<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02966665</url>
  </required_header>
  <id_info>
    <org_study_id>IRB_00030810</org_study_id>
    <nct_id>NCT02966665</nct_id>
  </id_info>
  <brief_title>: Vascular Function in Health and Disease</brief_title>
  <official_title>Vascular Function in Health &amp; Disease: Rehabilitation for Hypertension; Exercise and Skeletal Muscle Afferent Feedback</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Russell Richardson</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Many control mechanisms exist which successfully match the supply of blood with the metabolic&#xD;
      demand of various tissues under wide-ranging conditions. One primary regulator of vasomotion&#xD;
      and thus perfusion to the muscle tissue is the host of chemical factors originating from the&#xD;
      vascular endothelium and the muscle tissue, which collectively sets the level of vascular&#xD;
      tone. With advancing age and in many disease states, deleterious adaptations in the&#xD;
      production and sensitivity of these vasodilator and vasoconstrictor substances may be&#xD;
      observed, leading to a reduction in skeletal muscle blood flow and compromised perfusion to&#xD;
      the muscle tissue. Adequate perfusion is particularly important during exercise to meet the&#xD;
      increased metabolic demand of the exercising tissue, and thus any condition that reduces&#xD;
      tissue perfusion may limit the capacity for physical activity. As it is now well established&#xD;
      that regular physical activity is a key component in maintaining cardiovascular health with&#xD;
      advancing age, there is a clear need for further studies in populations where vascular&#xD;
      dysfunction is compromised, with the goal of identifying the mechanisms responsible for the&#xD;
      dysfunction and exploring whether these maladaptations may be remediable. Thus, to better&#xD;
      understand the etiology of these vascular adaptations in health and disease, the current&#xD;
      proposal is designed to study changes in vascular function with advancing age, and also&#xD;
      examine peripheral vascular changes in patients suffering from chronic obstructive pulmonary&#xD;
      disease (COPD), Sepsis, Pulmonary Hypertension, and cardiovascular disease. While there are&#xD;
      clearly a host of vasoactive substances which collectively act to govern vasoconstriction&#xD;
      both at rest and during exercise, four specific pathways that may be implicated have been&#xD;
      identified in these populations: Angiotensin-II (ANG-II), Endothelin-1 (ET-1), Nitric Oxide&#xD;
      (NO), and oxidative stress.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Angiotensin-II (ANG-II) is the end-product of the renin-angiotensin cascade, and acts as a&#xD;
      potent endogenous vasoconstrictor through binding to the angiotensin receptor (AT1) on&#xD;
      arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma&#xD;
      renin activity accompanied by decrements in circulating ANG-II and an increase in AT1&#xD;
      receptor density. However, the functional consequence of this age-related adaptation of the&#xD;
      renin-angiotensin system (RAS) on the peripheral circulation is not well understood.&#xD;
      Likewise, in recent years it has become apparent that cardiovascular disease is a major cause&#xD;
      of morbidity in COPD, which may be related to vascular dysfunction and associated adoption of&#xD;
      a sedentary lifestyle. In these patients, changes in RAS activity have been linked to&#xD;
      peripheral vascular dysfunction, with compelling evidence for improvements in peripheral&#xD;
      oxygen use following angiotensin-converting enzyme (ACE) inhibition. Like the aging&#xD;
      population, systematic studies evaluating AT1 receptor sensitivity and the efficacy of AT1&#xD;
      receptor blockade on peripheral hemodynamics have not been undertaken.&#xD;
&#xD;
      The ubiquitous substance nitric oxide (NO) is now recognized as a key pathway for&#xD;
      endothelium-dependent vasodilation, with the bioavailability of NO serving as an indicator&#xD;
      for overall vascular health. Cardiac risk factors have been shown to cause impairment in&#xD;
      endothelial vasodilator function in both the peripheral and coronary arteries. Coronary&#xD;
      vascular dysfunction is an important phase in atherogenesis and is associated with myocardial&#xD;
      ischemia. Furthermore, peripheral vascular function has been linked to coronary vascular&#xD;
      dysfunction which could have important clinical implications in terms of health screening.&#xD;
