Vascular Function in Pulmonary Arterial Hypertension

Overseen by Russell Richardson, Ph.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Russell Richardson

Disqualifiers: Severe COPD, Myocardial infarction, Renal disease, others

No Placebo Group

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.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of the drugs used in the clinical trial for pulmonary arterial hypertension?

The research highlights that drugs like endothelin receptor antagonists and phosphodiesterase 5 inhibitors, such as Bosentan and Sildenafil, have shown improvements in exercise capacity and functional class in patients with pulmonary arterial hypertension. These drugs have been effective in increasing the distance patients can walk in six minutes, which is a measure of improved physical function. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Research shows that treatments like acetylcholine, vitamin C, and sodium nitroprusside have been studied for their effects on blood flow and vascular function, often showing beneficial effects in managing conditions like hypertension. These treatments have been used in various studies without significant safety concerns, suggesting they are generally safe for human use. ^{1 6 7 8 9}

How does the drug Selexipag differ from other treatments for pulmonary arterial hypertension?

Selexipag is unique because it is an oral medication that specifically targets the prostacyclin receptor (IP) pathway, which is crucial for dilating blood vessels in the lungs and improving heart function. Unlike other treatments, it is a non-prostanoid, meaning it works differently from traditional prostacyclin-based therapies. ^{10 11 12 13 14}

Research Team

Russell Richardson, Ph.D.

Principal Investigator

George E Wahlen VA Medical Center

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.

Exclusion Criteria

I have a history of variant angina.

I have had a heart attack before.

I have unstable chest pain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo various pharmacologic interventions and exercise tests to assess vascular function and metabolic demand

6-8 weeks

Weekly visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to further assess vascular function

Long-term

Treatment Details

Interventions

• Acetylcholine (Vasodilator)
• Angiotensin-II (Vasoconstrictor)
• BH4 (Antioxidant)
• BQ-123 (Endothelin Receptor Antagonist)
• Fexofenadine (Antihistamine)
• L-NMMA (NOS Inhibitor)
• MitoQ (Mitochondrial Targeted Antioxidant)
• Norepinephrine (Vasoconstrictor)
• Phentolamine (Alpha Adrenergic Receptor Antagonist)
• Ranitidine (H2 Receptor Antagonist)
• Sodium Nitroprusside (Vasodilator)
• Valsartan (Angiotensin Receptor Blocker)
• Vitamin C (Antioxidant)
• Vitamin E (Antioxidant)
• α-Lipoic Acid and L-Ascorbate (Antioxidant)

Trial Overview 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.

Participant Groups

Group I: Pulmonary Arterial Hypertension patients Experimental Treatment 7 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 patients Experimental Treatment 7 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 patients Experimental Treatment 7 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 Treatment 7 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 Treatment 7 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 patients Experimental Treatment 7 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 patients Experimental Treatment 7 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.

Who Is Running the Clinical Trial?

Russell Richardson

Lead Sponsor

Trials

1

Recruited

420+

Findings from Research

LA-419, a hybrid organic nitrate, effectively prevents and treats pulmonary arterial hypertension in rats by reducing pulmonary pressure and improving heart and artery health, even when administered after the condition develops.

The treatment not only reduced mortality rates but also demonstrated antioxidant effects similar to vitamin E, suggesting that LA-419's mechanism involves a combination of nitric oxide donation and antioxidant properties, making it a promising candidate for treating severe pulmonary hypertension in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with LA-419 prevents monocrotaline-induced pulmonary hypertension and lung injury in the rat. Mourelle, M., Martin, MT., Giménez, F.[2013]

The combination of Bosentan and Sildenafil showed the greatest improvement in exercise capacity (measured by the 6-minute walking distance) for patients with pulmonary artery hypertension, indicating effective short-term treatment options.

Safety profiles for combination therapies were comparable to monotherapy, with no significant increase in adverse events, suggesting that these combinations can be safely used in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of endothelin receptor antagonists combined with phosphodiesterase 5 inhibitor in the treatment of pulmonary arterial hypertension: a network meta-analysis]. Fu, WH., Chen, PL., Xia, JL., et al.[2022]

Recent treatments for pulmonary arterial hypertension (PAH) have shown improvements in exercise capacity, with various new medications tested in over 1,100 patients, but none have demonstrated a significant effect on mortality.

While new therapies like terbogrel, treprostinil, and bosentan have improved walking distance in patients, they come with unpredictable side effects, highlighting the need for personalized treatment approaches based on individual patient profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging medical therapies for pulmonary arterial hypertension. Galiè, N., Manes, A., Branzi, A.[2018]

Recent clinical trials involving over 1,100 patients have shown that new treatments for pulmonary arterial hypertension, such as prostacyclin analogues and endothelin receptor antagonists, can improve exercise capacity as measured by the 6-minute walk test, although none have demonstrated a direct impact on mortality.

While these new therapies offer potential benefits, they also come with unpredictable side effects that require careful management, emphasizing the need for personalized treatment plans based on each patient's specific circumstances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Galiè, N., Manes, A., Branzi, A.[2021]

In a 5-year follow-up study of 11 patients with severe pulmonary arterial hypertension (PAH) who transitioned from intravenous prostacyclin to oral bosentan, most patients experienced prolonged stable functional class and walking distance, indicating a potential quality of life improvement.

Despite the transition, 64% of patients required resumption of prostacyclin therapy due to clinical deterioration, highlighting the need for careful monitoring and management in PAH treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of pulmonary hypertension subjects transitioned from intravenous prostacyclin to oral bosentan. Safdar, Z.[2018]

In a study involving 30 participants (15 healthy and 15 hypertensive), it was found that calcium antagonists like nifedipine can improve endothelial function in hypertensive patients by restoring nitric oxide (NO) availability, likely due to their antioxidant properties.

