Trial Summary
What is the purpose of this trial?Many control mechanisms exist which successfully match the supply of blood with the metabolic demand of various tissues under wide-ranging conditions. One primary regulator of vasomotion and thus perfusion to the muscle tissue is the host of chemical factors originating from the vascular endothelium and the muscle tissue, which collectively sets the level of vascular tone. With advancing age and in many disease states, deleterious adaptations in the production and sensitivity of these vasodilator and vasoconstrictor substances may be observed, leading to a reduction in skeletal muscle blood flow and compromised perfusion to the muscle tissue. Adequate perfusion is particularly important during exercise to meet the increased metabolic demand of the exercising tissue, and thus any condition that reduces tissue perfusion may limit the capacity for physical activity. As it is now well established that regular physical activity is a key component in maintaining cardiovascular health with advancing age, there is a clear need for further studies in populations where vascular dysfunction is compromised, with the goal of identifying the mechanisms responsible for the dysfunction and exploring whether these maladaptations may be remediable. Thus, to better understand the etiology of these vascular adaptations in health and disease, the current proposal is designed to study changes in vascular function with advancing age, and also examine peripheral vascular changes in patients suffering from chronic obstructive pulmonary disease (COPD), Sepsis, Pulmonary Hypertension, and cardiovascular disease. While there are clearly a host of vasoactive substances which collectively act to govern vasoconstriction both at rest and during exercise, four specific pathways that may be implicated have been identified in these populations: Angiotensin-II (ANG-II), Endothelin-1 (ET-1), Nitric Oxide (NO), and oxidative stress.
Is the drug Selexipag a promising treatment for pulmonary arterial hypertension?Yes, Selexipag is a promising drug for treating pulmonary arterial hypertension because it helps relax and widen the blood vessels in the lungs, improving heart function and potentially reversing damage.1231213
What safety data exists for the treatment in the clinical trial for pulmonary arterial hypertension?The research provides safety data for several treatments related to pulmonary arterial hypertension. LA-419, a nitric oxide donor, showed reduced mortality and improved pulmonary parameters in rats. Acetylcholine and sodium nitroprusside were studied for their vasodilatory effects, with vitamin C enhancing acetylcholine-induced vasodilation in hypertensive patients. Vitamin C and E demonstrated antioxidant effects, improving vascular function in hypertensive rats. These studies suggest potential safety and efficacy of these treatments in managing hypertension and related vascular issues.456911
What data supports the idea that Vascular Function in Pulmonary Arterial Hypertension is an effective treatment?The available research shows that various drugs have been tested for pulmonary arterial hypertension, improving exercise capacity as measured by a 6-minute walk test. For example, the combination of Bosentan and Sildenafil showed the greatest improvement in walking distance compared to a placebo. Other combinations like Bosentan with Tadalafil and Ambrisentan with Tadalafil also showed significant improvements. These findings suggest that these drugs can help improve physical activity levels in patients with pulmonary arterial hypertension. However, no trials have shown effects on mortality, and side effects can vary among individuals. Therefore, while these drugs can be effective in improving exercise capacity, the choice of treatment should be personalized based on the patient's specific needs and conditions.78101114
Do I need to stop my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
Eligibility Criteria
This trial is for healthy young adults (18-30), older adults (65+), and patients with mild to moderate COPD, Group 1 pulmonary arterial hypertension, or Class I-III heart failure. Excluded are those with severe diseases like unstable angina, significant renal disease, severe COPD requiring oxygen, recent heart attacks or surgeries, pregnant women, and anyone at risk from MRI.Inclusion Criteria
I have been diagnosed with mild to moderate COPD.
I have Group 1 pulmonary arterial hypertension that is idiopathic or heritable.
I am over 65 and healthy with no conditions affecting study participation.
I have heart failure symptoms that are mild to moderately severe.
I have been diagnosed with chronic high blood pressure.
I am between 18 and 30 years old and healthy with no conditions affecting study participation.
Exclusion Criteria
I have a history of variant angina.
I have had a heart attack before.
I have unstable chest pain.
My kidney function is reduced with a GFR less than 50 mL/min.
I have severe COPD and need extra oxygen or have very low lung function.
I have had a procedure to open blocked arteries in my heart.
I have had surgery to improve blood flow to my heart.
Treatment Details
The study investigates how blood supply meets tissue demand during exercise in aging and diseases like COPD. It tests the effects of various substances on vascular function: BH4, L-NMMA, vitamins C & E; α-Lipoic Acid; Fexofenadine; Ranitidine; Angiotensin-II; Valsartan; BQ-123; MitoQ through maximum exercise tests and drug responses.
