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The modulation of the renin angiotensin aldosterone system (RAAS) is an important pathway in managing high blood pressure, and its overexpression plays a key role in target end-organ damage. Telmisartan is an angiotensin II receptor blocker (ARB) with unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a significant and 24-h sustained reduction of blood pressure. Telmisartan has well-known antihypertensive properties, but there is also strong clinical evidence that it reduces left ventricular hypertrophy, arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection.This paper reviews telmisartan's pharmacological properties in terms of efficacy for hypertension control and, importantly, focuses on its new therapeutic indications and their clinical implications.ONTARGET (ongoing telmisartan alone and in combination with ramipril global endpoint trial) demonstrated, that telmisartan confers cardiovascular protective effects similar to those of ramipril, but with a better tolerability. Moreover, recent investigations focused on the capability of telmisartan to modulate the peroxisome proliferator-activated receptor-gamma (PPAR-γ), an established target in the treatment of insulin resistance, diabetes and metabolic syndrome, whose activation is also correlated to anti-inflammatory and, finally, anti-atherosclerotic properties. Telmisartan shows peculiar features that go beyond blood pressure control. It presents promising and unique protective properties against target end-organ damage, potentially able to open a scenario of new therapeutic approaches to cardiovascular disease.

Hypertension is one of the major risk factors associated with cardiovascular diseases. A range of blood pressure-lowering agents is available including diuretics, alpha- and beta-blockers, aldosterone antagonists, calcium-channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and direct renin inhibitors (DRI). Most patients require two or more medications to control their blood pressures within normal ranges. When high blood pressure cannot be controlled by low-dose monotherapy, physicians employ either high-dose monotherapy or combination therapy. High-dose ARB monotherapy is more effective for reducing proteinuria against low-dose ARB monotherapy or CCBs. Combination therapy is recommended for hypertension patients to facilitate prompt maintenance of blood pressure. Single-pill combination therapy simplifies treatment and optimizes long-term compliance. Thiazide diuretics such as hydrochlorothiazide (HCTZ), alone or in combination are still widely used as first-line hypertension treatment. Recent studies have shown that double (CCB+ARBs) or triple (CCB+ARBs+HCTZ) combination therapies have a greater lowering efficacy and are better tolerated. Moreover, the use of DRIs has been patented and proven effective in selected categories of hypertensive patients with or without concomitant target organ damage (TOD).

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Overactivation of the sympathetic nervous system (SNS) plays an important role in the pathogenesis of comorbidities related to AF such as hypertension, congestive heart failure, obesity, insulin resistance, and obstructive sleep apnea. Methods that reduce sympathetic drive, such as centrally acting sympatho-inhibitory agents, have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. Moxonidine acts centrally to reduce activity of the SNS, and clinical trials indicate that this is associated with a decreased AF burden in hypertensive patients with paroxysmal AF and reduced post-ablation recurrence of AF in patients with hypertension who underwent pulmonary vein isolation (PVI). Furthermore, device-based approaches to reduce sympathetic drive, such as renal denervation, have yielded promising results in the prevention and treatment of cardiac arrhythmias. In light of these recent findings, targeting elevated sympathetic drive with either pharmacological or device-based approaches has become a focus of clinical research. Here, we review the data currently available to explore the potential utility of sympatho-inhibitory therapies in the prevention and treatment of cardiac arrhythmias.

SUMMARYAccumulating data show that fibroblasts are important regulators in the development and maintenance of allergic airway inflammation. However, most studies so far have used individual recombinant cytokines in high concentrations, unlikely to be found in vivo. We aimed to investigate how cytokines produced by peripheral blood mononuclear cells (PBMC) affect fibroblast functions. Primary airway fibroblasts where incubated with allergen-stimulated or non-stimulated PBMC supernatants from allergic patients. The levels of cytokines in PBMC supernatants were measured and the expression of CD54, CD40 and CD106 as well as the production of eotaxin, interleukin (IL)-6 and IL-8 were assessed in fibroblasts. Although the levels of single cytokines measured in PBMC supernatants were low, a significant up-regulation of the surface molecules as well as of IL-6 and IL-8 production was found in fibroblasts cultured with allergen-stimulated PBMC supernatants as compared to non-stimulated, while the increase in eotaxin production was not significant. The evaluation of correlations between cytokines produced by PBMC and effects seen on fibroblasts did not indicate a crucial role for any single cytokine. Furthermore, the addition of comparably low concentrations of recombinant interferon (rIFN)-γ or recombinant tumour necrosis factor (rTNF)-α did not induce the same effects as PBMC supernatants, the only exception being TNF-α as a direct inducer of CD54 expression. Our results show that synergistic mechanisms has a more important role than single mediators, highlighting important differences between in vitro experiments, where effects of individual mediators are studied, versus the actual situation in vivo.

