An evaluation of written materials for supporting hypertensive patient education and counselling when performing a new medicine service in Poland.

BACKGROUND: The New Medicine Service (NMS) was developed in England more than ten years ago, as a three-stage consultation led by community pharmacists to support patients taking new medication for a chronic disease. In Poland, the scheme was officially introduced in January 2023. However, its implementation into common practice has been presented with various obstacles, including the need to develop relationships with general practitioners, resolve the payment structure, and provide training with adequate supporting materials. Hence, written materials have been designed for use as an optional tool for counselling patients receiving an NMS in community pharmacies. METHODS: The present study evaluates the ability of these materials to inform patients about the need to adhere to anti-hypertensive medication. A group of 401 randomly-selected adult visitors to pharmacies and/or healthcare centres were surveyed; one third had hypertension in their history. RESULTS: The structure, grammar and readability of the text achieved the required threshold of 40% according to the Plain Language Index. The designed materials effectively informed the patients about anti-hypertensive medication, reflected in an increased score in a knowledge test, and were rated positively regarding information level, comprehensibility and presentation. CONCLUSION: The proposed material may serve as an additional, "patient-friendly" educational tool for use as part of an NMS.

Comparative tolerability of targeted therapies in pulmonary hypertension.

Introduction: The objective of this study was to estimate the safety profile of pulmonary hypertension-specific therapies using placebo-controlled and active comparator trials. Material and methods: The search corpus comprised Medline, Scopus, Embase and Clinical Trials databases. A systematic review and meta-analysis was performed to assess the relative risk of severe events and discontinuations as well as of adverse drug reactions (ADRs) classified into 26 categories and 21 subcategories defined by the Medical Dictionary for Regulatory Activities (MedRA). Results: Pulmonary hypertension-specific therapies had the greatest effect on such events as flushing and headache as well as jaw pain, limb pain and myalgia or gastrointestinal disorders. The relative risk for ADRs in patients receiving monotherapy (vs. placebo/supportive therapies) and combined regimens (vs. monotherapy) was significantly increased. The risk of cessation for the combined regimen was slightly higher (Qinter-group, p = 0.0778). Such ADRs as blood and lymphatic system disorders with the anemia subgroup, gastrointestinal disorders with diarrhea and nausea subgroups, respiratory and thoracic diseases or nervous system disorders with headache tended to occur more often in combination regimens as compared to monotherapy. Conclusions: About half of the main categories and subcategories of adverse reactions according to MedRA were associated with a relatively high frequency and hazard ratio. Their risk can be increased when combination regimens are used, especially.

The current state of preclinical modeling of human diabetic cardiomyopathy using rodents.

The prevalence of diabetic cardiomyopathy (DCM), a specific cardiovascular complication of diabetes mellitus, has recently increased. Its pathogenesis is not fully understood, and no consensus regarding therapeutic options has been reached. Experimental studies on rodents are expected to yield further data at the preclinical stage. The present paper describes and quantitatively compares the experimental protocols intended to mimic human DCM. Experimental articles (conducted between 1990 and 2022) were identified from online electronic databases according to the PRISMA Protocol. The Cochrane Q-test was used to estimate study heterogeneity; the quality of each individual study was assessed using SYRCLE's risk of bias tool for animal studies. Sensitivity analysis was performed according to the leave-one-out method. Publication bias across studies was assessed using Egger's weighted regression and Duval and Tweedie 'trim and fill' method. A wide spectrum of protocols - from 651 papers, was examined (type 1 or 2 diabetes mellitus, as well as obesity models). They were found to vary in their presentation of DCM according to a variety of hemodynamic, echocardiographic, histopathologic and metabolic parameters. Particular attention was paid to comorbid conditions, and cardiac performance featured as systolic, diastolic dysfunction, or refractory heart failure. The majority of models displayed diastolic dysfunction, as well as myocardial fibrosis and left ventricle hypertrophy, which mimics early stage DCM. Unlike in humans, animal DCM rarely progressed to the symptomatic heart failure with reduced ejection fraction (HFrEF). The ability of individual procedures to reflect refractory heart failure or biventricular dysfunction - in the end-stage DCM has remained unclear.