7Treatment groups
Experimental Treatment
Group I: Pulmonary Arterial Hypertension patientsExperimental Treatment7 Interventions
Patients with idiopathic or heritable Group 1 pulmonary arterial hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group II: Hypertension patientsExperimental Treatment7 Interventions
Patients with chronic high blood pressure, but with less than severe hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group III: Heart Failure patientsExperimental Treatment7 Interventions
Patients with Class I - III New York Heart Association symptoms of Heart Failure who are not anemic or taking medications that affect blood clotting, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group IV: Healthy Young Volunteers (18-30 years)Experimental Treatment7 Interventions
Healthy volunteers between the ages of 18 and 30 years with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group V: Healthy Older Controls (over 65 years)Experimental Treatment7 Interventions
Healthy volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group VI: Coronary Angiography patientsExperimental Treatment7 Interventions
Patients undergoing routine coronary angiography, but who do not require intracoronary procedures or have history of myocardial disease, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
Group VII: Chronic Obstructive Pulmonary Disease patientsExperimental Treatment7 Interventions
Patients diagnosed with mild to moderate COPD, but not severe COPD patients, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
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Research locations nearbySelect from list below to view details:
George E Wahlen VA Medical CenterSalt Lake City, UT
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Who is running the clinical trial?
Russell RichardsonLead Sponsor
References
A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat. [2019]1. The mechanical and pharmacological properties of small pulmonary arteries (100-300 microns normalized lumen diameter) were directly compared with those of the left main pulmonary artery (1-2 mm) from the rat. The active and passive length-tension characteristics and responses to a variety of agonists and antagonists were dependent on arterial diameter. 2. Maximum contractile function was obtained in both groups of vessels when stretched so as to give an equivalent transmural pressure of 30 mmHg. This is substantially lower than that found for systemic vessels, and reflects the normal low pulmonary arterial pressure. 3. Noradrenaline was a powerful vasoconstrictor in large but not small pulmonary arteries (P less than 0.001). In contrast, bradykinin produced a significantly greater response in the small arteries (P less than 0.001). In comparison with large pulmonary arteries, small arteries were more sensitive to noradrenaline (P less than 0.05) and 5-hydroxytryptamine (P less than 0.001), less sensitive to endothelin-1 (P less than 0.001) and had the same sensitivity to prostaglandin F2 alpha. 4. The mechanism that maintains the low arterial tone of the pulmonary circulation is unknown, but it may involve the release of relaxing factors from the endothelium. In this preparation, basal resting tone could not be demonstrated in either large or small arteries. 5. Acetylcholine-induced relaxation of pre-contracted pulmonary arteries was reduced or absent in the small artery, despite histological evidence of an intact endothelium. In large arteries pre-contracted with prostaglandin F2 alpha, acetylcholine (100 mumol/l) caused 88.2% relaxation compared with 25.2% in the small artery.(ABSTRACT TRUNCATED AT 250 WORDS)
Vasodilator therapy in vasoconstrictor-induced pulmonary hypertension in sheep. [2019]A stable preparation of pulmonary hypertension in sheep was developed using a continuous infusion of the vasoconstrictor U46619, a stable endoperoxide thromboxane A2-mimetic. Using this model, the pulmonary and systemic effects of nitroglycerin, sodium nitroprusside, hydralazine, and prostaglandin E1 were compared at doses producing equivalent reductions in systemic blood pressure. Although all four drugs decreased pulmonary artery pressure and resistance, different drug hemodynamic profiles were found. Prostaglandin E1 demonstrated the greatest pulmonary specificity and resulted in the largest decrease in pulmonary artery pressure (from 33 +/- 1 to 23 +/- 1 mmHg). Nitroglycerin and sodium nitroprusside demonstrated intermediate pulmonary specificity and did not affect cardiac output. Hydralazine demonstrated the least pulmonary specificity and resulted in a large decrease in systemic vascular resistance, with only a moderate decrease in pulmonary artery pressure and resistance. Rational selection of pulmonary vasodilators for clinical application will vary depending on baseline heart rate and rhythm, pulmonary artery pressure, systemic artery pressure, and cardiac output.