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-β-induced expression of α-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-κB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.

Recently, airway fibroblasts captured the attention of both allergists and basic scientists since they are no longer considered as mere bystanders, as far as allergic airway diseases are concerned. The aim of the present study was to assess the effects of different Cetirizine (Cet) concentrations (0.01, 0.05, 0.1 mg/ml) on human airway fibroblast proliferation and on CD54 expression. By means of flow cytometry analysis, we evaluated CD54 expression by airway fibroblasts in basal conditions or after gammaIFN stimulation in the presence of Cetirizine; we also evaluated the effect of the drug on cell proliferation by a [3H]thymidine incorporation assay. All of the tested doses of Cetirizine were able to significantly reduce CD54 upregulation induced by gammaIFN; concerning the fibroblast proliferation, we observed a dose-dependent inhibition of [3H]thymidine incorporation. These results show that Cetirizine exerts a biologic effect directly on human airway fibroblasts, suggesting a new rationale in the use of this compound.

Background: Mizolastine is a potent, peripherally acting, selective H1-receptor antagonist with potential anti-inflammatory properties. The aim of the study was to evaluate the in vitro effects of mizolastine on the expression of adhesion molecules by primary human airway epithelial and stromal cultures; moreover, the activity of mizolastine on parameters which reflect the immune response efficacy was investigated. Methods: Airway epithelial and stromal cells were collected from hypereosinophilic subjects by enzymatic digestion of polyps or turbinates. Cells were stimulated with interferon (IFN)-γ (500 IU/ml) in the presence of various mizolastine concentrations (6 × 10–8–6 × 10–6 M) for 24 h and the expression of CD106, CD54, CD58 and HLA class I was evaluated. Peripheral blood mononuclear cells from healthy volunteers were incubated with 1% phytohemagglutinin or anti-CD3 monoclonal antibody (20 ng/ml) in the presence of mizolastine, then T lymphocyte proliferation, HLA-DR expression and T cell subpopulations were evaluated. Results: Both in epithelial and stromal cultures, IFN-γ significantly upregulated all of the tested surface molecules (p < 0.05). The highest dose of mizolastine (6 × 10–6 M), corresponding to 10-fold the peak plasma level after a single oral administration of 10 mg, was able to act on fibroblasts, significantly downregulating the expression of CD54 (p < 0.05). Regarding T lymphocyte proliferation, the addition of mizolastine did not induce any significant change; furthermore, mizolastine was ineffective at all of the tested concentrations on both HLA-DR expression and CD4+/CD8+ ratio. Conclusions: This study demonstrated that mizolastine is able to selectively downregulate CD54 expression on stimulated stromal but not epithelial cells without impairing the immune system effectors. The possible clinical significance of these results are an antiallergic property and CD54 modulation on fibroblasts with a good safety profile as far as the lymphocyte response is concerned.

Natural killer (NK) cells have the capability of lysing targets that have down-regulated the expression of HLA class I molecules. Herpes simplex virus (HSV) infection results in a profound reduction of HLA class I molecules on the surface of infected cells. For this reason, NK cell populations kill efficiently HSV-infected cells. The recent availability of a panel of monoclonal antibodies directed to NK receptors for HLA class I (CD158a, CD158b, anti-p70, anti-p140, and CD94) allowed an accurate dissection of the NK cell subpopulations. Using this approach, the relationship between the expression of NK cell receptors and the capability of lysing HSV-infected cell targets was analyzed at the clonal level. NK cell clones were derived from healthy donors, and cytolytic properties were assayed against HSV-infected autologous fibroblasts. NK cell clones, classified according to the expression of natural killer-cell receptors on their surface, displayed a great heterogeneity of cytolytic properties against HSV-infected cells. Nevertheless, a more accurate functional analysis demonstrated not only that HSV infection downregulated the expression of HLA-A and HLA-B and did not modify the expression of HLA-C, but also that NK cell clones expressing the "activating" form of the anti HLA-C NK cell receptor were more cytolytic than other clones. This finding suggests that two different and clonally distributed mechanisms of NK cell activation may be employed by NK cells to kill HSV-infected autologous target cells.