      Impaired endothelium-dependent vasodilation has been associated with the elderly, patients&#xD;
      with COPD, and most cardiovascular diseases including pulmonary hypertension, and heart&#xD;
      failure (HF), though the functional consequence of this adaptation on peripheral blood flow&#xD;
      regulation remains unclear. Thus, we propose the use of a compound which inhibits the enzyme&#xD;
      responsible for NO production in endothelial cells, N-monomethyl-L-arginine (L-NMMA), to&#xD;
      temporarily block production of NO and thus determine the importance of this pathway at rest&#xD;
      and during physical activity. Additionally, we propose the use of acetylcholine (Ach) to&#xD;
      determine endothelial-dependent vasodilation and sodium nitroprusside (SNP) and nitroglycerin&#xD;
      (NTG) to determine the endothelial-independent vasodilation in the coronary arteries and the&#xD;
      periphery. Oxidative stress associated with aging has been shown to reduce vascular function&#xD;
      and antioxidant supplementation restores vascular function to levels that are&#xD;
      indistinguishable from healthy young adults. The manner by which this improvement in vascular&#xD;
      function occurs is not known by may be acting through a NO dependent mechanism.&#xD;
&#xD;
      Histamine has been reported to mediate sustained post-exercise vasodilation through&#xD;
      histamine-1 (H1) and histamine-2 (H2) receptor activity, which results in a ~50% elevation in&#xD;
      femoral artery blood flow (above resting levels) that lasts for more than 100 minutes after a&#xD;
      single bout of moderate-intensity dynamic exercise. Vasodilation can be markedly reduced by&#xD;
      giving either fexofenadine (Allegra, a selective H1-receptor antagonist) or ranitidine&#xD;
      (Zantac, a selective H2-receptor antagonist). The combination of H1/H2 blockade abolishes&#xD;
      ~80% of the post-exercise vasodilation seen after whole-body exercise such as cycling and&#xD;
      this observation has been observed in multiple studies in young sedentary, recreationally&#xD;
      active, and endurance trained men and women. The impact of histamine on the post-exercise&#xD;
      vasodilatory response is substantial; however, the role of H1/H2 receptors in regulating&#xD;
      skeletal muscle blood flow during exercise is unknown. Thus, we intend to investigate the&#xD;
      role of H1/H2 receptors in the regulation of skeletal muscle blood during exercise as this&#xD;
      may be an important pathway in age and disease related reductions in blood flow during&#xD;
      exercise.&#xD;
&#xD;
      Exercise training and rehabilitation can be used as an alternative approach to combat the&#xD;
      deleterious effects oxidative stress on aging and disease. An effective exercise training&#xD;
      intervention can decrease sympathetic nervous system activity, improve arterial compliance&#xD;
      and vascular endothelial function, and alter the pro- and antioxidant balance resulting in&#xD;
      improved endogenous antioxidant defense mechanisms. Moreover, exercise training concomitantly&#xD;
      improves musculoskeletal strength and function, glucose regulation and insulin sensitivity,&#xD;
      cardiovascular function, body composition, blood chemistry (decreased triglyceride and&#xD;
      cholesterol levels), and overall well-being. The physiologic effect of an exercise&#xD;
      rehabilitation program in diseases such as COPD, and pulmonary arterial hypertension (PAH) is&#xD;
      incompletely understood. However, recent studies suggest that exercise training in this&#xD;
      patient population is well tolerated and associated with clinically significant physiologic&#xD;
      improvements as well as improvements in various quality of life scores.&#xD;
&#xD;
      A unique feature of the proposed studies identified herein is the inclusion of a novel&#xD;
      methodological approach to comprehensively evaluate the functional outcome of the proposed&#xD;
      pharmacologic interventions. The recent development of a unique combination of nuclear&#xD;
      magnetic resonance (NMR) techniques by members of our group enables near-simultaneous&#xD;
      measurements of both muscle perfusion and metabolism in vivo. The arterial spin labeling&#xD;
      (ASL) technique allows the measurement of both spatially and temporally resolved&#xD;
      quantification of perfusion, while the kinetics of phosphocreatine (PCr) depletion and&#xD;
      recovery provide high resolution measurements of muscle energetics. The interweaving of these&#xD;
