Pyridoxine, P2 Receptor Antagonism, and ATP-mediated Vasodilation in Young Adults

Pyridoxine, P2 Receptor Antagonism, and ATP-mediated Vasodilation in Young Adults

Sponsors

Lead Sponsor: Colorado State University

Source Colorado State University
Brief Summary

Previous research has identified adenosine triphosphate (ATP) as an important vasodilator that is released from red blood cells during exercise and exposure to hypoxic environments in adult humans. Further, older adults appear to have lower blood flow during both of these stressors and also have lower amounts of ATP released from their red blood cells. However, the contribution of ATP to vasodilation in response to exercise and hypoxia is currently unknown due to the lack of an effective ATP receptor antagonist. We aim to determine whether Vitamin B6 or its metabolite, Pyridoxal-5-Phosphate (PLP) is an effective ATP receptor antagonist.

Detailed Description

Adenosine triphosphate (ATP) is an established vasodilator that is released from red blood cells during a variety of stimuli including exercise and exposure to hypoxic environments. Many studies have shown that infusion of ATP can lead to vasodilation similar to that which is achieved during exercise, and that plasma ATP concentrations increase in a graded fashion during graded exercise. Further, older adults have lower levels of blood flow during exercise and hypoxia compared to their younger counterparts, and the reduced blood flow is coupled with impaired release of ATP from red blood cells during these stimuli. Thus, ATP is believed to be an important vasodilator. However, the role of ATP in the regulation of blood flow is not fully understood due to the lack of an effective ATP receptor (P2Y2) antagonist. Development of an effective P2Y2 antagonist will allow researchers to determine the role of ATP in vasodilation to stimuli such as exercise by comparing blood flow during exercise with and without the blocker. Preliminary data from our laboratory suggests that Vitamin B6 (pyridoxine hydrochloride) or its metabolite Pyridoxal-5-Phosphate (PLP) may be an effective blocker of ATP-mediated vasodilation. As a result, the purpose of this study is to determine whether Vitamin B6 or PLP can inhibit vasodilation in response to intra-arterial infusions of ATP. This study also aims to determine the specificity of Vitamin B6 or PLP by measuring its effect on vasodilation in response to infusion of several other vasodilators. Participants will be asked to complete one screening visit and one study visit. Once study eligibility has been determined, participants will report to the Human Performance Clinical Research Laboratory at Colorado State University following an overnight fast. A physician will then place a catheter in the brachial artery of the non-dominant arm, and participants will be randomized into one of three study arms to determine which drugs will be infused into the artery. Each arm includes ATP and two other vasodilators. The study will begin by measuring vasodilation in response to four standard doses of each vasodilator. Vasodilation in response to the vasodilators will then be assessed again following infusion of Vitamin B6 or PLP. Reduced vasodilation to any of the drugs during the second trial will suggest that Vitamin B6 or PLP is an antagonist to the channel through which the drug signals. Each study visit will last approximately 4-5 hours.

Overall Status Recruiting
Start Date 2019-02-07
Completion Date 2021-06-01
Primary Completion Date 2021-06-01
Phase Early Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Vascular Conductance Continuous measurement of vascular conductance during the 12 minute dose response for each drug. Measures are repeated following administration of Vitamin B6 or PLP.
Enrollment 30
Condition
Intervention

Intervention Type: Drug

Intervention Name: Adenosine Triphosphate

Description: See arm/group descriptions

Other Name: ATP

Intervention Type: Drug

Intervention Name: Acetylcholine

Description: See arm/group descriptions

Arm Group Label: ATP, Ach, SNP

Other Name: Ach

Intervention Type: Drug

Intervention Name: Sodium Nitroprusside

Description: See arm/group descriptions

Arm Group Label: ATP, Ach, SNP

Other Name: SNP

Intervention Type: Drug

Intervention Name: Adenosine Diphosphate

Description: See arm/group descriptions

Arm Group Label: ATP, ADP, AMP

Other Name: ADP

Intervention Type: Drug

Intervention Name: Adenosine Monophosphate

Description: See arm/group descriptions

Arm Group Label: ATP, ADP, AMP

Other Name: AMP

Intervention Type: Drug

Intervention Name: Uridine Triphosphate

Description: See arm/group descriptions

Arm Group Label: ATP, UTP, Adenosine

Other Name: UTP

Intervention Type: Drug

Intervention Name: Adenosine

Description: See arm/group descriptions

Arm Group Label: ATP, UTP, Adenosine

Other Name: Adenocard

Intervention Type: Drug

Intervention Name: Vitamin B 6

Description: See arm/group descriptions

Intervention Type: Drug

Intervention Name: Pyridoxal 5'-Phosphate

Description: See arm/group descriptions

Eligibility

Criteria:

Inclusion Criteria: - Sedentary-moderately active - Free of chronic disease Exclusion Criteria: - Current smoker - BMI > 29.9 kg/m2 - Blood pressure equal to or greater than 140/90 mmHg - Use of any medications including vitamin B6 supplements or antioxidants

Gender:

All

Minimum Age:

18 Years

Maximum Age:

30 Years

Healthy Volunteers:

Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Frank Dinenno, PhD Principal Investigator Colorado State University
Overall Contact

Last Name: Laurie Biela, MS

Phone: 970-491-2242

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: Human Performance and Clinical Research Laboratory Jennifer Richards, Ph.D. 970-491-6702 [email protected]
Location Countries

United States

Verification Date

2020-07-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Colorado State University

Investigator Full Name: Frank Dinenno

Investigator Title: Professor

Keywords
Has Expanded Access No
Number Of Arms 3
Arm Group

Label: ATP, Ach, SNP

Type: Experimental

Description: All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Acetylcholine: 1, 4, 8, and 16 μg/dl forearm volume/min for 3 minutes each. Sodium Nitroprusside: 0.25, 0.5, 1, and 2 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Label: ATP, ADP, AMP

Type: Experimental

Description: All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Adenosine Diphosphate: 20, 40, 80, and 160 μg/dl forearm volume/min for 3 minutes each. Adenosine Monophosphate: 25, 50, 100, and 200 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Label: ATP, UTP, Adenosine

Type: Experimental

Description: All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Uridine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Adenosine: 3.125, 6.25, 12.5, and 25 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: Participants will be assigned to one of three arms of the study. The arms of the study are based on the vasodilators being tested in order to determine the effect of pyridoxine or PLP on vasodilation in response to intra-arterial administration of the vasodilators.

Primary Purpose: Basic Science

Masking: None (Open Label)

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