Searching for Effective Treatments in HFpEF: Implications for Modeling the Disease in Rodents.

BACKGROUND: While the prevalence of heart failure with preserved ejection fraction (HFpEF) has increased over the last two decades, there still remains a lack of effective treatment. A key therapeutic challenge is posed by the absence of animal models that accurately replicate the complexities of HFpEF. The present review summarizes the effects of a wide spectrum of therapeutic agents on HF. METHODS: Two online databases were searched for studies; in total, 194 experimental protocols were analyzed following the PRISMA protocol. RESULTS: A diverse range of models has been proposed for studying therapeutic interventions for HFpEF, with most being based on pressure overload and systemic hypertension. They have been used to evaluate more than 150 different substances including ARNIs, ARBs, HMGR inhibitors, SGLT-2 inhibitors and incretins. Existing preclinical studies have primarily focused on LV diastolic performance, and this has been significantly improved by a wide spectrum of candidate therapeutic agents. Few experiments have investigated the normalization of pulmonary congestion, exercise capacity, animal mortality, or certain molecular hallmarks of heart disease. CONCLUSIONS: The development of comprehensive preclinical HFpEF models, with multi-organ system phenotyping and physiologic stress-based functional testing, is needed for more successful translation of preclinical research to clinical trials.

Multidimensional Interventions on Supporting Disease Management for Hospitalized Patients with Heart Failure: The Role of Clinical and Community Pharmacists.

BACKGROUND: existing trials on the role of clinical pharmacists in managing chronic disease patients have focused on variety of interventions, including preparing patients for the transition from hospital to home. However, little quantitative evidence is available regarding the effect of multidimensional interventions on supporting disease management for hospitalized patients with heart failure (HF). The present paper reviews the effects of inpatient, discharge and/or after-discharge interventions performed on hospitalized HF patients by multidisciplinary teams, including pharmacists. METHODS: articles were identified through search engines in three electronic databases following the PRISMA Protocol. Randomized controlled trials (RCTs) or non-randomized intervention studies conducted in the period 1992-2022 were included. In all studies, baseline characteristics of patients as well as study end-points were described in relation to a control group i.e., usual care and a group of subjects that received care from a clinical and/or community pharmacist, as well as other health professionals (Intervention). Study outcomes included all-cause hospital 30-day re-admission or emergency room (ER) visits, all-cause hospitalization within >30 days after discharge, specific-cause hospitalization rates, medication adherence and mortality. The secondary outcomes included adverse events and quality of life. Quality assessment was carried out using RoB 2 Risk of Bias Tool. Publication bias across studies was determined using the funnel plot and Egger's regression test. RESULTS: a total of 34 protocols were included in the review, while the data from 33 trials were included in further quantitative analyses. The heterogeneity between studies was high. Pharmacist-led interventions, usually performed within interprofessional care teams, reduced the rates of 30-day all-cause hospital re-admission (odds ratio, OR = 0.78; 95% CI 0.62-0.98; p = 0.03) and all-cause hospitalization >30 days after discharge (OR = 0.73; 95% CI 0.63-0.86; p = 0.0001). Subjects hospitalized primarily due to heart failure demonstrated reduced risk of hospital admission within longer periods, i.e., from 60 to 365 days after discharge (OR = 0.64; 95% CI 0.51-0.81; p = 0.0002). The rate of all-cause hospitalization was reduced by multidimensional interventions taken by pharmacists: reviews of medicine lists and/or their reconciliation at discharge (OR = 0.63; 95% CI 0.43-0.91; p = 0.014), as well as interventions that were based mainly on patient education and counseling (OR = 0.65; 95% CI 0.49-0.88; p = 0.0047). In conclusion, given that HF patients often have complex treatment regimens and multiple comorbid conditions, our findings highlight the need for greater involvement from skilled clinical and community pharmacists in disease management.

An updated review of experimental rodent models of pulmonary hypertension and left heart disease.