Effects of acetylcholine in the pulmonary circulation of rabbits. [2018]The pulmonary and systemic vascular beds differ in their response to several vasoactive substances. Acetylcholine (ACh) is a potent systemic vasodilator; however, its effects on the pulmonary circulation are not clear. Utilizing the isolated rabbit lung preparation perfused in situ under constant flow (92 +/- 3 ml/min) with an albumin-enriched physiologic salt solution, we studied the effects of graded concentrations of ACh (10(-10) to 10(-4) M) in the recirculating perfusate on pulmonary arterial pressure (PAP). The lungs were ventilated to 15 cm of water with 97% O2-3% CO2. ACh (10(-8) to 4 X 10(-7) M) produced a dose-dependent increase in PAP which required up to 20 min to return to predrug levels. Physostigmine (10(-5) M) maintained the maximal PAP response to ACh for the duration of the experiment (up to 2 hr). Higher concentrations of ACh produced rapid increases in PAP resulting in edema. Pre- or post-treatment with the muscarinic receptor antagonist atropine (10(-5) M) completely prevented or reversed the pressor effects of ACh, respectively. Histamine receptor (H1 and H2) or angiotensin II receptor blockade had no effect on the PAP actions of ACh, however pretreatment with the prostaglandin synthesis (cyclooxygenase) inhibitor indomethacin (10(-5) M) or aspirin (10(-3) M), completely abolished the PAP response to ACh up to concentrations of 10(-4) M. In experiments in which airway pressure was allowed to vary, it rose significantly in response to increasing concentrations of ACh. ACh-induced increases in airway pressure were unaffected by pretreatment with indomethacin (10(-5) M) but were totally inhibited by pretreatment with atropine (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. [2019]Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical-induced nitric oxide (NO) breakdown. Because calcium antagonists can improve endothelial function in patients with essential hypertension, in this study we tested the hypothesis that this beneficial effect could be related to restoration of NO availability by antioxidant properties. In 15 healthy subjects and 15 hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (ACh; 0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute), an endothelium-dependent vasodilator in basal conditions, during infusion of N:(G)-monomethyl-L-arginine (L-NMMA, 100 microg/100 mL forearm tissue per minute), an NO-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), and finally, simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (SNP; 1, 2, and 4 microg/100 mL forearm tissue per minute) was also evaluated. In control subjects, vasodilation to ACh was inhibited by L-NMMA and not changed by vitamin C. In hypertensive patients, vasodilation to ACh was blunted as compared with control subjects and resistant to L-NMMA. Vitamin C, which decreased plasma isoprostanes and increased plasma antioxidant capacity, increased the response to ACh and restored the inhibiting effect of L-NMMA. In hypertensive patients, the study was repeated after 3-month treatment with nifedipine gastrointestinal therapeutic system (30 to 60 mg/daily). Nifedipine treatment decreased circulating plasma lipoperoxides and isoprostanes and increased plasma antioxidant capacity. Moreover, nifedipine increased the vasodilation to ACh but not to SNP and restored the inhibiting effect of L-NMMA on ACh-induced vasodilation, whereas vitamin C no longer exerted its facilitating activity. These results indicate that nifedipine increases endothelium-dependent vasodilation by restoring NO availability, an effect probably determined by antioxidant activity.
Age-related reduction of NO availability and oxidative stress in humans. [2022]Age-related endothelial dysfunction could be caused by an alteration in the L-arginine-NO system and the production of oxidative stress in both normotensive and hypertensive individuals. In 47 normotensive subjects and 49 patients with essential hypertension, we evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial sodium nitroprusside (1, 2, and 4 microg/100 mL per minute) and acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute), an endothelium-independent vasodilator and an endothelium-dependent vasodilator, respectively. Acetylcholine was repeated in the presence of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 100 microg/100 mL per minute), the antioxidant vitamin C (8 mg/100 mL per minute), or both. Vasodilation to acetylcholine, but not to sodium nitroprusside, was lower (P60 years). In young hypertensive patients (age 30 years, vitamin C enhanced endothelium-dependent vasodilation and restored the inhibiting effect of L-NMMA on response to acetylcholine. In normotensive individuals, an earlier primary dysfunction of the NO system and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation. These alterations are similar but anticipated in hypertensive patients compared with normotensive subjects.
Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. [2022]Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have antioxidant properties that could improve redox-sensitive vascular changes associated with hypertension. We determined whether vitamins C and E influence vascular function and structure in hypertension by modulating activity of NADPH oxidase and superoxide dismutase (SOD). Adult stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 3 groups: control (C; n=6), vitamin C-treated (vit C, 1000 mg/day; n=7), and vitamin E-treated (vit E, 1000 IU/day; n=8). All rats were fed 4% NaCl. Blood pressure was measured weekly. After 6 weeks of treatment, the rats were killed, and mesenteric arteries were mounted as pressurized preparations. Vascular O(2)(-) generation and NADPH oxidase activity were measured by chemiluminescence. Vascular SOD activity and plasma total antioxidant status (TAS) were determined spectrophotometrically. Blood pressure increased from 212+/-7 to 265+/-6 mm Hg in controls. Treatment prevented progression of hypertension (vit C, 222+/-6 to 234+/-14 mm Hg; vit E, 220+/-9 to 227+/-10 mm Hg). Acetylcholine-induced vasodilation was improved (P
The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. [2021]Past medical therapy for pulmonary arterial hypertension included the use of calcium-channel antagonists in acute vasoreactive subjects and oral anticoagulants and continuous intravenous administration of epoprostenol in the more severe cases. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in >1,100 patients. Except for terbogrel, all compounds improved the mean exercise capacity by different degrees, as assessed by the 6-min walk test. In the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered, such as baseline functional class and concomitant favourable effects on combined clinical events (including hospitalisations, mortality and rescue therapies), quality of life and haemodynamics. No trials have shown effects on mortality, as the study protocols were not designed for assessing this end-point. Each new compound presents side-effects that are unpredictable in the individual patient and require appropriate attention upon treatment initiation and maintenance. These new therapeutic options will be available in the near future and will allow tailoring of the most appropriate treatment to the single patient, according to an individualised benefit-to-risk ratio.
Emerging medical therapies for pulmonary arterial hypertension. [2018]Until a few years ago, "conventional" treatment for pulmonary arterial hypertension (PAH) included oral anticoagulants, calcium channel blockers, diuretics, digoxin, and oxygen. In the 1990s, 3 randomized studies demonstrated that the continuous intravenous infusion of epoprostenol improved functional capacity, cardiopulmonary hemodynamics, and survival in patients with severe PAH. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost, and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in more than 1,100 patients. Except for terbogrel, all compounds have improved by different degrees the mean exercise capacity as assessed by 6 minutes walking distance. Conversely, these trials differ for the severity and etiology of included PAH patients as well as for the effects on combined clinical events, on quality of life, and on hemodynamics. No trials have shown effects on mortality, and each new compound presents different side effects that seem unpredictable in the individual patient. At present, additional new compounds such as sitaxentan, ambisentan, L-arginine, and sildenafil are studied in clinical trials. The new therapeutic options are currently in different phases of approval by regulatory agencies, and when they will become available we will have the opportunity to select the most appropriate treatment for the single patient, according to an individualized benefit-to-risk ratio.
Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine. [2013]Nitrovasodilators-sodium nitroprusside (SNP; 10(-9)-10(-4) M) and 3-morpholino-sydnonimine (SIN-1; 10(-9)-10(-4) M) produced concentration-dependent relaxation of the fourth generation sheep pulmonary artery, preconstricted with 5-hydroxytryptamine (1 microM). Oxidizing agents [oxidized glutathione (GSSG, 1 mM) and CuSO4 (5 and 20 microM)] and reducing agents [dithiothreitol (DTT, 0.1 mM), ascorbic acid (1 mM) and reduced glutathione (GSH, 1 mM)] caused opposite effects on nitric oxide (NO)-induced vasodilation in the artery. Ascorbic acid and GSH potentiated the NO responses, while GSSG and CuSO4 inhibited relaxation caused by the nitrovasodilators. DTT, however, reduced the relaxant potency and efficacy of SNP and SIN-1. Pretreatment of the pulmonary artery strips with DTT (0.1 mM) inhibited SNP (10 microM)-induced Na(+)-K(+)-ATPase activity, while ascorbic acid (1 mM) and GSH (1 mM) had no effect either on basal or SNP (10 microM)-stimulated 86Rb uptake, an index of Na(+)-K(+)-ATPase activity, in ovine pulmonary artery. The results suggest that reducing agents like ascorbic acid may have beneficial effect in improving the vascular function under oxidative stress.
Outcome of pulmonary hypertension subjects transitioned from intravenous prostacyclin to oral bosentan. [2018]Prostacyclin (PG) remains the gold standard therapy for severe pulmonary arterial hypertension (PAH). Previously, we reported the successful transitioning of PAH subjects from intravenous prostacyclin to oral bosentan (Suleman et al. Chest 2004;126:808-15). We report here the 5-year follow-up data.