      imaging and spectroscopic modules provides the opportunity for determination of skeletal&#xD;
      muscle perfusion and metabolism kinetics during and following the stress of physical&#xD;
      exercise. Thus, this NMR-based approach, combined with direct measures of muscle fatigue,&#xD;
      offers the potential to further define the individual and collective contribution of these&#xD;
      variables to the attenuated limb blood flow in the elderly and in patients with COPD and PAH.&#xD;
&#xD;
      We propose that each of these pathways outlined above represent an avenue by which vascular&#xD;
      function is compromised in the elderly and in patients with COPD, PAH and cardiovascular&#xD;
      disease. However, because these pathways are not mutually exclusive, the proposed studies are&#xD;
      designed to systematically evaluate hemodynamic responses to intra-arterial or intravenous&#xD;
      administration of pharmacologic agents specific for the AT1 receptor (ANG-II and Diovan, AT1&#xD;
      agonist and antagonist, respectively), the Endothelin receptor Type-A (ETA receptor) (BQ-123,&#xD;
      ETA antagonist), and the NO pathway (L-NMMA, Ach, and SNP) both before and after exercise&#xD;
      training.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>September 2008</start_date>
  <completion_date type="Anticipated">August 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Limb Blood Flow</measure>
    <time_frame>Baseline and 1 hour</time_frame>
    <description>Change in local limb blood flow as measured by ultrasound Doppler in units of milliliters per minute (mL/min) from baseline to up to 1 hour following study interventions</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Blood Pressure</measure>
    <time_frame>Baseline and 1 hour</time_frame>
    <description>Change in local limb blood pressure measured in millimeters of mercury (mmHg) from baseline to up to 1 hour following study interventions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Maximum Exercise Capacity</measure>
    <time_frame>Baseline and 1 hour</time_frame>
    <description>Change in maximal exercise capacity - handgrip strength measured by dynamometer in units of kilograms from baseline to up to 1 hour following study interventions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Peak Rate of Mitochondrial Adenosine Triphosphate (ATP) Synthesis</measure>
    <time_frame>Baseline and 1 hour</time_frame>
    <description>Change in muscle peak rate of mitochondrial ATP synthesis as measured by 31P-magnetic resonance spectroscopy (31P-MRS) from baseline up to 1 hour following study interventions</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Anticipated">420</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <condition>Pulmonary Artery Hypertension</condition>
  <condition>Heart Failure</condition>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Healthy volunteers between the ages of 18 and 30 years with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Healthy volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients undergoing routine coronary angiography, but who do not require intracoronary procedures or have history of myocardial disease, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients diagnosed with mild to moderate COPD, but not severe COPD patients, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with idiopathic or heritable Group 1 pulmonary arterial hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with Class I - III New York Heart Association symptoms of Heart Failure who are not anemic or taking medications that affect blood clotting, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with chronic high blood pressure, but with less than severe hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Maximum Exercise Tests</intervention_name>
    <description>Graded exercise test to volitional exhaustion (stationary bike or treadmill), maximal handgrip test, maximal leg extension test, and maximal plantar flexion test.</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, passive leg movement test, exercise bouts, electromyography and exercise training regimen at baseline and following treatment with Nitric Oxide blockade via infusion of N-monomethyl-L-arginine (L-NMMA) (0.4 mg/kg/min), antioxidant cocktail (Vitamin C, Vitamin E, alpha-lipoic acid) ingestion, L-ascorbate injection, BH4 ingestion.</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BQ-123</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with endothelin-1 receptor antagonist BQ-123 (D-tryptamine-D-aspartic acid-L-proline-D-valine-L-leucine).</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fexofenadine, Ranitidine</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with Histamine H1 receptor antagonist fexofenadine (Allegra) and Histamine H2 receptor antagonist ranitidine (Zantac).</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