Background Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient’s therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated. Methods/design The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension - both in the office and in ambulatory conditions over 24 h - and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n=84) or HBPT (n=168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets ( Discussion The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients. Trial registration Clinical Trials.gov: NCT01541566

Objective: Renal sympathetic denervation (RDN) has been largely studied, but the still poor knowledge of the nerves distribution in the thickness of renal artery could lead to procedural inefficacy, that, as recently suggested by some experimental studies, could explain unsatisfactory response to renal denervation. Recent evidences show that proportion of fibers available for RDN is small in proximal portion of renal artery but increases towards its distal part. Our aim was to assess whether in clinical practice there were differences in effectiveness between make ablations only at the level of the main arterial trunk or even at the level of peripheral branches. Design and Method: A total of 12 consecutive patients with resistant hypertension were included. The first 5 patients were treated with unipolar catheter; for the last 7 patients, the multi-electrode catheter was used. The first group (A) was treated with 4 to 5 ablation points for artery in the main trunk only. The second group (B) was treated with 10 to 14 ablation points for artery distributed among the main trunk plus distal branches. Office BP and ABPM was measured at baseline, 1, 3, 6 and 12 months after RDN. Results: Office and 24-hours SBP and DBP decreased at 1, 3, 6 and 12 months in all 12 patients. While office SBP decreased in Group A likewise in the Group B (−24 and −22 mmHg, respectively; Fig.1), the reduction in office DBP was stronger in Group B than Group A (−23 vs −14 mmHg). Similarly, Group B 24-hours SBP and DBP values decreased more than in Group A (A: −12/−6, B: −19/−10, mmHg). Conclusions: Our data confirm the results of recent studies and suggest that ablation of main trunk plus distal branch of the artery may be more effective in reducing BP in clinical practice as much as shown in controlled clinical studies.

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure and mediator of hypertension-related complications, is a prime target for cardiovascular drug therapy. Angiotensin-converting enzyme inhibitors (ACEIs) were the first drugs to be used to block the RAAS. Angiotensin II receptor blockers (ARBs) have also been shown to be equally effective for treatment. Although these drugs are highly effective and are widely used in the management of hypertension, current treatment regimens with ACEIs and ARBs are unable to completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior than to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes, but dual RAAS blockade with the combination of an ACEI and an ARB is sometimes associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The recent introduction of the direct renin inhibitor, aliskiren, has made available new combination strategies to obtain a more complete blockade of the RAAS with fewer adverse events. Renin system blockade with aliskiren and another RAAS agent has been, and still is, the subject of many large-scale clinical trials and furthermore, is already available in some countries as a fixed combination.

The treatment of moderate or severe hypertension in most cases requires the contemporaneous use of multiple antihypertensive agents. The most available two-drug combinations have an agent that addresses renin secretion and another one that is statistically more effective in renin-independent hypertension. The practice of combining agents that counteract different mechanisms is the most likely explanation for the fact that most available two-drug combinations have an agent that addresses renin secretion (beta-blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker or direct renin inhibitor) and another one that is more effective in renin-independent hypertension (diuretic, dihydropyridine or non-dihydropyridine calcium channel blocker). Based on these considerations, addition of hydrochlorothiazide to the combination of an antagonist of the renin-angiotensin system with a calcium channel blocker would constitute a logical approach. Inclusion of a diuretic in the triple combination is based on the evidence that these agents are effective and cheap, enhance the effect of other antihypertensive agents, and add a specific effect to individuals with salt-sensitivity of blood pressure. The benefit of triple combination therapy with amlodipine, valsartan and hydrochlorothiazide over its dual component therapies has been demonstrated, and the use of a single pill will simplify therapy resulting in better blood pressure control.