Left heart disease (LHD) is the leading cause of pulmonary hypertension (PH). Its recent growth has not been matched by the design of therapeutic agents directly targeting the disease. Effective therapies approved for pulmonary arterial hypertension (PAH) have been shown to be inefficient in patients with PH-LHD. Hence, there is a need for an animal model that would closely mimic PH-LHD in preclinical experiments. The current study describes and compares a number of rodent models of left ventricular failure and their potential to induce PH. It also evaluates whether, and to what extent, common PH models could develop LV failure. Articles were identified in the Pubmed/Medline and Web of Science online electronic databases following the PRISMA Protocol between 1992 and 2022. Quality assessment was carried out using the SYRCLE risk-of-bias tool for animal studies. Publication bias across studies using Egger's regression test statistic, was performed together with sensitivity analysis. A wide spectrum of protocols-135 studies and 207 interventions, was examined, including systemic hypertensive models, pressure-overload-induced HF, model of ischemic heart failure, and metabolic approaches based on high fat diet or metabolic syndrome. The most pronounced alterations in PH-related parameters were demonstrated for the common PH models, but were also seen in animals with LV failure induced by ischemic conditions, pressure overload or metabolic conditions. Models based on aortic banding, transverse aortic constriction (TAC), or with myocardial infarction (MI) caused by coronary artery ligation, demonstrated more pronounced worsening in PH due to LV failure; however, they also demonstrated poor survival, especially the ischemic-HF model. Common PH models, excluding prolonged exposure to monocrotaline, do not promote LV hypertrophy. Prolonged exposure to a high-fat diet, or a two-hit model of an obese ZSF1 rat combined with SU5416-induced pulmonary endothelial impairment (a VEGF receptor antagonist) worsened PH and impaired diastolic dysfunction. Due to the limited number of protocols, further trials are needed to confirm the utility of such approaches for modeling PH in subjects with metabolic syndrome. This would provide a clearer insight into the complexity of LHD, PH and metabolic disorders in PH-LHD, and thus accelerate the development of new therapies in clinical trials.

Training programs in preclinical studies. The example of pulmonary hypertension. Systematic review and meta-analysis.

BACKGROUND: Exercise and cardiopulmonary exercise testing are essential in the evaluation of physiological, biochemical, and molecular responses in the experimental studies on chronic diseases such as diabetes, heart failure and hypertension. The exercise tolerance and seem to be a valuable contribution to the experiments that are performed in animal models of pulmonary hypertension (PH), as well. The current survey uses detailed quantitative analyses to assess the advantages of exercise training programs performed in preclinical studies based on outcomes such as exercise capacity, cardiopulmonary hemodynamics, and mortality. METHODS: Articles were identified through search engines in the online electronic databases Pubmed/Medline, Web of Science following the PRISMA Protocol. Studies conducted between 1991 and 2022 without language restrictions were included in this study. Heterogeneity was assessed using the Cochrane Q-test and I2 test statistics. Subgroup analysis was employed with evidence of heterogeneity. Quality assessment was carried out using SYRCLE's risk of bias tool for animal studies. Publication bias across studies was determined using the funnel plot and Egger's regression test statistic. RESULTS: The available protocols typically included treadmill running, swimming, and voluntary wheel running with a different series of intensities, times and durations; these were also used in studies examining the efficacy of chronic training programs. In 66 interventions, PH induction reduced exercise endurance by half compared to healthy subjects, while exposure to tested medical agents normalized exercise capacity. The other 58 interventions demonstrated the advantages of various exercise training programs for PH. Induction of PH reduced exercise endurance by half compared to healthy subjects (R = 0.52; 0.48 - 0.55 95%CI; P<0.0001; I2 = 98.9%), while the exposure to tested medical agents normalized exercise capacity (R = 1.75; 1.61 - 1.91 95%CI; P<0.0001; I2 = 97.8%). CONCLUSION: Despite a wide spectrum of study protocols to measure exercise endurance in animals with PH, there is a significant correlation between worsening of exercise-related parameters and PH development, manifested by alterations in haemodynamic and remodeling parameters. Familiarization with exercise, training program schedule, method used for PH induction, or detailed training parameters such as slope, exercise intensity or individualization, can influence the final outcome. This in turn can impact on the diversity and reproducibility of results being obtained in particular experimental studies.