    <other_name>Allegra</other_name>
    <other_name>Zantac</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Angiotensin-II, Valsartan</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement, and exercise bouts at baseline and following treatment with Angiotensin-II receptor agonist (angiotensin-II) and antagonist Valsartan (Diovan).</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
    <other_name>Diovan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement; vasodilation with nitroglycerin followed by Angiotensin-II and Alpha Adrenergic blockade with infusions of Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine and Phentolamine (Regitine).</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
    <other_name>Regitine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BQ-123, MitoQ, BH4</intervention_name>
    <description>Catheter placement in femoral artery and femoral vein and muscle biopsy; Nuclear Magnetic Resonance (NMR) scanning and exercise bouts at baseline and following treatment with BQ-123 with or without oral mitochondria-targeted antioxidant (MitoQ) or oral BH4.</description>
    <arm_group_label>Chronic Obstructive Pulmonary Disease patients</arm_group_label>
    <arm_group_label>Coronary Angiography patients</arm_group_label>
    <arm_group_label>Healthy Older Controls (over 65 years)</arm_group_label>
    <arm_group_label>Healthy Young Volunteers (18-30 years)</arm_group_label>
    <arm_group_label>Heart Failure patients</arm_group_label>
    <arm_group_label>Hypertension patients</arm_group_label>
    <arm_group_label>Pulmonary Arterial Hypertension patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy Young Volunteers: 18-30 years of age with no diseases or conditions that would&#xD;
             affect their participation in the study&#xD;
&#xD;
          -  Healthy Older Controls: volunteers 65 years of age or older with no diseases or&#xD;
             conditions that would affect their participation in the study&#xD;
&#xD;
          -  Coronary Angiography subjects: patients undergoing routine coronary angiography&#xD;
&#xD;
          -  Chronic Obstructive Pulmonary Disease subjects: patients diagnosed with mild to&#xD;
             moderate COPD&#xD;
&#xD;
          -  Pulmonary Arterial Hypertension subjects: patients with idiopathic or heritable Group&#xD;
             1 pulmonary arterial hypertension&#xD;
&#xD;
          -  Heart Failure subjects: patients with Class I, II or III New York Heart Association&#xD;
             symptoms of Heart Failure&#xD;
&#xD;
          -  Hypertension subjects: patients diagnosed with chronic high blood pressure&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe COPD (use of supplemental oxygen, or have a one-second forced expiratory volume&#xD;
             of less than 30% predicted)&#xD;
&#xD;
          -  History of myocardial infarction&#xD;
&#xD;
          -  History of percutaneous coronary revascularization&#xD;
&#xD;
          -  History of coronary artery bypass grafting&#xD;
&#xD;
          -  Unstable angina pectoris&#xD;
&#xD;
          -  History of variant angina&#xD;
&#xD;
          -  Ejection fraction &lt; 50%&#xD;
&#xD;
          -  Significant renal disease (Glomerular Filtration Rate &lt; 50 mL/min/1.73m2)&#xD;
&#xD;
          -  Subjects whose medical care or safety may be at risk from undergoing a Magnetic&#xD;
             Resonance Imaging examination (e.g. pacemaker, metal implants, certain types of heart&#xD;
             valves)&#xD;
&#xD;
          -  Subject is pregnant&#xD;
&#xD;
          -  Subject has physical ailments (other than COPD, PAH, HF, or hypertension) that would&#xD;
             prevent them from study participation in the judgment of the investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Russell Richardson, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>George E Wahlen VA Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maydeen Ogara</last_name>
    <phone>801-584-2522</phone>
    <email>maydeen.ogara@hsc.utah.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>George E Wahlen VA Medical Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Russell Richardson, Ph.D.</last_name>
      <phone>801-582-1565</phone>
      <email>r.richardson@hsc.utah.edu</email>
