compared to human DNA samples for several primer pairs. The sequences made available provide the basis for designing molecular tools such as primers for real time PCR specific for A. infulatus and/or S. sciureus. The nucleotide sequences reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned accession numbers DQ985386 to DQ985389, DQ989356 to DQ989369, FJ89020 to FJ89024, and FJ89029.

Change in augmentation index during NOS inhibition, an index of basal NO production, is an independent determinant of large-artery function.

BACKGROUND/AIMS: Arterial wave reflection, measured as augmentation index (AIx), and central pulse pressure (PP) closely predict cardiovascular events. We hypothesized that basal nitric oxide (NO) production would be a determinant of AIx and central PP. METHODS: AIx and central PP were assessed at baseline by pulse wave analysis in 86 male subjects across a wide range of age, blood pressure and lipid values. The basal NO production in the cardiovascular system was then determined as change in AIx during NO synthase blockade with N(G)-monomethyl-L-arginine (L-NMMA, 3.25 mg/kg). RESULTS: AIx increased from 17.5 ± 14.6 to 23.1 ± 14.2 during L-NMMA infusion (p < 0.001). The increase in AIx during NO synthase blockade, an index of basal NO production, was inversely related to baseline central AIx and PP, and positively to PP amplification. Multiple linear regression analyses disclosed that in addition to age and mean blood pressure, change of AIx to L-NMMA is a strong and independent determinant of baseline central AIx, central PP and PP amplification. CONCLUSION: Greater change of AIx to L-NMMA, an index of basal NO production, is associated with better large-artery function. Therefore, therapeutic interventions which increase the basal NO production might be particularly effective in reducing cardiovascular risk.

[More HIV-positive women are referred to a medication adherence clinic than men]. / Plus de femmes que d'hommes VIH positifs sont réferees à une consultation d'adhésion thérapeutique.

HIV-positive patients with antiretroviral medication adherence issues are referred to an outpatient adherence clinic. Surprisingly, two-third of referred patients are women although more than 60% of the patients at the Infectious Disease Outpatient service are men. Women seem to be referred because of specific social factors: children at home, black sub-Saharan ethnicity, difficulties in medication and disease management due to stigmatization. Literature is poor and controversial and it is not possible to conclude whether medication adherence varies with gender. However, recent data seem to show that reasons for nonadherence vary according to gender.

Population genetic studies of Alouatta belzebul from the Amazonian and Atlantic Forests.

Cytochrome b DNA sequence data (ca. 1,140 bp) of 66 Alouatta belzebul from the Amazonian and the Atlantic Forests of Brazil were used for phylogenetic reconstructions and population studies. Our sample consisted of 60 specimens from the Amazonian Forest (captured in 1984 and 1998 in Pará-PA state) and six specimens from the Atlantic Forest (Paraíba-PB state). We found 32 haplotypes, 23 in PA-1984 (with 12 present in more than one individual), 11 in PA-1998 (with two present in more than one individual), and a single haplotype in the PB sample. Animals from PA-1984 and PA-1998 shared three haplotypes while animals from Pará and Paraíba did not share any haplotype. We found 57 variable sites, consisting of 53 transitions and four transversions, with most replacements occurring at third codon position (77.19%) and less frequently at first and second positions (10.53 and 12.28%, respectively). Genetic distance between all haplotypes varied between 0 and 1.2%. Nucleotide diversity estimates between PA-1984 haplotypes and PA-1998 haplotypes were the same (π=0.01), and haplotype diversity estimates were very similar (h=0.96 and 0.93 for PA-1984 and PA-1998, respectively). Maximum parsimony, median-joining, split decomposition, and TCS showed that PA and PB haplotypes had not drastically diverged and that subsequent radiation within these regions was not apparent. No temporal structure was found between PA-1984 and PA-1998. The sum of square deviation estimate for PA-1984 equaled 0.01 (P=0.23), in agreement with a hypothetical model of sudden expansion contrary to PA-1998 whose sum of square deviation estimate (0.40; P=0.04) was not compatible with this model, although the small sample size of PA-1998 as well as the smaller area of capture could have also accounted for this result. Fu's F(s) and R(2) statistical neutrality tests corroborated these propositions. Lack of drastic differentiation was attributable to the once existing connection between the Atlantic and the Amazonian forests at a non-distant past.

FISH-mapping of LEP and SLC26A2 genes in sheep, goat and cattle R-banded chromosomes: comparison between bovine, ovine and caprine chromosome 4 (BTA4/OAR4/CHI4) and human chromosome 7 (HSA7).

Sheep (OAR), goat (CHI) and cattle (BTA) R-banded chromosome preparations, obtained from synchronized cell cultures, were used to FISH-map leptin (LEP) and solute carrier family 26 member 2 (SLC26A2) genes on single chromosome bands. LEP maps on OAR4q32 and CHI4q32, being the first assignment of this gene to these two species. SLC26A2 maps on BTA7q24, OAR5q24 and CHI7q24. This gene, too, was assigned for the fist time to both sheep and goat chromosomes, while it was more precisely localized on a single chromosome band in cattle. Improved cytogenetic maps of BTA4/OAR4/CHI4 were constructed and compared with HSA7 revealing five main conserved segments and complex chromosome rearrangements, including a centromere repositioning, differentiating HSA7 and BTA4/OAR4/CHI4.

