The Autonomic Nervous System and Obesity
Condition: OBESITY; HYPERTENSION; PURE AUTONOMIC FAILURE; SHY-DRAGER SYNDROME
MeSH terms: Pure Autonomic Failure; Shy-Drager Syndrome; Multiple System Atrophy; Hypertension; Obesity
Study type: Interventional
Phase: Phase 1

Summary: 
      In its simplest terms, obesity is the results of a positive balance between food intake and
      energy expenditure (EE). I.e., we take in more energy, in the form of food, than we expend,
      e.g., by exercise. In our sedentary society, resting EE accounts for most of total energy
      expenditure. The sympathetic nervous system (SNS, the one that produces adrenaline) is
      thought to contribute to resting EE. This conclusion is based on experiments where resting EE
      is decreased by beta-blockers, high blood pressure medicines that block only one aspect of
      the sympathetic nervous system. The investigators propose to use a different approach, by
      using a medication called trimethaphan that produces transient withdrawal of the autonomic
      nervous system. The investigators will then compare the measured resting EE before and after
      SNS withdraw and quantify the degree of contribution to the resting EE by the SNS and
      delineate differences between healthy normal, healthy obese, and patients with autonomic
      dysfunctions.
    

Detailed description: 
      The rationale for this study is that even small alterations to energy metabolism can
      significantly change energy balance and body weight in the long term. We will test the
      hypothesis that the sympathetic nervous system (SNS) activity contributes to resting and
      thermogenic components of energy expenditure (EE).

      This study is divided in four different parts: (1), (2), (3), (4).

      Part (1): we will gauge the contribution of the sympathetic nervous system to resting energy
      expenditure, blood pressure, and determine differences between lean, obese, and patients with
      primary autonomic failure .

      Part (2): we will determine the degree of sympathetic blockade by a gradual infusion of the
      ganglionic blocker trimethaphan.[Part 2 has been closed]

      Part (3): we will determine the energy balance in patients with primary autonomic failure.

      Part (4): we will determine the contribution of the sympathetic nervous system to
      lipolysis.[Part 4 has been closed]

      Subjects selections*:

      For part (1) and (2) we will study six groups of subjects (n = 40 for each group): patients
      with pure autonomic failure, patients with multiple system atrophy, healthy normal controls
      (BMI <= 25), obese controls (BMI 30-40) and obese hypertensive (BMI 30-40) and lean
      hypertensive (BMI 20-28). A time interval of at least 1 week is required for those subjects
      who wish to participate in part (1) and part (2). For part (3) we will study two groups of
      subjects (n=12 for each group): patients with autonomic failure, and their age sex-matched
      sedentary, healthy controls. For part (4) we will study two groups of subjects (n=12 for each
      group): healthy normal controls (BMI 20-25), obese controls (BMI 30-40).

      *Part 2 and 4 have been closed.
    

Intervention name(s): Trimethaphan; Trimethaphan; Pseudoephedrine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Start dose: 0.05 ml/min (0.5 mg/min), IV infusion. The dose will be increased every 2-4 minutes to 1, 2, 4, and 5 mg/min. Total duration: 1 hour; Start dose: 0.05 ml/min (0.5 mg/min), IV infusion. The dose will be increased every 30 minutes to 1, 2, 4, and 5 mg/min. Total duration: 1-2 hours; 30mg tablet,VO. Single dose.
Other intervention name(s): Sudafed
Intervention MeSH terms: Trimethaphan; Pseudoephedrine; Ephedrine; Trimethaphan camsylate
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: OBESITY; RESTING ENERGY EXPENDITURE; SYMPATHETIC NERVOUS SYSTEM; HYPERTENSION; AUTONOMIC FAILURE