The Effectiveness of Pharmacist Interventions in the Management of Patient with Renal Failure: A Systematic Review and Meta-Analysis.

The existing trials have focused on a variety of interventions to improve outcomes in renal failure; however, quantitative evidence comparing the effect of performing multidimensional interventions is scarce. The present paper reviews data from previous randomized controlled trials (RCTs), examining interventions performed for patients with chronic kidney disease (CKD) and transplants by multidisciplinary teams, including pharmacists. Methods: A systematic search with quality assessment was performed using the revised Cochrane Collaboration's 'Risk of Bias' tool. Results and Conclusion: Thirty-three RCTs were included in the review, and the data from nineteen protocols were included in further quantitative analyses. A wide range of outcomes was considered, including those associated with progression of CKD, cardiovascular risk factors, patient adherence, quality of life, prescription of relevant medications, drug-related problems (DRPs), rate of hospitalizations, and death. The heterogeneity between studies was high. Despite low-to-moderate quality of evidence and relatively short follow-up, the findings suggest that multidimensional interventions, taken by pharmacists within multidisciplinary teams, are important for improving some clinical outcomes, such as blood pressure, risk of cardiovascular diseases and renal progression, and they improve non-adherence to medication among individuals with renal failure.

Searching for an experimental rodent model of heart failure with preserved ejection fraction: Re-visited.

Heart failure with preserved ejection fraction (HFpEF) currently accounts for over 50% of all heart failure cases. It displays a large number of comorbidities, and the pathophysiological mechanisms underlying the disease remain uncertain and treatment options are limited. The heterogeneity and complexity of the disease, and its specific comorbidities, can limit the number of animal models that could ideally mimic it. The current study describes and compares the efficacy of the most popular approaches from a quantitative point of view. A review and meta-analysis of more than 500 experimental protocols was performed with special attention to these models created to induce heart failure by the most common comorbidities associated with human HFpEF, e.g., hypertension, diabetes, obesity and aging. The analysis included a wide spectrum of outcomes (alterations in body weight, lung and left ventricle weights, laboratory, hemodynamic, echocardiographic, and histopathological data as well as animal mortality) and possible covariates that could determine the utility of the particular model, such as animal age, species, experimental period and genetic modification. A wide range of systemic hypertension as well as diabetes (obesity) - related animal models are used for pre-clinical studies on heart failure, but some of them fail to replicate HFpEF. Future studies should include an evaluation of other features besides diastolic dysfunction that confirm that this is an HFpEF model, or the potential to progress to heart failure with reduced ejection fraction (HFrEF).

A review of genetically-driven rodent models of pulmonary hypertension.

An increasing number of models used to examine the role of particular signaling pathways in vasculature and the development of pulmonary hypertension (PH) are based on animals with different genetic modifications. The present study explores the severity of PH-related lesions that can be provided by a genetic particular model in accordance to the most common non-genetic PH inducers such as chronic exposure to hypoxia or single injection of monocrotaline. A review of 516 interventions on a variety of animal models was performed. It examined the advantages of various genetically-driven procedures intended to develop spontaneous PH, and the effects of combining such procedures with common PH models or other stimuli ('second-hit') with the aim of exacerbating pulmonary artery remodeling, right ventricle hypertrophy and hemodynamics or animal mortality. A wide range of genetically-modified rodents are used for pre-clinical studies on PH, with different response to the genetic modification as compared to the most common non-genetic stimuli. Nevertheless, they could highlight the mechanisms and pathways that contribute to the expression of pathophysiological features of the disease, and they could be helpful in the identification of additional targets for new drugs.

A review of rodent models for metabolic syndromes and pulmonary hypertension.