After 3 months of nifedipine treatment, hypertensive patients showed increased vasodilation in response to acetylcholine, indicating improved endothelial function, while vitamin C's role diminished, suggesting that nifedipine's effects are more significant in enhancing NO availability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Taddei, S., Virdis, A., Ghiadoni, L., et al.[2019]

In a study of 96 participants (47 normotensive and 49 hypertensive), it was found that endothelium-dependent vasodilation, measured by the response to acetylcholine, was significantly lower in hypertensive patients compared to normotensive individuals, indicating a dysfunction in the endothelial system related to hypertension.

Aging was associated with a decline in endothelium-dependent vasodilation in both groups, but the antioxidant vitamin C improved vasodilation in older hypertensive patients, suggesting that oxidative stress plays a role in age-related endothelial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related reduction of NO availability and oxidative stress in humans. Taddei, S., Virdis, A., Ghiadoni, L., et al.[2022]

In a study involving stroke-prone spontaneously hypertensive rats, treatment with vitamins C and E significantly prevented the progression of hypertension and improved vascular function over 6 weeks.

Both vitamins reduced oxidative stress by decreasing the activity of NADPH oxidase and increasing superoxide dismutase activity, leading to better blood vessel health and lower blood pressure compared to control rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Chen, X., Touyz, RM., Park, JB., et al.[2022]

Nitrovasodilators like sodium nitroprusside and SIN-1 effectively relax the pulmonary artery in sheep, indicating their potential use in managing pulmonary hypertension.

Reducing agents such as ascorbic acid enhance nitric oxide-induced vasodilation, suggesting they could improve vascular function under oxidative stress, while oxidizing agents inhibit this effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine. Sardar, KK., Sarkar, SN., Bawankule, DU., et al.[2013]

In a study using a sheep model of pulmonary hypertension, Prostaglandin E1 was found to be the most effective pulmonary vasodilator, significantly reducing pulmonary artery pressure from 33 to 23 mmHg.

While all tested drugs (nitroglycerin, sodium nitroprusside, hydralazine, and Prostaglandin E1) lowered pulmonary artery pressure, they exhibited different hemodynamic profiles, indicating that the choice of vasodilator should consider individual patient factors like heart rate and cardiac output.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasodilator therapy in vasoconstrictor-induced pulmonary hypertension in sheep. Prielipp, RC., Rosenthal, MH., Pearl, RG.[2019]

Selexipag is a newly approved oral medication that acts as an IP receptor agonist, targeting the prostacyclin pathway to treat pulmonary arterial hypertension (PAH) by promoting pulmonary vasodilation and improving right ventricular function.

While selexipag shows promise as a treatment option for PAH, its effectiveness as a first-line therapy is uncertain, and it is likely to be used in combination with other PAH-specific medications rather than as a standalone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. Richter, MJ., Gall, H., Grimminger, J., et al.[2018]

In a study of 43 children with idiopathic pulmonary arterial hypertension (IPAH), the pulmonary flow reserve (PFR) in response to acetylcholine was found to be significantly related to the severity of the disease and clinical outcomes, with a mean PFR of 1.58.

A PFR of less than 1.4 was identified as a strong predictor of serious cardiovascular events, such as lung transplantation or death, highlighting its potential as a valuable prognostic tool in managing IPAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. Apitz, C., Zimmermann, R., Kreuder, J., et al.[2014]

Acetylcholine (ACh) causes a dose-dependent increase in pulmonary arterial pressure (PAP) in isolated rabbit lungs, indicating that it can have significant effects on pulmonary circulation, unlike its known vasodilatory effects in systemic circulation.

The increase in PAP from ACh can be prevented or reversed by the muscarinic receptor antagonist atropine, suggesting that ACh's effects are mediated through these receptors, while the response is also influenced by prostaglandin synthesis, as indicated by the abolishment of the PAP response when using cyclooxygenase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetylcholine in the pulmonary circulation of rabbits. Catravas, JD., Buccafusco, JJ., El Kashef, H.[2018]

Small pulmonary arteries (100-300 microns) and large pulmonary arteries (1-2 mm) in rats exhibit different mechanical and pharmacological properties, with maximum contractile function achieved at a lower pressure (30 mmHg) compared to systemic vessels, reflecting the unique low pressure of the pulmonary circulation.

Noradrenaline is a strong vasoconstrictor in large pulmonary arteries but not in small ones, while small arteries show greater sensitivity to bradykinin and other agents, indicating distinct responses based on arterial size that could influence treatment strategies for pulmonary conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat. Leach, RM., Twort, CH., Cameron, IR., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment with LA-419 prevents monocrotaline-induced pulmonary hypertension and lung injury in the rat. [2013]

2. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of endothelin receptor antagonists combined with phosphodiesterase 5 inhibitor in the treatment of pulmonary arterial hypertension: a network meta-analysis]. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Emerging medical therapies for pulmonary arterial hypertension. [2018]

4. England pubmed.ncbi.nlm.nih.gov

The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Outcome of pulmonary hypertension subjects transitioned from intravenous prostacyclin to oral bosentan. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Age-related reduction of NO availability and oxidative stress in humans. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. [2022]

9. India pubmed.ncbi.nlm.nih.gov

Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

Vasodilator therapy in vasoconstrictor-induced pulmonary hypertension in sheep. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. [2014]

13. United States pubmed.ncbi.nlm.nih.gov

Effects of acetylcholine in the pulmonary circulation of rabbits. [2018]

14. England pubmed.ncbi.nlm.nih.gov

A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat. [2019]