Peripheral Dopamine in Postural Tachycardia Syndrome

Kidney Dopamine Effects on Urinary Sodium Excretion in Postural Tachycardia Syndrome

The purpose of the proposed research is to determine how changes in kidney dopamine (DA) activity influence urinary sodium excretion. We will decrease DA activity in the kidney by inhibiting DA synthesis via carbidopa administration. We want to compare findings in normal volunteers and in patients with postural tachycardia syndrome (POTS). We will test the null hypothesis (Ho) that the effects of oral carbidopa administration on urinary sodium excretion will not differ between patients with POTS and healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Orthostatic Intolerance; Postural Tachycardia Syndrome
• Intervention / Treatment: Drug: Carbidopa; Drug: Placebo

Detailed Description

We will determine whether inhibition of renal dopamine formation by carbidopa administration leads to a decrease in urinary excretion of dopamine and sodium and whether the response differs in POTS and control populations. Carbidopa effects will be compared to those of a matching placebo, and the sequence of treatments (carbidopa before placebo or placebo before carbidopa) will be randomized.

Each subject will undergo a complete history and physical examination, including an electrocardiogram (EKG).

• After achieving sodium balance on a 200 mEq/day sodium diet, subjects will collect urine over 24hr for baseline assessment of sodium and catecholamines.
• On this day, the subjects will be admitted to the CRC.
• An 18 gauge intravenous catheter will be inserted in order to draw blood.
• The subjects will fast from 7 pm until after the next morning's testing.
• In the morning, while still supine after the overnight sleep, heart rate and blood pressure will be recorded, and blood will be drawn. The subjects will then stand for 10 minutes. Heart rate and blood pressure will be measured at intervals, and an upright blood sample will be collected.
• The subjects will be asked to collect their urine to end the 24hr urine collection. Another 24hr urine collection will be started.
• Treatment A (Carbidopa 200mg or placebo) will be given orally following the void, at approximately 7 am. Additional doses will be taken every 6 hours with the last dose at 7 am the following morning.
• Subjects will be free to follow their normal routine during the day until returning to the CRC for the night. However, they will need to consume the 200 mEq/day study diet for each meal, collect all urine, and take study medication on schedule
• After returning to the CRC, the subjects will fast after 7 pm.
• In the morning, supine and standing heart rate and blood pressure will be recorded, and the subjects will be asked to collect their urine to end the 24hr urine collection.
• The final dose of study medication (Carbidopa 200mg or placebo) will be given orally following the void, at approximately 7 am.
• Supine heart rate and blood pressure will be measured and supine blood samples will be collected hourly for 4 hours after the treatment and at 8 hours after the treatment. Subjects must rest supine for at least 30 minutes before each blood draw.
• At 2 hours after treatment, subjects will stand for 10 minutes for upright blood pressure and heart rate measurements and collection of an upright blood sample, as described above. Participants will be asked to rate the severity of common orthostatic symptoms while supine and upright.
• Urine will be collected for two 4-hour periods after treatment and from 8 hours to 24 hours after treatment.
• Fixed-sodium study diet will be provided after the 4-hour measurements and in the evening.

After at least a 1 day washout period, the study will be repeated with Treatment B

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients diagnosed with POTS by the Vanderbilt Autonomic Dysfunction Center based on the following stringent criteria: 1) history of daily orthostatic symptoms for at least 6 months; 2) increase in heart rate (HR) of at least 30 bpm with standing or a standing HR of at least 120 bpm; 3) absence of orthostatic hypotension (defined as a fall in blood pressure (BP)>20/10 mm Hg); and 4) absence of conditions, such as dehydration, substantial weight loss, or systemic illnesses, that could provoke orthostatic intolerance
• Upright plasma NE at least 600 pg/mL in patients
• Non-smoking
• Free of medications with the potential to influence BP
• Able and willing to provide informed consent -

Exclusion Criteria:

