Vascular Response Study in Obesity

Overseen By Jacqueline K Limberg, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Missouri-Columbia

Must not be taking: Anticoagulants, Prescription medications

Disqualifiers: Pregnancy, Sleep apnea, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how different treatments affect blood vessel function in people with obesity, focusing on differences between men and women. Researchers aim to understand how obesity influences the body's response to low oxygen levels, particularly through the nervous system. The trial involves three medications that affect blood vessel and nervous system activity: Isoproterenol (which stimulates the heart and widens blood vessels), Phentolamine Mesylate (which blocks certain nerve signals to help widen blood vessels), and Propranolol Hydrochloride (a beta-blocker that affects the heart and circulation). It is suitable for men and women with a body mass index (BMI) over 18 who do not have conditions like high blood pressure or diabetes. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a chance to contribute to groundbreaking medical insights.

Will I have to stop taking my current medications?

The trial excludes participants who are on prescription medications, so you would need to stop taking them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatments in this trial—Isoproterenol, Phentolamine Mesylate, and Propranolol Hydrochloride—are generally safe based on previous studies and uses.

Isoproterenol often treats heart rhythm problems. Studies have demonstrated that it can improve blood flow by reducing resistance in blood vessels, particularly in muscles. It is usually well-tolerated in controlled settings.

Phentolamine Mesylate helps widen blood vessels and works for a short duration. It is frequently used after dental procedures to aid recovery. Some studies suggest it might lower blood pressure, so doctors monitor this effect.

Propranolol Hydrochloride treats high blood pressure and other heart issues. It can lower heart rate and blood pressure. Some individuals might experience dizziness or fatigue, but these are known effects that doctors monitor.

The trial is in an early stage, and researchers are still studying how these treatments work together and their safety in this specific situation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores how the body’s vascular system responds to hypoxia, especially in individuals with obesity. Unlike other studies that might focus solely on medications or lifestyle changes, this trial uses isocapnic hypoxia, where participants breathe through a mask to achieve controlled low oxygen levels. This method is unique because it directly examines how blood vessels react under specific oxygen conditions, potentially revealing new insights into managing vascular health in obese individuals. By understanding these responses, researchers hope to develop more effective strategies for improving cardiovascular health in this population.

What evidence suggests that this trial's treatments could be effective for obesity?

This trial will investigate the effects of various treatments on vascular response in obesity. Research has shown that Isoproterenol, one of the treatments under study, can help keep blood vessels open in healthy individuals, which might be useful for conditions affecting blood flow. Studies have found that Phentolamine Mesylate increases blood flow when oxygen levels are low, enhancing blood vessel response. Additionally, animal research suggests that Propranolol Hydrochloride, also under study in this trial, can lower blood pressure and improve blood vessel function, potentially benefiting people with obesity. While these treatments appear promising, further studies on humans are needed to confirm their effectiveness for obesity-related blood vessel issues. ^{1 6 7 8 9}

Who Is on the Research Team?

Jacqueline Limberg, Ph.D.

Principal Investigator

University of Missouri-Columbia

Are You a Good Fit for This Trial?

This trial is for adults who are either at a healthy weight (BMI between 18 and 25) or obese (BMI of 30 or more). It's not suitable for those with nerve diseases, sleep apnea, major organ disease, high blood pressure, on prescription meds, sensitive to lidocaine, pregnant/breastfeeding women, smokers/nicotine users, or with bleeding/clotting disorders.

Inclusion Criteria

BMI >18 kg/m2

Exclusion Criteria

I have been diagnosed with sleep apnea or have more than 10 breathing pauses per hour.

Pregnancy, breastfeeding

I have a nerve or neurological condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Hypoxia Exposure

Men and women will be exposed to isocapnic hypoxia. Participants will wear a mask and systemic oxygen levels will be titrated to attain hypoxemia as assessed by pulse oximetry.

1 session

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after hypoxia exposure

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acetylcholine
• Isoproterenol
• Norepinephrine
• Phentolamine Mesylate
• Propranolol Hydrochloride
• Sodium Nitroprusside

Trial Overview The study investigates how well blood vessels can widen in response to low oxygen levels in men vs. women and how obesity affects this process. Participants will receive drugs like Propranolol Hydrochloride and others that influence heart rate and blood vessel function.

How Is the Trial Designed?

Group I: Hypoxia Exposure Experimental Treatment 4 Interventions

Men and women will be exposed to isocapnic hypoxia. Participants will wear a mask and systemic oxygen levels will be titrated to attain hypoxemia as assessed by pulse oximetry.

Isoproterenol is already approved in United States, European Union for the following indications:

Approved in United States as Isuprel for:

• Cardiac Arrhythmia
• Adams-Stokes Syndrome
• AV Heart Block
• Shock
• Bronchospasm During Anesthesia
• Asthma
• Bronchitis
• Emphysema

Approved in European Union as Isoprenaline for:

• Cardiac Arrhythmia
• Adams-Stokes Syndrome
• AV Heart Block
• Shock
• Bronchospasm During Anesthesia
• Asthma
• COPD

Who Is Running the Clinical Trial?

