Peripheral Dopamine 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.

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

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)

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.

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.

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.

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)

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)

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.

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.

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

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