Background: Increasing the dose or adding a second antihypertensive agent are 2 possible therapeutic choices when blood pressure (BP) is poorly controlled with monotherapy.Objective: This study investigated the effectiveness and tolerability of barnidipine 10 or 20 mg added to losartan 50 mg versus losartan 100 mg alone in patients with mild to moderate essential hypertension whose BP was uncontrolled by losartan 50-mg monotherapy.Methods: This was a 12-week, multicenter, randomized, open-label, parallel-group study. Eligible patients (aged 30-74 years) had uncontrolled hypertension, defined as office sitting diastolic BP (DBP) 90 mm Hg and/or systolic BP (SBP) 140 mm Hg, and mean daytime DBP 85 mm Hg and/or SBP 135 mm Hg. All were being treated with losartan 50 mg at enrollment. After a 1-week run-in period while taking losartan 50 mg, patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg or losartan 100-mg monotherapy. At the end of this period, patients with uncontrolled BP had barnidipine doubled to 20 mg and continued for an additional 6 weeks, whereas patients not achieving control on treatment with losartan 100 mg were discontinued. Office BP was measured at each visit, whereas 24-hour ambulatory BP monitoring (ABPM) was performed at randomization and at the final visit (ie, after 12 weeks of treatment, or at 6 weeks for patients not controlled on losartan 100 mg). The intent-to-treat population included all randomized patients who received at least one dose of study treatment and had valid ABPM recordings at baseline and the final visit. The primary end point was the change in daytime DBP between baseline and 12 weeks of treatment, compared between the combination treatment and monotherapy. Adverse events (AEs) were evaluated during each study visit.Results: A total of 93 patients were enrolled (age range, 30-75 years; 60% [56/93] men). After the 1-week run-in period, 68 patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg (n = 34) or losartan 100-mg monotherapy (n = 34). A total of 53 patients were evaluable (barnidipine plus losartan, n = 28; losartan, n = 25). After 6 weeks of treatment, 18 patients in the combination treatment group (64.3%) had their dose of barnidipine doubled from 10 to 20 mg because BP was not normalized by treatment, whereas 8 patients in the losartan group (32.0%) were discontinued for the same reason. The between-treatment difference (losartan alone - combination treatment) for changes from baseline in daytime DBP was -1.7 mm Hg (95% CI, -5.8 to 2.4 mm Hg; P = NS). A similar result was observed for daytime SBP (-3.2 mm Hg; 95% CI, -8.1 to 1.7 mm Hg; P = NS). Likewise, no significant differences were found for nighttime values (mean [95% CI] DBP, 0.5 mm Hg [-3.7 to 4.7 mm Hg]; SBP, 1.5 mm Hg [-4.1 to 7.1 mm Hg]) or 24-hour values (DBP, -0.9 mm Hg [-4.8 to 2.9 mm Hg]; SBP, -1.6 mm Hg [-5.9 to 2.7 mm Hg]). Combination treatment was associated with a significantly higher rate of SBP responder patients (ie

Angiotensin II is a vasoactive hormone of the renin-angiotensin system and plays an important role in the pathophysiology of several organ damages. Angiotensin II receptor blockers have been shown to be effective in treating both hypertension and connected organ damages. It is well known that although the angiotensin II receptor blockers have structural and pharmacokinetic differences, few pharmacological differences separate them. One of these is the degree of binding to the angiotensin II receptor type 1 compared with the angiotensin II receptor type 2; olmesartan medoxomil exhibits more than a 12,500-fold greater affinity for the angiotensin II receptor type 1 receptor than for the angiotensin II receptor type 2, making it theoretically the second most potent agent. However, olmesartan's excellent receptor interaction is based on the combination of several specific pharmacokinetic factors. Potential advantages of this drug include once-daily dosing, a very low incidence of significant adverse reactions and/or events and a well-tolerated side effect profile. Nowadays, we have a lot of information about the pharmacology, antihypertensive efficacy and safety of olmesartan medoxomil, to further extend many clinical studies are still continuing to evaluate the potential benefits of high dosages and/or combination of this molecule.

Lung myofibroblasts play a major role in the pathophysiology of asthma, contributing not only to tissue remodelling but also to airway inflammation. Nevertheless, only recently, attention has been focused on these cells as potential targets for anti-allergic drugs. Herein, we analysed the pharmacological response of lung myofibroblasts to beta2-agonists associated or not to inhaled corticosteroids, investigating their effects on (i) the constitutive and transforming growth factor-beta (TGF-beta)-induced expression of alpha-smooth muscle actin (alpha-SMA), the main functional marker of myofibroblastic differentiation and contractility; (ii) isometric contraction and (iii) tumour necrosis factor-alpha (TNF-alpha)-induced nuclear translocation of the pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB). The beta2-agonist salmeterol (SMl) has on human lung myofibroblasts new direct anti-contractile/anti-inflammatory effects that are amplified by the combined use of low concentrations of the glucocorticoid fluticasone propionate (FP). First, SMl and/or FP (10(-12) M) inhibits the constitutive and TGF-beta-induced expression of alpha-SMA. Second, the two drugs block the TNF-alpha-induced nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Finally, SMl decreases TNF- alpha-induced production of the inflammatory cytokine IL-6. The complementary anti-inflammatory/ anti-contractile effects displayed by SMl and FP on lung myofibroblasts in vitro may be related to the improvement in lung function and symptom control obtained in vivo by the early use of low doses of glucocorticoids in combination with long-acting beta2-agonists.