University of Missouri-Columbia

Lead Sponsor

Trials

387

Recruited

629,000+

Published Research Related to This Trial

Isoproterenol effectively reduces pelvic pressure in the renal pelvis of pigs, achieving up to a 78% decrease at a concentration of 0.1 microg/ml without causing cardiovascular side effects.

The study indicates that isoproterenol is safe for use in this porcine model, suggesting its potential utility in endourological procedures where pressure management is critical.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local and systemic effects of endoluminal pelvic perfusion of isoproterenol: a dose response investigation in pigs. Jakobsen, JS., Holst, U., Jakobsen, P., et al.[2013]

The study evaluated the effectiveness of various beta-adrenoceptor agonists, including new compounds BRL 28410, BRL 35113, and BRL 35135, showing that these new drugs selectively enhance lipolysis in rat adipocytes, indicating potential for targeted fat metabolism treatments.

Findings suggest that the receptors involved in lipolysis in rat adipocytes do not conform to the traditional beta 1/beta 2-adrenoceptor classification, as evidenced by differing pA2 values for antagonists across different tissues, highlighting a need for revised understanding of these receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The rat lipolytic beta-adrenoceptor: studies using novel beta-adrenoceptor agonists. Wilson, C., Wilson, S., Piercy, V., et al.[2019]

The study identified the presence of atypical beta-adrenoceptors in the vascular smooth muscle of the rat common carotid artery, suggesting a unique mechanism of action for relaxation in this tissue.

Isoprenaline and other beta-agonists like salbutamol and BRL 37344 effectively relaxed precontracted artery segments, indicating that these atypical receptors can mediate vascular responses independently of the traditional beta-adrenoceptor pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atypical beta-adrenoceptors in the rat isolated common carotid artery. Oriowo, MA.[2019]

In a study of rat adipose cells, the lipolytic effects of various beta-adrenergic agonists showed that isoprenaline was the most potent, followed by noradrenaline, salbutamol, and prenalterol, indicating that different beta-adrenergic receptors play distinct roles in fat breakdown.

The research suggests the existence of a 'beta-3' or beta-hybrid adrenoceptor, which could explain why cardio-selective beta-blockers like betaxolol may be beneficial for obese patients by allowing better fat utilization during anti-hypertensive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the beta-adrenoceptor of the adipose cell of the rat. Tan, S., Curtis-Prior, PB.[2014]

In elderly patients with mild heart failure, intravenous propranolol significantly reduced heart rate and cardiac output, indicating increased adrenergic activity in this population.

A small dose of propranolol (0.03 mg/kg) caused negligible hemodynamic deterioration, suggesting it is a safe option for managing heart failure symptoms, while responses to isoproterenol were notably depressed in patients with severe heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Studies on heart failure in old age (Part II). Hemodynamic effects of propranolol and isoproterenol in elderly patients with heart failure. Mifune, J.[2013]

The study confirmed that beta-adrenergic receptors are present on rat brain microvessels, with a high affinity for the antagonist hydroxybenzylpindolol (IHYP), indicated by a KD value of 69.4 pM.

Binding of IHYP to these receptors was specific and saturable, showing that the binding was reversible and stereospecific, as demonstrated by the stronger inhibitory effects of (-)-propranolol compared to its (+)-isomer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of beta-adrenergic receptor binding sites in rat brain microvessels, using [125I]iodohydroxybenzylpindolol. Kobayashi, H., Memo, M., Spano, PF., et al.[2019]

Isoprenaline, a beta-adrenoceptor agonist, causes increased heart rate and vasodilation in anesthetized rats, primarily through both propranolol-sensitive and -insensitive beta-adrenoceptors, indicating its potential as a therapeutic agent for cardiovascular effects.

Blocking nitric oxide synthase with L-NAME alters the effectiveness of propranolol, suggesting that the activity of propranolol-sensitive beta-adrenoceptors decreases while propranolol-insensitive beta-adrenoceptors increase when nitric oxide is inhibited, which could impact treatment strategies for cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Downregulation of propranolol-sensitive beta-adrenoceptor signaling after inhibition of nitric oxide synthesis. Whalen, EJ., Bates, JN., Johnson, AK., et al.[2018]

Isoproterenol (Iso) significantly reduces leptin release in human adipose tissue, with a 30% decrease observed acutely and a 20-30% reduction in leptin accumulation after 24 hours of culture with insulin.

Iso not only decreases leptin secretion but also lowers leptin mRNA levels by 40-65% when combined with insulin and dexamethasone, suggesting that beta-adrenergic stimulation can modulate leptin expression through both immediate and longer-term mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isoproterenol decreases leptin expression in adipose tissue of obese humans. Ricci, MR., Fried, SK.[2019]

Underweight individuals showed a significantly greater cardiovascular response to Isoproterenol, a beta-agonist, compared to normal weight individuals, indicating enhanced beta-adrenoceptor responsiveness in this group.