[Drug compliance in the elderly: determinants and support]. / L'adhésion thérapeutique du patient âgé ambutatoire: quels déterminants et quet soutien?

Drug adherence needs to be promoted in elderly patients taking multiple medications. Barriers to adherence are numerous and each barrier needs to be addressed specifically. Patients should be included in the therapeutic decision making process. Patient's life expectations and disease/treatment beliefs should be addressed. Healthcare practitioners should discuss the course of treatment with the patient proactively before any problem arises by using open-ended and informative questions. Functional and organizational barriers to adherence should be assessed throughout the treatment. A multidisciplinary approach to promote adherence is crucial and allows healthcare practitioners to combine specific skills (physician, pharmacist, nurse, etc.).

Cytochrome b polymorphisms and population structure of two species of Alouatta (Primates).

We carried out a phylogenetic and population study in Alouatta caraya and Alouatta belzebul based on cytochrome b DNA sequence data. Maximum Parsimony and Median-Joining analyses grouped A. caraya from different localities showing a population structure in accordance with geographic distribution. The relation between A. caraya haplotypes could be explained with respect to the species range in the Cerrado, one of the most ancient morphoclimatic domains of South America, and the Chaco. Conversely, A. belzebul from the Amazonas and Atlantic forests grouped in a paraphyletic arrangement without an evident geographic pattern. Recent geologic events resulting in the separation of A. belzebul might explain why these geographically distant groups shared similar haplotypes and why ancestral polymorphisms might have been maintained in this species. Time of divergence estimates indicated that the splitting of the Alouatta lineage leading to A. caraya occurred some 4.58 MYA while the lineage leading to A. belzebul emerged 4.14 MYA.

Sequences of the primate epsilon-globin gene: implications for systematics of the marmosets and other New World primates.

Sequences of the epsilon-globin gene were determined for five species of marmosets, along with approximately 2 kb of 5' flanking sequence. An analysis of these data, compared with those of other primates strongly supports the classification of Callithrix jacchus and C. geoffroyi into the jacchus group, and C. argentata and C. mauesi into the argentata group. The pygmy marmoset, formerly identified as Cebuella pygmaea joined strongly to the argentata group, indicating that without the pygmy marmoset the genus Callithrix would be paraphyletic. Our data support recent studies which indicate that C. pygmaea should be included in the genus Callithrix. Relationships among other primates were as indicated by previous studies of epsilon-globin sequences. Divergence times were estimated according to a local molecular clock. These calculations indicated the divergence of C. mauesi and C. argentata to be approximately 1.6-1.9 Myr (million years ago), and the most recent common ancestor of the marmosets to be between 4.5 and 4.7 Myr. The latter estimate corresponds well to the date of 4.6 Myr calculated from an independent data set.

Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions.

OBJECTIVE: Incomplete compliance is one of several possible causes of uncontrolled hypertension. Yet, non-compliance remains largely unrecognized and is falsely interpreted as treatment resistance, because it is difficult to confirm or exclude objectively. The goal of this study was to evaluate the potential benefits of electronic monitoring of drug compliance in the management of patients with resistant hypertension. METHODS: Forty-one hypertensive patients resistant to a three-drug regimen (average blood pressure 156/ 106 +/- 23/11 mmHg, mean +/- SD) were studied prospectively. They were informed that for the next 2 months, their presently prescribed drugs would be provided in electronic monitors, without any change in treatment, so as to provide the treating physician with a measure of their compliance. Thereafter, patients were offered the possibility of prolonging the monitoring of compliance for another 2 month period, during which treatment was adapted if necessary. RESULTS: Monitoring of compliance alone was associated with a significant improvement of blood pressure at 2 months (145/97 +/- 20/15 mmHg, P < 0.01). During monitoring, blood pressure was normalized (systolic < 140 mmHg or diastolic < 90 mmHg) in one-third of the patients and insufficient compliance was unmasked in another 20%. When analysed according to tertiles of compliance, patients with the lowest compliance exhibited significantly higher achieved diastolic blood pressures (P = 0.04). In 30 patients, compliance was monitored up to 4 months and drug therapy was adapted whenever necessary. In these patients, a further significant decrease in blood pressure was obtained (from 150/100 +/- 18/15 to 143/94 +/- 22/11 mmHg, P = 0.04/0.02). CONCLUSIONS: These results suggest that objective monitoring of compliance using electronic devices may be a useful step in the management of patients with refractory hypertension, as it enables physicians to take rational decisions based on reliable and objective data of drug compliance and hence to improve blood pressure control.

Functional gene testing of the Glu298Asp polymorphism of the endothelial NO synthase.