PURPOSE: Emerging evidence suggests that metabolic disorders, such as diabetes and obesity, may affect the pathogenesis and development of pulmonary hypertension (PH), and therefore some treatments could be beneficial for both disorders. The present study investigates whether such metabolic diseases increase susceptibility to PH in rodent models, and identifies which models are suitable for research on PH and its potential therapeutic candidates. It also explores whether particular PH model can worsen the metabolic parameters. RESULTS: A review of 200 interventions on a variety of animal models was performed. The advantages of various diabetes (obesity)-related procedures, including dietary and genetic modifications, intended to provoke 'spontaneous' PH were reviewed, as well as the effects of combinations of such procedures with common PH models, with the aim of exacerbating pulmonary artery remodeling, right ventricle hypertrophy and hemodynamics. The paper describes the efficacy of particular agents toward PH-related lesions, according to particular study protocols (animal model, dosage schedule). CONCLUSIONS: A wide range of diabetes (obesity)-related animal models are used for pre-clinical studies on PH and several factors should be considered when planning research; special attention should be paid to the linkage between the molecular background of the disease, the rationale for a particular animal model and the molecular activity of the tested agent.

Reporting experimental studies on animals - The problems with translating of outcomes to clinical benefits. Methodological and statistical considerations: The example of pulmonary hypertension.

The variability inherent in animal models and the methods used to define drug response can lead to highly divergent results when evaluating new drug candidates. Several guidelines exist for high-quality and comprehensive reporting of experiments with animals. The present survey makes a quantitative demonstration of whether compliance with good preclinical practice guidelines can affect the results and reduce risk of over- or underestimation of treatment benefit. This meta-analysis was performed on more than 400 animal studies concerning pulmonary hypertension, where a wide range of potential therapeutic agents have been recently positively assessed in preclinical experiments. The experiments were reviewed according to the selected methodological and statistical items being recommended to report in papers. A quantitative evaluation was performed of their impact on effect size, which defined the efficacy of particular drug candidates. In addition, the paper also examines whether the quality score calculated for the papers included in the analysis changed over the previous 25 years. In conclusion, some information in experimental studies is often missed or incomplete, which complicates the correct evaluation and comprehension of obtained results. This in turn could subsequently increase the potential hazards involved in translating positive experimental outcomes to possible clinical benefits in patients.

Toward Better Reproducibility in Experimental Research on New Agents for Pulmonary Hypertension. An Analysis of Data from Four Hundred Animal Studies.

PURPOSE: Pre-clinical data can provide a rationale for subsequent clinical trials and they are the first step in drug development; however, the therapeutic effect observed during animal studies does not necessarily translate to similar results in humans. METHODS: Taking the example of pulmonary hypertension, the present study explores whether the methodological aspects of preclinical experiments can determine the final result. RESULTS: The present paper describes a systematic analysis of 409 studies conducted on a variety of animal models to identify potential drug candidates for PH treatment; it explores the influence of various aspects of study design on the final outcome, e.g. type of animal model of PH, dosage schedules of tested agents, type of anesthesia, measurement of exercise intolerance or animal survival. CONCLUSIONS: The animal models of PH used for pre-clinical studies are diverse and there are several methodological items within the established protocols that can determine the obtained result. Graphical abstract.

Involvement of vascular endothelial growth factor (VEGF) and mitogen-activated protein kinases (MAPK) in the mechanism of neuroleptic drugs.

BACKGROUND: Recent evidence suggests that the mitogen activated protein kinase (MAPK)-associated signaling pathway in the frontal cortical areas demonstrates abnormal activity in cases of schizophrenia. Moreover, schizophrenia patients often display alterations in the regional cellular energy metabolism and blood flow of the brain; these are shown to parallel changes in angiogenesis primarily mediated by vascular endothelial growth factor (VEGF). METHODS: The present study examines the differential effects of time-dependent treatment with haloperidol, olanzapine and amisulpride (20µM) on VEGF and MAPK mRNA expression and VEGF level, using the T98 cell line as an example of nerve cells. For the purposes of comparison, the effect of neuroprotective pituitary adenylate cyclase-activating polypeptide (PACAP) on the expression of VEGF mRNA and secretion were also evaluated in this cell model. RESULTS: RT-PCR analysis revealed that all the tested neuroleptics increased VEGF mRNA expression after 72-h incubation; however, only haloperidol and olanzapine also increased the level of VEGF detected by ELISA, and they demonstrated significantly stronger effects than PACAP. Haloperidol and olanzapine, but not amisulpride, decreased MAPK14 mRNA expression in T98G cells after 72-h incubation. CONCLUSION: The obtained results suggest that haloperidol and olanzapine can trigger the MAPK and VEGF signaling pathway, which may contribute to their neuroprotective mechanism of action.

