• Inhaled Treprostinil
• Macitentan
• Pulmonary hypertension
• Remote pulmonary artery pressure monitoring
• Sotatercept
• Tadalafil

• canine
• congenital heart defect
• echocardiography

Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR.

• L-NAME
• fetal growth restriction
• mTOR signaling
• placenta
• preeclampsia
• tadalafil

• Animals
• Female
• Fetal Growth Retardation/chemically induced
• Fetal Growth Retardation/drug therapy
• Fetal Growth Retardation/metabolism
• Mice
• NG-Nitroarginine Methyl Ester/adverse effects
• NG-Nitroarginine Methyl Ester/pharmacology
• Placenta
• Pre-Eclampsia/chemically induced
• Pre-Eclampsia/drug therapy
• Pre-Eclampsia/metabolism
• Pregnancy
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism
• Tadalafil/pharmacology

• PDE5 inhibition
• Pulmonary embolism
• Pulmonary vasodilation
• Sildenafil

• Administration, Oral
• Aged
• Aged, 80 and over
• Arterial Pressure/drug effects
• Cardiac Catheterization
• Echocardiography
• Female
• Heart Ventricles/drug effects
• Humans
• Male
• Middle Aged
• Pulmonary Embolism/drug therapy
• Sildenafil Citrate/pharmacology
• Sildenafil Citrate/therapeutic use
• Treatment Outcome
• Vascular Resistance/drug effects
• Vasodilation/drug effects

• NNF16OC0023244 Novo Nordisk Fonden

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

• oxygen-sensing
• pulmonary hypertension
• vascular
• vasodilator

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration “as needed”, to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH).

Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs).

Results: RT234 was generally safe and well tolerated at single doses of 0.2–2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The t_max occurred at the time that the first blood sample following completion of dosing. After C_max was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra^®) than after administration of any dose level of RT234. During repeated dose administration of RT234, C_max was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t_1/2 values were comparable after single- and repeated-dose administration.

Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

• inhalation
• pharmacokinetics
• pulmonary arterial hypertension
• vardenafil

• animal models
• pulmonary circulation
• right heart failure
• right ventricular afterload

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exert suppressive function on the immune response. MDSCs expand in tumor-bearing hosts or in the tumor microenvironment and suppress T cell responses via various mechanisms, whereas a reduction in their activities has been observed in autoimmune diseases or infections. It has been reported that the symptoms of various diseases, including malignant tumors, can be alleviated by targeting MDSCs. Moreover, MDSCs can contribute to patient resistance to therapy using immune checkpoint inhibitors. In line with these therapeutic approaches, diverse oligonucleotide-based molecules and small molecules have been evaluated for their therapeutic efficacy in several disease models via the modulation of MDSC activity. In the current review, MDSC-targeting oligonucleotides and small molecules are briefly summarized, and we highlight the immunomodulatory effects on MDSCs in a variety of disease models and the application of MDSC-targeting molecules for immuno-oncologic therapy.

• Immune suppression
• MDSC-targeting agents
• Myeloid-derived suppressor cells (MDSCs)
• Oligonucleotide-based molecules
• Small molecules
• Tumor microenvironment

• Cyanosis
• Dog
• Phosphodiesterase inhibitor
• Respiratory
• Syncope

• Adult
• Child
• Endothelin Receptor Antagonists/therapeutic use
• Humans
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/mortality
• Numbers Needed To Treat
• Phosphodiesterase 5 Inhibitors/adverse effects
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Placebos/therapeutic use
• Quality of Life
• Randomized Controlled Trials as Topic
• Walk Test

• PAH
• Pulmonary hypertension
• acute kidney injury
• chronic kidney disease
• pathophysiology
• transplantation.