    </contact>
    <contact_backup>
      <last_name>Ashley Nelson, MD</last_name>
      <phone>801-582-1565</phone>
      <phone_ext>4127</phone_ext>
      <email>ash.nelson@hsc.utah.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>October 19, 2016</study_first_submitted>
  <study_first_submitted_qc>November 14, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 17, 2016</study_first_posted>
  <last_update_submitted>October 3, 2022</last_update_submitted>
  <last_update_submitted_qc>October 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Utah</investigator_affiliation>
    <investigator_full_name>Russell Richardson</investigator_full_name>
    <investigator_title>Ph.D.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamins</mesh_term>
    <mesh_term>Vitamin E</mesh_term>
    <mesh_term>Thioctic Acid</mesh_term>
    <mesh_term>Fexofenadine</mesh_term>
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Nitroprusside</mesh_term>
    <mesh_term>Phentolamine</mesh_term>
    <mesh_term>cyclo(Trp-Asp-Pro-Val-Leu)</mesh_term>
    <mesh_term>Norepinephrine</mesh_term>
    <mesh_term>Angiotensin II</mesh_term>
    <mesh_term>Giapreza</mesh_term>
    <mesh_term>Acetylcholine</mesh_term>
    <mesh_term>Ranitidine</mesh_term>
    <mesh_term>Angiotensinogen</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02966665
org study id: IRB_00030810
nct id: NCT02966665
lead sponsor: 
has dmc: No
Many control mechanisms exist which successfully match the supply of blood with the metabolic
      demand of various tissues under wide-ranging conditions. One primary regulator of vasomotion
      and thus perfusion to the muscle tissue is the host of chemical factors originating from the
      vascular endothelium and the muscle tissue, which collectively sets the level of vascular
      tone. With advancing age and in many disease states, deleterious adaptations in the
      production and sensitivity of these vasodilator and vasoconstrictor substances may be
      observed, leading to a reduction in skeletal muscle blood flow and compromised perfusion to
      the muscle tissue. Adequate perfusion is particularly important during exercise to meet the
      increased metabolic demand of the exercising tissue, and thus any condition that reduces
      tissue perfusion may limit the capacity for physical activity. As it is now well established
      that regular physical activity is a key component in maintaining cardiovascular health with
      advancing age, there is a clear need for further studies in populations where vascular
      dysfunction is compromised, with the goal of identifying the mechanisms responsible for the
      dysfunction and exploring whether these maladaptations may be remediable. Thus, to better
      understand the etiology of these vascular adaptations in health and disease, the current
      proposal is designed to study changes in vascular function with advancing age, and also
      examine peripheral vascular changes in patients suffering from chronic obstructive pulmonary
      disease (COPD), Sepsis, Pulmonary Hypertension, and cardiovascular disease. While there are
      clearly a host of vasoactive substances which collectively act to govern vasoconstriction
      both at rest and during exercise, four specific pathways that may be implicated have been
      identified in these populations: Angiotensin-II (ANG-II), Endothelin-1 (ET-1), Nitric Oxide
      (NO), and oxidative stress.
Angiotensin-II (ANG-II) is the end-product of the renin-angiotensin cascade, and acts as a
      potent endogenous vasoconstrictor through binding to the angiotensin receptor (AT1) on
      arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma
      renin activity accompanied by decrements in circulating ANG-II and an increase in AT1
      receptor density. However, the functional consequence of this age-related adaptation of the
      renin-angiotensin system (RAS) on the peripheral circulation is not well understood.
      Likewise, in recent years it has become apparent that cardiovascular disease is a major cause
      of morbidity in COPD, which may be related to vascular dysfunction and associated adoption of
      a sedentary lifestyle. In these patients, changes in RAS activity have been linked to
      peripheral vascular dysfunction, with compelling evidence for improvements in peripheral
      oxygen use following angiotensin-converting enzyme (ACE) inhibition. Like the aging
      population, systematic studies evaluating AT1 receptor sensitivity and the efficacy of AT1
      receptor blockade on peripheral hemodynamics have not been undertaken.