CD40/CD40 ligand interaction is an important pathway for B and T cell cooperation and function; functional CD40 molecules have recently been found on nonhematopoietic cells. We detected CD40 in vivo on normal human respiratory epithelial cells and showed that its expression is increased on inflamed airway epithelium. Subsequently, we analyzed its expression and function on primary cultures of human airway epithelial cells. Our data show that CD40 is up-regulated by IFN-β and IFN-γ, its ligation increases the surface expression of CD54 and CD106 and it may stimulate the release of IL-6 and IL-8. The use of Janus kinase 3 (JAK3) and NF-κB inhibitors suggests that both basal and CD40-induced release of the two cytokines is JAK3-dependent. Using colocalization techniques, we revealed the existence of CD40/JAK3 and CD40/TNFR-associated factor 2 interplay. The extent of these interactions may be partial (2–40% of the cells) or massive (80–90% of the cells) in cultured cells. Stimulation via CD40 causes a significant increase in the number of cells expressing colocalization only in the cultures displaying low frequency of initial colocalization. Thus, airway epithelial cells, activated by CD40, may behave as effector cells of the inflammation process and should be considered priority targets for anti-inflammatory therapy. This work identifies CD40 and the correlated JAK3 signaling molecule as potential molecular targets to block the inflammatory functions of epithelial cells.

Background: Lung fibroblasts may have a pivotal role in airway inflammation as they are involved in continuous cycles of mediator secretion, proliferation, activation and cross-talk with recruited inflammatory cells. The role of fibroblasts as intermediate participants in the inflammatory network suggests that they could represent an important target for drugs commonly used in asthma; thus, we investigated the effects of triamcinolone acetonide (TAA) on primary human lung fibroblasts. Methods: The in vitro activity of increasing concentrations (10–9 to 10–7 M) of TAA in fibroblast cultures was evaluated as regards the following parameters: proliferation, extracellular matrix (ECM) release, cytokine/chemokine secretion and surface antigen expression. Results: All concentrations of TAA decreased fetal calf serum (FCS)-induced fibroblast proliferation, whereas in the presence of FCS plus basic fibroblast growth factor TAA was only effective at 10–8 and 10–7M. TAA failed to decrease ECM, whereas at 10–8 and 10–7M it decreased IL-6 and IL-8 secretion to different extents. In the presence of IFN-γ the drug was able to reduce VCAM-1 expression at all of the tested concentrations; on the other hand, in TGF-β1-driven cultures a decrease in CD54 expression was detected with TAA at 10–8 and 10–7M. Conclusions: TAA acts on some functional properties of human lung fibroblasts that make these cells active participants in the inflammatory network. The ability of TAA to inhibit lung fibroblast proliferation may prevent or even reverse some of the histological changes that characterize airway remodeling in chronic inflammatory diseases; moreover, IL-6, IL-8 and surface molecule decreases by TAA may suggest a direct anti-inflammatory effect of the drug by suppression of resident lung cell function.

An in vitro flow cytometric model has been developed to evaluate the effects of antiallergic drugs such as cetirizine (CTZ) on the expression of surface molecules on primary cultured normal cells. Quantitative analysis demonstrated that HLA class I and ICAM-1/CD54 molecules are present on both epithelial and stromal cells, and that their expression is strongly enhanced by treatment with interferon-gamma (IFN-gamma). Nevertheless, the IFN-gamma-mediated upregulation of ICAM-1/CD54 was inhibited by treatment with CTZ, demonstrating a direct effect on both cell types. This finding is particularly interesting because ICAM-1/CD54 is the main rhinovirus receptor, and rhinoviruses are the principal cause of asthma exacerbation in children. Thus, according to data derived from this in vitro model, CTZ should have an important role in the reduction of infectious exacerbation of asthma in atopic patients.