• Hemodynamic monitoring
• Hypertension, Pulmonary
• Phosphodiesterase 5 inhibitors

The aim was to evaluate the tadalafil‐mediated effects at molecular level on bone marrow‐derived mesenchymal stem cells (MSCs) survival and their homing into the infarcted hearts to promote cardiac repair and improve function. MSCs were pretreated in vitro with inhibitors of PKG, MAPK, FasL, nitric oxide synthase (NOS) (L‐NAME), CXCR4 (AMD3100), or miR‐21 inhibitors (+/−luciferase construction +/−Fas) prior to tadalafil treatment for 2 h. These MSCs were then subjected to H₂O₂ stress to assess their injury. Rats were subjected to acute myocardial infarction (AMI), and then followed by injection of saline or 1.5 x 10⁶ MSCs‐treated ± tadalafil into infarcted and peri‐infarcted area. In another group, AMI was performed in 1‐month post‐myelo‐ablated rats and were injected intraperitoneally (IP) with tadalafil ± AMD3100 or L‐NAME for 5 days. Also, in another group, AMI mice were treated with IP ± tadalafil before intravenous injection with ¹¹¹In‐oxine‐MSCs followed by CT/SPECT imaging to locate mobilized MSCs. Cardiac function was assessed by echocardiography. MSCs and heart extracts were analyzed by molecular bioassays. Tadalafil‐treated MSCs had higher expression of cGMP, NOS, SDF‐1α, p‐VASP, p‐Erk1/2, p‐STAT3, p‐Akt, PKG1 and Bcl‐xl; expression of these molecules was reduced with PKG1, MAPK, NOS or FasL inhibitors. Tadalafil inhibited apoptosis through increased miR‐21 expression and improved cell survival by inhibiting Fas (restored by PKG1, MAPK or miR‐21 inhibitors). In vivo, heart function, grafted cell survival, MSCs mobilization and homing were improved in tadalafil‐treated AMI animals versus controls. Conclusions: Tadalafil prolonged MSCs survival via up‐regulation of miR‐21 dependent suppression of Fas, and increased MSCs mobilization and their homing into infarcted myocardium resulting in improved cardiac repair and function.

• 111In‐oxine imaging
• myelo‐ablation
• pharmacological preconditioning
• stem cell survival

Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.

An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.

Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.

The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

• Adenosine A2 Receptor Agonists/pharmacology
• Adenosine A2 Receptor Agonists/therapeutic use
• Animals
• Benzamides/pharmacology
• Benzamides/therapeutic use
• Drug Synergism
• Hydrazones/pharmacology
• Hydrazones/therapeutic use
• Hypertension, Pulmonary/chemically induced
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/physiopathology
• Male
• Monocrotaline
• Phosphodiesterase 5 Inhibitors/pharmacology
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Pulmonary Artery/drug effects
• Pulmonary Artery/physiopathology
• Rats
• Rats, Wistar
• Sildenafil Citrate/pharmacology
• Sildenafil Citrate/therapeutic use
• Vasodilator Agents/pharmacology
• Vasodilator Agents/therapeutic use

• Instituto Nacional de Ciência e Tecnologia (INCT-INOFAR)
• Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
• Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq)
• Conselho Nacional de Desenvolvimento Científico e Tecnológico

Portopulmonary hypertension (PPH) is a relatively rare but well-recognized complication of end-stage liver disease. Moderate or severe PPH (mean pulmonary artery pressure [mPAP] ≥ 35 mmHg) is usually a contraindication for liver transplantation due to high operation-related mortality. Here, we report on a patient with moderate PPH whose condition was successfully managed with a phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) and prostaglandin E1, who experienced rapid improvement of PPH after living-donor liver transplantation (LDLT).

A 63-year-old woman with alcoholic decompensated cirrhosis was referred to our hospital for LDLT. She had mild dyspnea on exertion as well as fatigue. Echocardiography and subsequent cardiac catheterization revealed a high mPAP (35 mmHg), and she was diagnosed with moderate PPH. We commenced treatment with oral tadalafil for the PPH. A second preoperative echocardiography demonstrated improved PPH, and she underwent LDLT. An intravenous infusion of prostaglandin E1 was introduced instead of tadalafil during and after the operation.