• Overt cause for postural tachycardia (such as acute dehydration)
• Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or screening results
• Positive urine b-hcg pregnancy test
• Evidence of cardiac structural disease (by clinical examination or prior echocardiogram)
• Hypertension defined as a BP>145/95 (off medications) or need for antihypertensive medications
• Evidence of significant conduction system delay (QRS duration >120 ms) on electrocardiogram
• Inability to give, or withdraw, informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Carbidopa then Placebo; Carbidopa 200 mg every 6 hours orally for 5 doses followed by Placebo every 6 hours for 5 doses	Drug: Carbidopa; 200 mg every 6 hours for 5 doses given orally; Drug: Placebo; every 6 hours for 5 doses, given orally, and matching Carbidopa
EXPERIMENTAL: Placebo then Carbidopa; Placebo matching carbidopa given every 6 hours orally for 5 doses followed by Carbidopa	Drug: Carbidopa; 200 mg every 6 hours for 5 doses given orally; Drug: Placebo; every 6 hours for 5 doses, given orally, and matching Carbidopa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24 Hour Urinary Sodium Excretion During Treatment Normalized to Creatinine	Urine was collected for 24hr during treatment. Urinary volume was measured and the urine was analyzed for sodium and creatinine concentrations. Total amounts of sodium and creatinine excreted over the 24 hr were calculated and results expressed as ratio of sodium:creatinine.	Immediately before the 1st dose of placebo or carbidopa to immediately before the 5th dose (approximately 24 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure Measured at 8 Hours After the Last Dose of Placebo or Carbidopa	Systolic blood pressure was measured once using a Dinamap non-invasive oscillometric blood pressure monitor, 2-4 hours after lunch and after at least 30 minutes of resting supine.	8 hours after the last dose of placebo or carbidopa
Plasma Catecholamines (Norepinephrine) After the Last Dose of Placebo or Carbidopa	Blood samples were collected while resting supine for at least 30 minutes and 2 to 4 hours after lunch. For catecholamine measurements, blood was collected in chilled vacuum tubes with EDTA. Plasma was separated and stored with added reduced glutathione (Amersham International PLC) at -70°C until the assay. Plasma catecholamines were measured by a method that involves batch alumina extraction followed by high-performance liquid chromatography (HPLC) for separation with electrochemical detection and quantification.	8 hours after the last dose of placebo or carbidopa
Plasma Catecholamines (DOPA) After the Last Dose of Placebo or Carbidopa	Blood samples were collected while resting supine for at least 30 minutes and 2 to 4 hours after lunch. For catecholamine measurements, blood was collected in chilled vacuum tubes with EDTA. Plasma was separated and stored with added reduced glutathione (Amersham International PLC) at -70°C until the assay. Plasma catecholamines were measured by a method that involves batch alumina extraction followed by high-performance liquid chromatography (HPLC) for separation with electrochemical detection and quantification.	8 hours after the last dose of placebo or carbidopa
24 Hour Urinary Catecholamine (DOPA) Excretion During Treatment Normalized to Creatinine	Urine was collected over 24 hours during treatment. The urinary volume was measured and the urine was analyzed for creatinine and catecholamines. Total amounts of creatinine and catecholamines were calculated and the results are expressed as catecholamine:creatinine.	Immediately before the 1st dose of Placebo or Carbidopa and ending immediately before the last dose (approximately 24 hours)
24 Hour Urinary Catecholamine (Dopamine) Excretion During Treatment Normalized to Creatinine	Urine was collected over 24 hours during treatment. The urinary volume was measured and the urine was analyzed for creatinine and catecholamines. Total amounts of creatinine and catecholamines were calculated and the results are expressed as catecholamine:creatinine.	Immediately before the 1st dose of Placebo or Carbidopa and ending immediately before the last dose (approximately 24 hours)
Supine Plasma Renin Activity 2 Hours After the Last Dose of Placebo or Carbidopa	Blood samples were collected while resting supine for at least 30 minutes and 1 1/2 to 2 hours after breakfast. Samples were processed and sent to the Vanderbilt Clinic Laboratory for assay.	2 hours after the last dose of placebo or carbidopa
Plasma Sodium After the Last Dose of Placebo or Carbidopa	Blood samples were collected while resting supine for at least 30 minutes and 2 to 4 hours after lunch. Samples were processed and sent to the Vanderbilt Clinical Laboratory for assay.	8 hours after the last dose of placebo or carbidopa

Collaborators and Investigators

• Sponsor: Vanderbilt University

Publications and helpful links

General Publications

• Carey RM. Theodore Cooper Lecture: Renal dopamine system: paracrine regulator of sodium homeostasis and blood pressure. Hypertension. 2001 Sep;38(3):297-302. doi: 10.1161/hy0901.096422.
• Goldstein DS, Stull R, Eisenhofer G, Gill JR Jr. Urinary excretion of dihydroxyphenylalanine and dopamine during alterations of dietary salt intake in humans. Clin Sci (Lond). 1989 May;76(5):517-22. doi: 10.1042/cs0760517.
• Jose PA, Eisner GM, Felder RA. Renal dopamine and sodium homeostasis. Curr Hypertens Rep. 2000 Apr;2(2):174-83. doi: 10.1007/s11906-000-0079-y.
• Kuchel O, Buu NT, Unger T. Dopamine-sodium relationship: is dopamine a part of the endogenous natriuretic system? Contrib Nephrol. 1978;13:27-36. doi: 10.1159/000402132.
• Stokes GS, Monaghan JC, Pillai DN. Effects of carbidopa and of intravenous saline infusion into normal and hypertensive subjects on urinary free and conjugated dopamine. J Hypertens. 1997 Jul;15(7):761-8. doi: 10.1097/00004872-199715070-00008.
• Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system. Am J Med. 1997 Aug;103(2):128-33. doi: 10.1016/s0002-9343(97)00133-2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2008
• Primary Completion (ACTUAL): July 1, 2020
• Study Completion (ACTUAL): December 1, 2021

Study Registration Dates

• First Submitted: May 27, 2008
• First Submitted That Met QC Criteria: May 27, 2008
• First Posted (ESTIMATE): May 29, 2008

Study Record Updates

• Last Update Posted (ACTUAL): January 24, 2022
• Last Update Submitted That Met QC Criteria: January 14, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Dopamine; Natriuresis; Catecholamines
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Neurologic Manifestations; Disease; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Autonomic Nervous System Diseases; Primary Dysautonomias; Syndrome; Tachycardia; Postural Orthostatic Tachycardia Syndrome; Orthostatic Intolerance; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa
• Other Study ID Numbers: 101499; HL071784-05A1