Despite the increased responsiveness to Isoproterenol, the cardiovascular responses to head-up tilt were similar between underweight and normal weight subjects, suggesting that the overall cardiovascular function may not be compromised in underweight individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased cardiovascular beta-adrenoceptor responsiveness in underweight subjects. Jayarajan, MP., Balasubramanyam, A., Shetty, PS.[2013]

Selective beta-adrenergic agonists prenalterol and procaterol stimulate lipolysis in hamster adipocytes, but require much higher concentrations than isoprenaline for half-maximal stimulation, indicating differences in receptor sensitivity.

The study suggests a heterogeneous population of beta 1- and beta 2-adrenergic receptors on hamster adipocytes, as beta 2 stimulation was found to be approximately twice as effective as beta 1 stimulation, which could impact therapeutic strategies targeting these receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of the lipolytic beta-adrenergic receptors in hamster adipocytes. Björgell, P., Belfrage, P.[2019]

A study involving 12 normal volunteers showed that withdrawal from atenolol, a beta-blocker without partial agonist activity, resulted in signs of adrenergic overactivity, such as increased plasma cortisol, insulin, and glucose levels.

In contrast, withdrawal from bopindolol, which has partial agonist activity, led to elevated prolactin levels and persistent increases in plasma potassium and adrenaline, indicating different withdrawal syndromes associated with the properties of the drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Withdrawal phenomena after atenolol and bopindolol: hormonal changes in normal volunteers. Walden, RJ., Tomlinson, B., Graham, B., et al.[2019]

The beta-3 adrenergic receptor agonist BRL37344 effectively reduces mean arterial pressure and increases total peripheral conductance, demonstrating its potential role in regulating blood flow, even after blocking other adrenergic receptors.

In contrast to beta-1 and beta-2 receptor stimulation, which showed diminished effects after receptor blockade, BRL37344 maintained its hemodynamic effects, suggesting a unique mechanism of action for the beta-3 adrenergic receptor in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral vascular effects of beta-3 adrenergic receptor stimulation in conscious dogs. Shen, YT., Zhang, H., Vatner, SF.[2017]

In a study with male Wistar rats treated with isoproterenol (ISO) for 7 days, β-adrenoceptor overstimulation led to enhanced relaxation of pulmonary arteries, indicating improved vascular reactivity.

This enhanced relaxation was linked to increased nitric oxide (NO) production and signaling, specifically through elevated endothelial NOS (eNOS) and cGMP levels, suggesting a protective mechanism in pulmonary circulation against potential damage from β-AR overactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced endothelium-dependent relaxation of rat pulmonary artery following β-adrenergic overstimulation: involvement of the NO/cGMP/VASP pathway. Davel, AP., Victorio, JA., Delbin, MA., et al.[2015]

Citations

1. ahajournals.org ahajournals.org/doi/full/10.1161/01.HYP.30.4.918?doi=10.1161/01.HYP.30.4.918

Decreased Vasodilator Response to Isoproterenol During ... Abstract The vasodilator effect of β-adrenergic agonists has traditionally been ascribed solely to a direct effect on vascular smooth muscle.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8698505/

Preserved β-adrenergic-mediated vasodilation in skeletal ... Isoproterenol (Iso) data from a subset of normal weight participants were previously published (22, 28). All participants reported being healthy, nonsmokers, ...

3. journals.physiology.org journals.physiology.org/doi/prev/20211105-aop/pdf/10.1152/ajpheart.00449.2021

Preserved β-adrenergic mediated vasodilation in skeletal ... Table 4: Contribution of NOS and COX to the hemodynamic response to isoproterenol. Data are reported as a change (Δ) from baseline and are presented as Mean ± ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00226551?term=ISOPROTERENOL&rank=2

Vascular Response to Isoproterenol and β2 Adrenergic Receptor ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK526042/

Isoproterenol - StatPearls - NCBI Bookshelf There is no human data available regarding the effect of isoproterenol ... isoproterenol therapy, resulting in improved outcomes with fewer adverse events.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2013/010515s031lbl.pdf

Isuprel - accessdata.fda.gov Intravenous infusion of isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/010515Orig1s033lbl.pdf

ISUPREL® (isoproterenol hydrochloride ... - accessdata.fda.gov Safety and efficacy of ... Intravenous infusion of isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal.

8. go.drugbank.com go.drugbank.com/drugs/DB01064

Isoprenaline: Uses, Interactions, Mechanism of Action Isoprenaline is indicated to treat mild or transient episodes of heart block not requiring electric shock or pacemakers, serious episodes of heart block and ...

9. medsafe.govt.nz medsafe.govt.nz/profs/Datasheet/i/Isuprelinj.pdf

Isuprel Isuprel™ is indicated for: 1. Mild or transient episodes of heart block that do not require electric shock or pacemaker therapy.