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

Trial Summary

What is the purpose of this trial?

The purpose of this project is to examine key mechanisms contributing to sex-differences in hypoxic vasodilation and the impact of obesity, with particular emphasis on the sympathetic nervous system.

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.

What data supports the effectiveness of the drug Isoproterenol in the Vascular Response Study in Obesity?

Research shows that Isoproterenol, a beta-adrenergic agonist, can decrease leptin expression in adipose tissue of obese humans, suggesting it may influence fat metabolism. Additionally, Isoproterenol has been shown to have significant cardiovascular effects, such as increasing heart rate and reducing diastolic pressure, which may be relevant in studying vascular responses in obesity. ^{1 2 3 4 5}

Is Isoproterenol generally safe for humans?

Isoproterenol, a beta-adrenergic agonist, has been studied for its effects on the cardiovascular system and has shown increased responsiveness in underweight individuals, suggesting it can affect heart rate and blood pressure. While these studies provide some insight into its effects, they do not directly address its safety profile in humans. ^{1 2 6 7 8}

How does the drug Isoproterenol, Phentolamine Mesylate, Propranolol Hydrochloride differ from other treatments for obesity?

This drug combination is unique because it targets beta-adrenergic receptors, which are involved in regulating heart rate and blood vessel dilation, potentially affecting vascular responses in obesity. The use of isoproterenol and propranolol together may modulate these receptors differently, offering a novel approach compared to standard obesity treatments that typically focus on diet, exercise, or metabolic pathways. ^{9 10 11 12 13}

Research Team

Jacqueline Limberg, Ph.D.

Principal Investigator

University of Missouri-Columbia

Eligibility Criteria

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

Pregnancy, breastfeeding

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

I have a nerve or neurological condition.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Increased cardiovascular beta-adrenoceptor responsiveness in underweight subjects. [2013]

2. Netherlands pubmed.ncbi.nlm.nih.gov

The rat lipolytic beta-adrenoceptor: studies using novel beta-adrenoceptor agonists. [2019]

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

Isoproterenol decreases leptin expression in adipose tissue of obese humans. [2019]

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

Characterization of the beta-adrenoceptor of the adipose cell of the rat. [2014]

5. Japan 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. [2013]

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

Local and systemic effects of endoluminal pelvic perfusion of isoproterenol: a dose response investigation in pigs. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Withdrawal phenomena after atenolol and bopindolol: hormonal changes in normal volunteers. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Characteristics of the lipolytic beta-adrenergic receptors in hamster adipocytes. [2019]

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

Peripheral vascular effects of beta-3 adrenergic receptor stimulation in conscious dogs. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Identification of beta-adrenergic receptor binding sites in rat brain microvessels, using [125I]iodohydroxybenzylpindolol. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Enhanced endothelium-dependent relaxation of rat pulmonary artery following β-adrenergic overstimulation: involvement of the NO/cGMP/VASP pathway. [2015]

12. England pubmed.ncbi.nlm.nih.gov

Downregulation of propranolol-sensitive beta-adrenoceptor signaling after inhibition of nitric oxide synthesis. [2018]

13. England pubmed.ncbi.nlm.nih.gov

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