The mPAP value showed a rapid decrease in mPAP value to 22 mmHg in 2 days. After discontinuation of the prostaglandin E1, the mPAP value remained 23 mmHg. Postoperative catheterization 2 months after LDLT showed no exacerbation of PPH. She was discharged on foot 70 days after LDLT in good condition and has shown a good clinical condition more than 2 years after LDLT.

LDLT could be a radical treatment for PPH with careful management and adequate patient selection. PDE5 inhibitor and PGE1 is effective and feasible for perioperative management of the patient with moderate portopulmonary hypertension in LDLT.

• Cardiac complication
• Living-donor liver transplantation
• Phosphodiesterase type 5 inhibitor
• Portopulmonary hypertension

• Cyclic nucleotides
• Heart failure
• Myocardium
• Phosphodiesterases
• Protein kinase A
• Protein kinase G

• Endothelin receptor antagonists
• Guanylyl cyclase, soluble
• Phosphodiesterase type 5 inhibitors
• Prostacyclin receptor
• Prostanoids

• Antihypertensive Agents/adverse effects
• Antihypertensive Agents/therapeutic use
• Dyspnea/diagnosis
• Dyspnea/drug therapy
• Dyspnea/etiology
• Endothelin Receptor Antagonists/adverse effects
• Endothelin Receptor Antagonists/therapeutic use
• Guanylate Cyclase
• Humans
• Hypertension, Pulmonary/diagnosis
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/etiology
• Phosphodiesterase 5 Inhibitors/adverse effects
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Prognosis
• Prostaglandins/adverse effects
• Prostaglandins/therapeutic use
• Receptors, Epoprostenol/agonists
• Risk Factors
• Vascular Remodeling/physiology
• Ventricular Dysfunction, Right/diagnosis
• Ventricular Dysfunction, Right/drug therapy
• Ventricular Dysfunction, Right/etiology

• Phosphodiesterase type 5 inhibitors
• postmarketing surveillance
• pulmonary arterial hypertension
• tadalafil

• Adolescent
• Adult
• Aged
• Female
• Humans
• Hypertension, Pulmonary/drug therapy
• Japan
• Male
• Marketing
• Middle Aged
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Prospective Studies
• Tadalafil/therapeutic use
• Young Adult

Perioperative management of severe pulmonary hypertension (PH) is challenging. Anaesthesiologists come across perioperative management of such cases during incidental surgeries, surgery for various congenital heart diseases and valvular heart diseases and for caesarean section or painless labour in pregnant patient with Eisenmenger syndrome. Knowledge of pathophysiology of PH and novel drugs acting through different mechanisms is paramount in managing such patients. This review will help understanding pathophysiology of PH, anaesthetising patients with PH, use of novel drugs for PH and use of new mechanical devices for rescue of failing right ventricle.

• Anaesthesia
• non-cardiac surgery
• pulmonary artery hypertension
• pulmonary hypertension
• right ventricular assist device
• right ventricular dysfunction
• right ventricular failure

• Cardiovascular disease
• Endothelial function
• PDE5
• Remodeling
• cGMP

• Animals
• Cardiotonic Agents/adverse effects
• Cardiotonic Agents/pharmacology
• Cardiotonic Agents/therapeutic use
• Cardiovascular Agents/adverse effects
• Cardiovascular Agents/pharmacology
• Cardiovascular Agents/therapeutic use
• Cardiovascular Diseases/drug therapy
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/physiopathology
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/physiopathology
• Heart/drug effects
• Heart/physiopathology
• Heart Diseases/drug therapy
• Heart Diseases/physiopathology
• Humans
• Microvessels/drug effects
• Microvessels/metabolism
• Microvessels/physiopathology
• Myocardium/enzymology
• Myocardium/metabolism
• Phosphodiesterase 5 Inhibitors/adverse effects
• Phosphodiesterase 5 Inhibitors/pharmacology
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Reproducibility of Results