Treatment with LA-419 prevents monocrotaline-induced pulmonary hypertension and lung injury in the rat. [2013]We evaluated the therapeutic potential of LA-419, a hybrid organic nitrate that donates nitric oxide and thiol groups, to improve pulmonary arterial hypertension in an experimental model induced by monocrotaline in the rat. Treatment with LA-419 from the first day after monocrotaline administration prevented the increase in pulmonary pressure as well as the increases in ventricle/body weight and pulmonary artery wall thickness. Administration of LA-419 after establishment of hypertensive status also resulted in an improvement of these parameters. Both preventive and therapeutic treatments reduced mortality. The antioxidant effect of LA-419 was comparable to that achieved with a-tocopherol. Pulmonary remodeling accomplished by LA-419 could be attributed to a balanced antioxidant effect associated with its nitric oxide/SH donor capability. Thus, LA-419 might represent a new therapeutic approach in severe pulmonary hypertension in humans.
Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. [2014]The purpose of our study was to assess pulmonary endothelial function by vasodilator response to acetylcholine (Ach) administered in segmental pulmonary arteries in children with idiopathic pulmonary arterial hypertension (IPAH). We hypothesized that there was a relationship among pulmonary endothelial response to Ach, severity of the disease, and clinical outcome.
Selexipag for the treatment of pulmonary arterial hypertension. [2018]Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe.
[Efficacy and safety of endothelin receptor antagonists combined with phosphodiesterase 5 inhibitor in the treatment of pulmonary arterial hypertension: a network meta-analysis]. [2022]Objective: To examine the efficacy and safety of endothelin receptor antagonists (ERA) combined with phosphodiesterase 5 inhibitors (PDE5i) in the treatment of pulmonary artery hypertension (PAH). Methods: Computer-based retrieval was performed on PubMed, Cochrane Library, CNKI, Wanfang, and VIP database (up to February 12th, 2021). Randomized controlled trials about endothelin receptor antagonists (ERAs) or PDE5i in patients with PAH were collected. The change of 6-minute walking distance (6MWD) in 12-16 weeks was used as primary outcome index. Case fatality rate, worsening clinical events, WHO functional class (FC) improvement, adverse events (AEs), serious adverse events (SAE) were the key secondary outcomes indicators. STATA 16.0 software was used for network meta-analysis, and the pooled estimates of odds ratios (ORs) or weighted mean differences (WMDs) and 95% confidence intervals (CIs) of the results were shown. To help explain ORs and WMDs, we used the surface under the cumulative ranking curve (SUCRA) to calculate the probability of each intervention. Results: We included 29 trials with 5 949 participants. In network meta-analysis, Bosentan combined with Sildenafil (WMD=53.93, 95%CI=6.19-101.66) had shown the greatest improvement in 6MWD compared with placebo, followed by Bosentan combined with Tadalafil (WMD=50.84, 95%CI=7.05-94.62), Ambrisentan combined with Tadalafil (WMD=46.67, 95%CI=15.88-77.45), Bosentan (WMD=29.44, 95%CI=5.86-53.02), Ambrisentan (WMD=23.90, 95%CI=0.31-47.48) and Macitentan (WMD=21.57, 95%CI=2.45-40.69). According to SUCRA, the effects of different intervention measures on improving 6MWD in patients with arterial pulmonary hypertension were as follows: Bosentan+Sildenafil (82.9%)>Bosentan+Tadalafil (78.4%)>Ambrisentan+Tadalafil (77.1%)>Bosentan (49.2%)>Sildenafil (48.5%)>Ambrisentan (40.3%)>Macitentan (37.3%)>Tadalafil (33.0%)>Placebo (3.3%). For the WHO functional class, Sildenafil (OR=2.90, 95%CI=1.04-8.08) was optimal compared with placebo, followed by Bosentan (OR=2.15, 95%CI=1.15-4.04), and there was no significant difference in the rest. For clinical worsening, Bosentan combined with Tadalafil (OR=0.08, 95%CI=0.01-0.49) performed best compared with placebo, followed by Bosentan (OR=0.20, 95%CI=0.11-0.38), Bosentan combined with Sildenafil (OR=0.21, 95%CI=0.09-0.46), Ambrisentan combined with Tadalafil (OR=0.27, 95%CI=0.15-0.50), Sildenafil (OR=0.33, 95%CI=0.17-0.66) and Tadalafil (OR=0.44, 95%CI=0.21-0.90). There was no statistical difference between all interventions and placebo in terms of the incidence of adverse events and serious adverse events. For case fatality rate, Ambrisentan (OR=0.28, 95%CI=0.11-0.74) was statistically superior to placebo and there was no statistics difference in the rest. Conclusions: The combination therapy of ERAs and PDE5i performed well in the short-term improvement of motor function. Furthermore, there was no significant difference with monotherapy in terms of safety. However, it is worth emphasizing that the choice of treatment should be based on the patient's individualized situation and the patient's requirements.