      The ubiquitous substance nitric oxide (NO) is now recognized as a key pathway for
      endothelium-dependent vasodilation, with the bioavailability of NO serving as an indicator
      for overall vascular health. Cardiac risk factors have been shown to cause impairment in
      endothelial vasodilator function in both the peripheral and coronary arteries. Coronary
      vascular dysfunction is an important phase in atherogenesis and is associated with myocardial
      ischemia. Furthermore, peripheral vascular function has been linked to coronary vascular
      dysfunction which could have important clinical implications in terms of health screening.
      Impaired endothelium-dependent vasodilation has been associated with the elderly, patients
      with COPD, and most cardiovascular diseases including pulmonary hypertension, and heart
      failure (HF), though the functional consequence of this adaptation on peripheral blood flow
      regulation remains unclear. Thus, we propose the use of a compound which inhibits the enzyme
      responsible for NO production in endothelial cells, N-monomethyl-L-arginine (L-NMMA), to
      temporarily block production of NO and thus determine the importance of this pathway at rest
      and during physical activity. Additionally, we propose the use of acetylcholine (Ach) to
      determine endothelial-dependent vasodilation and sodium nitroprusside (SNP) and nitroglycerin
      (NTG) to determine the endothelial-independent vasodilation in the coronary arteries and the
      periphery. Oxidative stress associated with aging has been shown to reduce vascular function
      and antioxidant supplementation restores vascular function to levels that are
      indistinguishable from healthy young adults. The manner by which this improvement in vascular
      function occurs is not known by may be acting through a NO dependent mechanism.

      Histamine has been reported to mediate sustained post-exercise vasodilation through
      histamine-1 (H1) and histamine-2 (H2) receptor activity, which results in a ~50% elevation in
      femoral artery blood flow (above resting levels) that lasts for more than 100 minutes after a
      single bout of moderate-intensity dynamic exercise. Vasodilation can be markedly reduced by
      giving either fexofenadine (Allegra, a selective H1-receptor antagonist) or ranitidine
      (Zantac, a selective H2-receptor antagonist). The combination of H1/H2 blockade abolishes
      ~80% of the post-exercise vasodilation seen after whole-body exercise such as cycling and
      this observation has been observed in multiple studies in young sedentary, recreationally
      active, and endurance trained men and women. The impact of histamine on the post-exercise
      vasodilatory response is substantial; however, the role of H1/H2 receptors in regulating
      skeletal muscle blood flow during exercise is unknown. Thus, we intend to investigate the
      role of H1/H2 receptors in the regulation of skeletal muscle blood during exercise as this
      may be an important pathway in age and disease related reductions in blood flow during
      exercise.

      Exercise training and rehabilitation can be used as an alternative approach to combat the
      deleterious effects oxidative stress on aging and disease. An effective exercise training
      intervention can decrease sympathetic nervous system activity, improve arterial compliance
      and vascular endothelial function, and alter the pro- and antioxidant balance resulting in
      improved endogenous antioxidant defense mechanisms. Moreover, exercise training concomitantly
      improves musculoskeletal strength and function, glucose regulation and insulin sensitivity,
      cardiovascular function, body composition, blood chemistry (decreased triglyceride and
      cholesterol levels), and overall well-being. The physiologic effect of an exercise
      rehabilitation program in diseases such as COPD, and pulmonary arterial hypertension (PAH) is
      incompletely understood. However, recent studies suggest that exercise training in this
      patient population is well tolerated and associated with clinically significant physiologic
      improvements as well as improvements in various quality of life scores.

      A unique feature of the proposed studies identified herein is the inclusion of a novel
      methodological approach to comprehensively evaluate the functional outcome of the proposed
      pharmacologic interventions. The recent development of a unique combination of nuclear
      magnetic resonance (NMR) techniques by members of our group enables near-simultaneous
      measurements of both muscle perfusion and metabolism in vivo. The arterial spin labeling
      (ASL) technique allows the measurement of both spatially and temporally resolved
      quantification of perfusion, while the kinetics of phosphocreatine (PCr) depletion and
      recovery provide high resolution measurements of muscle energetics. The interweaving of these
      imaging and spectroscopic modules provides the opportunity for determination of skeletal
      muscle perfusion and metabolism kinetics during and following the stress of physical
      exercise. Thus, this NMR-based approach, combined with direct measures of muscle fatigue,
      offers the potential to further define the individual and collective contribution of these
      variables to the attenuated limb blood flow in the elderly and in patients with COPD and PAH.