• oral therapy
• pulmonary arterial hypertension
• right heart failure
• survival

Pulmonary arterial hypertension (PAH) is a chronic and disabling condition characterized by an elevated pulmonary vascular resistance and an elevated mean pulmonary arterial pressure. Despite recent improvements in treatment availability, PAH remains challenging to treat, burdensome for patients, and ultimately incurable. Tadalafil is a phos-phodiesterase-5 inhibitor that is administered once daily by mouth for the treatment of PAH. Current treatment guidelines recommend tadalafil as an option for patients with World Health Organization functional class II or III PAH. In a placebo-controlled clinical trial, patients taking tadalafil demonstrated significantly improved exercise capacity as measured by the 6-minute walk distance. Patients also experienced decreased incidence of clinical worsening, increased quality of life, and improved cardiopulmonary hemodynamics. Uncontrolled studies and smaller trials have indicated a possible role for tadalafil as a suitable alternative to sildenafil and as a beneficial add-on option when used in combination with other treatments for PAH. Tadalafil is generally safe and well tolerated. Adverse events are typically mild-to-moderate in intensity, and discontinuation rates are usually low. The purpose of this review is to provide an evidence-based evaluation of the clinical utility of tadalafil in the treatment of PAH.

• phosphodiesterase-5 inhibitor
• pulmonary arterial hypertension
• tadalafil

• Clinical trials
• Co-morbidities
• Diastolic dysfunction
• Preserved ejection fraction

• Chronic thromboembolic pulmonary hypertension
• Congenital heart disease
• Connective tissue disease
• Endothelin receptor antagonists
• Guidelines
• Heart failure
• Left heart disease
• Lung disease
• Phosphodiesterase type 5 inhibitors
• Prostacyclin analogues
• Pulmonary arterial hypertension
• Pulmonary hypertension
• Respiratory failure

• Acute vasodilator test
• Adenosine
• Haemodynamics
• Pulmonary hypertension
• Right heart catheterisation
• Vardenafil

• Adenosine/administration & dosage
• Adenosine/pharmacology
• Adult
• Aged
• Blood Gas Analysis
• Cardiac Catheterization
• Drug Administration Routes
• Female
• Hemodynamics
• Humans
• Hypertension, Pulmonary/drug therapy
• Male
• Middle Aged
• Vardenafil Dihydrochloride/administration & dosage
• Vardenafil Dihydrochloride/pharmacology
• Vasodilator Agents/administration & dosage
• Vasodilator Agents/pharmacology

• nitric oxide
• pulmonary arterial hypertension
• sildenafil
• vasoreactivity testing

• Alzheimer's
• ascorbic acid
• clinical trial
• dietary supplement
• epigenetic
• histone deacetylase
• phosphodiesterase inhibitor
• tadalafil

• Catheter Ablation
• Endothelin Receptor Antagonists/therapeutic use
• Guanylate Cyclase/therapeutic use
• Humans
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/pathology
• Hypertension, Pulmonary/surgery
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Prostaglandins/therapeutic use
• Pulmonary Artery/drug effects
• Pulmonary Artery/pathology
• Pulmonary Artery/surgery
• United States
• United States Food and Drug Administration

Some patients with group 3 pulmonary hypertension (PH) (PH due to lung disease and/or hypoxia) exhibit disproportionately advanced or “out-of-proportion” PH. In the present case series, we document four consecutive patients with progressive out-of-proportion group 3 PH. All patients exhibited progressive dyspnea or peripheral edema and were treated by pulmonary artery hypertension (PAH)-specific vasodilator(s). At the follow-up assessment 3–4 months later, symptoms/signs and pulmonary hemodynamic measurements improved in all four patients (45 ± 8% decrease in pulmonary vascular resistance). Pulmonary oxygenation deteriorated in one patient but improved or did not significantly change in the remaining three cases. Importantly, the background lung parenchymal disease (early-onset chronic obstructive pulmonary disease, rheumatoid arthritis-associated interstitial pneumonia, and combined pulmonary fibrosis and emphysema) was stable upon progression of the right heart failure symptoms/signs, and also during the 3–4-month follow-up period in all cases. We herein describe the clinical features of the four cases and discuss the potential benefits and risks of PAH-specific treatment in this emerging population.