OBJECTIVES: To test whether the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene is of functional relevance in humans by altering endothelium-dependent vasodilation. BACKGROUND: The Asp298 variant of the eNOS gene product has been associated with arterial hypertension, coronary artery disease and myocardial infarction. The pathogenetic mechanism has not yet been elucidated. Since endothelium-dependent vasodilation has been shown to be impaired in these disorders, we hypothesized that the Glu298Asp polymorphism of the eNOS gene influences endothelium-dependent vasodilation. METHODS: In 80 patients with normal or elevated cholesterol, endothelium-dependent and -independent vasodilation was assessed. Forearm blood flow was measured by plethysmography in response to intra-arterial (i.a.) infusion of 12 and 48 microg/min acetylcholine and 3.2 and 12.8 microg/min nitroprusside, respectively. NG-monomethyl-L-arginine (L-NMMA) in doses of 4, 8 and 16 micromol/min was infused to test basal nitric oxide (NO) production and release. Genomic DNA was extracted from blood samples to determine the Glu298Asp polymorphism of the eNOS gene at position 1917 G/T after BanII restriction. RESULTS: Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. Genotype frequencies did not deviate from the Hardy-Weinberg equilibrium. No differences in forearm blood flow to i.a. acetylcholine (average increase: + 554 +/- 371%), nitroprusside or L-NMMA infusion were found across the eNOS genotypes, neither for endothelium-dependent or endothelium-independent vasodilation, nor for basal NO production and release. Our sample size of n = 80 had a power of > 80% (beta = 0.20) with a P value < 0.05 (alpha = 0.05) to detect a 200% difference in forearm blood flow response to 48 microg/min acetylcholine. CONCLUSIONS: At a power of 80%, we can exclude a relevant effect on endothelium-dependent vasodilation due to the eNOS Glu298Asp polymorphism. Thus, our functional genetic study does not suggest any biological effect of the eNOS Glu298Asp genotype on the cardiovascular system via an influence on endothelium-dependent vasodilation.

Plasma endothelin is increased in early essential hypertension.

Local vascular generation of endothelin-1 (ET-1) may contribute to elevated peripheral resistance in hypertension. We tested the hypothesis that immunoreactive ET production in the forearm circulation is increased in early essential hypertensive subjects. Ten young, previously untreated male patients with mild essential hypertension and no signs of target organ damage were compared with matched normotensive subjects in an outpatient setting. Arterial and venous samples were obtained from indwelling catheters in the brachial artery and the medial cubital vein, respectively. Samples were collected at baseline and after induction of endothelium-dependent (acetylcholine) vasodilation. Immunoreactive ET (ET) was measured after column extraction by a sensitive radioimmunoassay employing a C-terminal ET-1 antibody with negligible cross-reaction to big-ET. Individual recovery rates were determined for each sample. Basal ET was significantly higher in hypertensive than in normotensive subjects, both in venous and arterial samples (P < .01). This difference was also present after correction for recovery (P < .01). There was no significant difference between venous and arterial ET concentrations. Local vasodilation did not change arterial or venous ET levels. In conclusion, plasma ET is increased in young, untreated, essential hypertensive subjects with no signs of target organ damage. The increased circulating immunoreactive ET may point to a role for the peptide early in the development of high blood pressure.

The effect of statins on angiotensin II-induced hemodynamic changes in young, mildly hypercholesterolemic men.

BACKGROUND: Angiotensin II type 1 (AT(1)) receptors are well known to mediate angiotensin II (Ang II)-induced pro-atherosclerotic effects. It has been found that hypercholesterolemia influences the expression of AT(1) receptors on vascular smooth muscle cells and that increased density of AT(1) receptors exaggerates the hemodynamic response to Ang II. We analyzed to what extent statins and AT(1) receptor antagonists diminish the vasoconstrictive response to Ang II infusion in hypercholesterolemic patients. METHODS: A total of 24 male patients with LDL cholesterol levels >130 mg/dL were enrolled in a randomized, cross-over study. After baseline evaluation, 12 patients received first cerivastatin (0.3 mg/day) and the other 12 patients initially received candesartan (8 mg/day) for 3 weeks, with subsequent cross-over of the medication for the second 3-week drug period. The vascular response was analyzed by the increase in mean arterial pressure (MAP) and total peripheral resistance (TPR) during infusion of increasing doses of Ang II at baseline and the end of each treatment period. Hemodynamic changes were also compared with those in 24 normocholesterolemic subjects without any therapy. RESULTS: At baseline, Ang II provoked a similar increase of MAP and TPR in patients and control subjects. Treatment with cerivastatin did not affect the response to Ang II compared with baseline. By contrast, treatment with candesartan attenuated significantly the response to Ang II compared with baseline and cerivastatin. CONCLUSIONS: Our hemodynamic data indicate the hypothesis that statins do not reduce the responsiveness to Ang II in resistance arteries of young, mildly hypercholesterolemic patients.