Systematic review and meta-analysis of interventions tested in animal models of pulmonary hypertension.

A systematic review and meta-analysis was performed to test candidate therapeutic approaches in pulmonary hypertension (PH). The efficacy of 522 interventions with >200 unregistered drugs was tested on 7254 animals. We propose a modified formula to assess meta-data that concerns the contribution of PH animal model to the denoted efficacy of tested agents. The measure of efficacy expressed as a response ratio for right ventricle systolic pressure was 0.48 (95% CI, 0.46-0.50; P < 0.00001), mean pulmonary artery pressure was 0.54 (0.52-0.56; P < 0.00001), right ventricle hypertrophy was 0.49 (0.48-0.51; P < 0.00001) and pulmonary artery wall thickness was 0.58 (0.56-0.61; P < 0.00001). Only 41 out of 522 interventions were ineffective. The most potent agents to improve both haemodynamic and hypertrophic parameters were ATP-sensitive potassium channel openers with iptakalim, Rho/ROCK inhibitors with fasudil, RAAS regulators with adenosine and ACE2 activators, and anti-inflammatories with n-3 polyunsaturated fatty acids and NF-кB inhibitors.

The differential effects of neuroleptic drugs and PACAP on the expression of BDNF mRNA and protein in a human glioblastoma cell line.

Despite numerous studies, the molecular mechanisms underpinning the action of antipsychotic drugs remain not fully understood. It has been suggested that, in addition to the modulation of monoaminergic neurotransmission, antipsychotic drugs can also affect the expression of neurotrophic factors in the brain. The present study examines the effects of a first-generation neuroleptic drug (FGA; haloperidol) and two second-generation neuroleptic drugs (SGAs; olanzapine and amisulpride) on the expression and levels of brain-derived neurotrophic factor (BDNF) in an astrocyte-like T98G glioblastoma cell line. The effects of these drugs were compared to the action of PACAP38, a neuropeptide with well-known BDNF-mediated neuroprotective effects. The tested neuroleptics differentially regulated the mRNA expression and protein level of BDNF depending on concentration and incubation time. Real-time PCR analysis demonstrates that, of the three tested neuroleptics, both haloperidol and olanzapine at a concentration of 5 µM (but not at 20 µM) increased BDNF mRNA expression with similar efficacy after 72-hour incubation. In order to confirm the observed changes in the mRNA expression of BDNF, a protein expression assay was performed. The exposure of cells to 5 µM olanzapine alone for 72 hours increased BDNF concentration in the culture medium by 29%. Additionally, PACAP significantly up-regulated BDNF mRNA expression in T98G cells and the obtained results correlated positively with the increased production of BDNF protein, 22% above control values. Our findings show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of non-neuronal origin. The results of the paper show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of nonneuronal origin. The results of the present paper confirm the findings that BDNF may represent the key target for olanzapine and PACAP.

[Current issues in etiology, diagnostics and management in pulmonary hypertension].

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions characterizing with by an abnormal increase in mean pulmonary arterial pressure. It is a rare, debilitating disease with a poor prognosis. Despite significant progress in diagnosis and management, including disease-targeted therapies as well as development of specialized centres, PH remains a chronic disease without a cure. If untreated, it leads to right heart failure and premature death, and a multifactorial pathomechanism impacts negatively on further prognosis. Insufficient social awareness or non-specific initial symptoms accompany to delayed diagnosis and specialist treatment. In the following pages, we will review the currently classification, etiology as well as and diagnostic algorithms in PH. We discuss approved treatments, especially specific dug therapy for pulmonary arterial hypertension, and recently approved strategies for its refund. We also summarize the general measures for patients and their caregivers, as well as the role of support groups, and specialized centers in Poland.