• Chronic obstructive pulmonary disease
• Combined pulmonary fibrosis and emphysema
• Interstitial pneumonia
• Pulmonary hypertension
• Sildenafil
• Vasodilator

• Anabolic Agents/adverse effects
• Anabolic Agents/poisoning
• Androgens/adverse effects
• Androgens/poisoning
• Andrology/trends
• Athletic Injuries/epidemiology
• Doping in Sports/prevention & control
• Exercise
• Humans
• Hypogonadism/etiology
• Hypogonadism/physiopathology
• Hypogonadism/prevention & control
• Hypothalamo-Hypophyseal System/physiology
• Hypothalamo-Hypophyseal System/physiopathology
• Male
• Men's Health
• Performance-Enhancing Substances/adverse effects
• Performance-Enhancing Substances/therapeutic use
• Phosphodiesterase 5 Inhibitors/adverse effects
• Phosphodiesterase 5 Inhibitors/therapeutic use
• Reproduction/drug effects
• Reproductive Medicine/trends
• Sedentary Behavior
• Sports
• Sports Medicine/trends
• Testis/physiology
• Testis/physiopathology
• Varicocele/epidemiology
• Varicocele/etiology
• Varicocele/prevention & control
• Varicocele/therapy

Pulmonary arterial hypertension (PAH) is a chronic progressive disease of the pulmonary vasculature characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. PAH is considered a life-threatening condition unless treated. This article provides a comprehensive review of controlled and uncontrolled trials to define the risk-benefit for different therapeutic options of this clinical disorder. Relevant published articles were identified through searches of the National Center for Biotechnology PubMed database. All therapeutic measures for PAH were discussed. Six drugs have been approved in the United States for the treatment of PAH. Extensive medical advancement has been achieved in treatment of PAH. However, none of the approved therapies have shown ability to cure the disease. New research should be performed to develop promising new therapies.

Pulmonary arterial hypertension (PAH) is a heterogeneous, hemodynamic, and pathophysiological state which is commonly found throughout the world, but the disease burden is greater in India and in other developing countries. It is a disease characterized by vascular obstruction and vasoconstriction leading to progressive increase in pulmonary vascular resistance and right ventricular failure. PAH is a progressive disorder carrying a poor prognosis; however, dramatic progress has occurred in our knowledge of its pathogenesis and consequently, its treatment over the last two decades. In this article, we attempt to provide an overview of the etiology, pathophysiology, and current therapeutic modalities in the treatment of PAH. Patients suspected to have PAH should be submitted to a battery of investigations which help in establishing the diagnosis, identifying the etiology, guiding in treatment and informing the prognosis. All patients should be considered for standard therapy with oxygen, anticoagulation, and diuretics for right heart failure. Oral calcium channel blockers should be used in patients with a favorable response to acute vasodilator challenge. Disease targeted therapies include prostacyclines, endothelin receptor blockers, and phosphodiesterase-5 inhibitors. A brief mention of new and potential therapeutic strategies is also included.

• Management
• pathophysiology
• pulmonary arterial hypertension

Phosphodiesterase type-5 (PDE-5) inhibitors are novel and important options for the treatment of pulmonary arterial hypertension (PAH). Therefore, we aimed to examine effects of vardenafil, a PDE-5 inhibitor, on the pulmonary arteries isolated from rats with monocrotaline- (MCT-) induced pulmonary hypertension. MCT (60 mg/kg) or its vehicle was administered by a single intraperitoneal injection to 6-week-old male Sprague Dawley rats. Rats were sacrificed 21 days after MCT injection, and the main pulmonary arteries were isolated and then mounted in 20 mL organ baths. Concentration-response curves for vardenafil (10⁻¹⁰–10⁻⁵ M) were constructed in phenylephrine- (Phe-) precontracted rings. PAH caused marked rightward shift in the curves to vardenafil whereas maximal responses were not affected. Inhibition of NO synthase (L-NAME, 10⁻⁴ M) or guanylyl cyclase (ODQ, 10⁻⁵ M) caused similar attenuation in responses evoked by vardenafil. Moreover, contraction responses induced by CaCl₂ (3×10⁻⁵–3×10⁻² M) were significantly reduced in concentration-dependent manner by vardenafil. In conclusion, vardenafil induced pulmonary vasodilatation via inhibition of extracellular calcium entry in addition to NO-cGMP pathway activation. These results provide evidence that impaired arterial relaxation in PAH can be prevented by vardenafil. Thus, vardenafil represents a valuable therapeutic approach in PAH besides other PDE-5 inhibitors.

There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension.

• pulmonary arterial hypertension
• pulmonary hypertension
• therapy
• treatment

Eisenmenger syndrome is the most severe form of pulmonary arterial hypertension and arises on the basis of congenital heart disease with a systemic-to-pulmonary shunt. Due to the chronic slow progressive hypoxemia with central cyanosis, adult patients with the Eisenmenger syndrome suffer from a complex and multisystemic disorder including coagulation disorders (bleeding complications and paradoxical embolisms), renal dysfunction, hypertrophic osteoarthropathy, heart failure, reduced quality of life and premature death.

For a long time, therapy has been limited to symptomatic options or lung or combined heart-lung transplantation. As new selective pulmonary vasodilators have become available and proven to be beneficial in various forms of pulmonary arterial hypertension, this targeted medical treatment has been expected to show promising effects with a delay of deterioration also in Eisenmenger patients. Unfortunately, data in Eisenmenger patients suffer from small patient numbers and a lack of randomized controlled studies.

To optimize the quality of life and the outcome, referral of Eisenmenger patients to spezialized centers is required. In such centers, specific interdisciplinary management strategies of physicians specialized on congenital heart diseases and PAH should be warranted.

This medical update emphasizes the current diagnostic and therapeutic options for Eisenmenger patients with particularly focussing on the medical treatment and corresponding study results.

• Cardiovascular diseases
• Competence Network for Congenital Heart Defects.
• Eisenmenger syndrome
• adult congenital heart defects
• follow-up studies
• pulmonary hypertension

• Adolescent
• Adult
• Antihypertensive Agents/adverse effects
• Antihypertensive Agents/therapeutic use
• Chi-Square Distribution
• China
• Ductus Arteriosus, Patent/complications
• Ductus Arteriosus, Patent/physiopathology
• Exercise Tolerance/drug effects
• Familial Primary Pulmonary Hypertension
• Female
• Heart Defects, Congenital/blood
• Heart Defects, Congenital/complications
• Heart Defects, Congenital/physiopathology
• Heart Septal Defects, Atrial/complications
• Heart Septal Defects, Atrial/physiopathology
• Heart Septal Defects, Ventricular/complications
• Heart Septal Defects, Ventricular/physiopathology
• Hemodynamics/drug effects
• Humans
• Hypertension, Pulmonary/blood
• Hypertension, Pulmonary/drug therapy
• Hypertension, Pulmonary/etiology
• Hypertension, Pulmonary/physiopathology
• Male
• Oxygen/blood
• Piperazines/adverse effects
• Piperazines/therapeutic use
• Prospective Studies
• Purines/adverse effects
• Purines/therapeutic use
• Sildenafil Citrate
• Sulfones/adverse effects
• Sulfones/therapeutic use
• Time Factors
• Treatment Outcome
• Vasodilator Agents/adverse effects
• Vasodilator Agents/therapeutic use
• Young Adult