Animal models of pulmonary arterial hypertension: A systematic review and meta-analysis of data from 6126 animals.

Numerous animal models of pulmonary hypertension are currently available. A systematic review and meta-analysis was performed of a number of experimental studies of disease induction based on several animal models. A meta-analysis was performed of 291 publications discussing the efficacy of 611 interventions to introduce disease pulmonary hypertension in 6126 animals. A meta-regression analysis was done to assess the effect of prolonged periods of disease induction on the outcomes. A random-effects meta-analysis was used to assess the impact of study characteristics and seek evidence of publication bias. A more pronounced worsening in hemodynamics or right ventricle hypertrophy was observed in animals exposed to Sugen combined with hypoxia, or left pneumonectomy followed by monocrotaline. Chronic hypoxia induced the poorest, but the most stable, response to disease induction with regard to elevated hemodynamic parameters, right ventricle hypertrophy and wall thickening. The greatest elevation of right ventricle systolic pressure was observed in animals exposed to isoflurane and the weakest to chloral hydrate. This result was true for different animal models and lengths of induction of pulmonary hypertension. Publication bias was found for all the crucial parameters. Development of pulmonary hypertension depends on the choice of animal model. Classic models, especially these related to chronic hypoxia, provoke a less severe response with regard to poorer hemodynamics and myocardial hypertrophy. The outcome of disease development can be strongly determined by the duration of induction, detailed experimental conditions and anesthesia procedure.

Novel strategies for treatment of pulmonary arterial hypertension.

Pulmonary hypertension (PH) is a rare disorder associated with abnormally elevated pulmonary pressures that, if untreated, leads to right heart failure and premature death. Special population include patents with pulmonary arterial hypertension (PAH). A greater understanding of the epidemiology, pathogenesis, and pathophysiology of PAH has led to significant advances over the past few years. Modern drug therapy provides a significant improvement in patient symptomatic status and a slower rate of clinical deterioration. Despite this, PAH remains a chronic disease without a cure. There is a need for the development of novel therapies and therapeutic strategies, as treatment options are neither universally available nor always effective, possibly due to the large number of mediator and signaling pathways with downstream effectors which are implicated in the pathobiology of PH, and which are not fully reversed during PAH therapy. In the following pages, we review novel strategies for treatment of PAH. For this purpose we summarized the role of specific drug therapies that involve: endothelin receptor antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE-5i) and prostacyclin and prostanoids (PGI2). We focused on novel molecular mechanisms in PAH of recently approved: Guanylate cyclase stimulator and non-prostanoid IP receptor agonist. We discussed novel approach to combined therapy, as well as a new generation of investigational drugs and promising PAH-associated signaling pathways, such as, PDGF, RhoA/ROCK RAAS, HT-5 and others.

Treatment with platelet-derived growth factor (PDGF) and rock inhibitors is related to declined nerve growth factor (NGF) signaling in an experimental model of rat pulmonary hypertension.

BACKGROUND: Recent studies reveal that nerve growth factor (NGF) plays a critical role in the pathobiology of pulmonary hypertension (PH). The aim of the present study is to clarify the relationship between NGF signaling and treatment with PDGF or ROCK inhibitors in an animal model of PH. METHODS: Lung tissues were obtained from animals with monocrotaline (MCT)-challenged PH which had been administered long term imatinib, fasudil or statin. Reversal of disease was indicated by decreases in right ventricle pressure (RVP) and hypertrophy. NGF expression was examined at the mRNA and protein levels using quantitative real-time PCR reaction and ELISA. RESULTS: MCT significantly increased NGF mRNA and protein content in lung tissue. ROCK inhibitor (fasudil) and PDGF inhibitor (imatinib) caused significant decreases in NGF mRNA and protein content when administered alone, with no further effects noted when used in combination. CONCLUSION: The beneficial reversal of MCT-mediated effects in PH caused by PDGF or ROCK inhibition may be also partially mediated by decreased NGF signaling.