      We propose that each of these pathways outlined above represent an avenue by which vascular
      function is compromised in the elderly and in patients with COPD, PAH and cardiovascular
      disease. However, because these pathways are not mutually exclusive, the proposed studies are
      designed to systematically evaluate hemodynamic responses to intra-arterial or intravenous
      administration of pharmacologic agents specific for the AT1 receptor (ANG-II and Diovan, AT1
      agonist and antagonist, respectively), the Endothelin receptor Type-A (ETA receptor) (BQ-123,
      ETA antagonist), and the NO pathway (L-NMMA, Ach, and SNP) both before and after exercise
      training.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in Limb Blood Flow
time frame: Baseline and 1 hour
description: Change in local limb blood flow as measured by ultrasound Doppler in units of milliliters per minute (mL/min) from baseline to up to 1 hour following study interventions
measure: Change in Blood Pressure
time frame: Baseline and 1 hour
description: Change in local limb blood pressure measured in millimeters of mercury (mmHg) from baseline to up to 1 hour following study interventions
measure: Change in Maximum Exercise Capacity
time frame: Baseline and 1 hour
description: Change in maximal exercise capacity - handgrip strength measured by dynamometer in units of kilograms from baseline to up to 1 hour following study interventions
measure: Change in Peak Rate of Mitochondrial Adenosine Triphosphate (ATP) Synthesis
time frame: Baseline and 1 hour
description: Change in muscle peak rate of mitochondrial ATP synthesis as measured by 31P-magnetic resonance spectroscopy (31P-MRS) from baseline up to 1 hour following study interventions
arm group label: Healthy Young Volunteers (18-30 years)
arm group type: Experimental
description: Healthy volunteers between the ages of 18 and 30 years with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Healthy Older Controls (over 65 years)
arm group type: Experimental
description: Healthy volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Coronary Angiography patients
arm group type: Experimental
description: Patients undergoing routine coronary angiography, but who do not require intracoronary procedures or have history of myocardial disease, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group type: Experimental
description: Patients diagnosed with mild to moderate COPD, but not severe COPD patients, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Pulmonary Arterial Hypertension patients
arm group type: Experimental
description: Patients with idiopathic or heritable Group 1 pulmonary arterial hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Heart Failure patients
arm group type: Experimental
description: Patients with Class I - III New York Heart Association symptoms of Heart Failure who are not anemic or taking medications that affect blood clotting, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
arm group label: Hypertension patients
arm group type: Experimental
description: Patients with chronic high blood pressure, but with less than severe hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.
intervention type: Other
intervention name: Maximum Exercise Tests
description: Graded exercise test to volitional exhaustion (stationary bike or treadmill), maximal handgrip test, maximal leg extension test, and maximal plantar flexion test.
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
intervention type: Drug
intervention name: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate
description: Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, passive leg movement test, exercise bouts, electromyography and exercise training regimen at baseline and following treatment with Nitric Oxide blockade via infusion of N-monomethyl-L-arginine (L-NMMA) (0.4 mg/kg/min), antioxidant cocktail (Vitamin C, Vitamin E, alpha-lipoic acid) ingestion, L-ascorbate injection, BH4 ingestion.
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
intervention type: Drug
intervention name: BQ-123
description: Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with endothelin-1 receptor antagonist BQ-123 (D-tryptamine-D-aspartic acid-L-proline-D-valine-L-leucine).
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
intervention type: Drug
intervention name: Fexofenadine, Ranitidine
description: Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with Histamine H1 receptor antagonist fexofenadine (Allegra) and Histamine H2 receptor antagonist ranitidine (Zantac).
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
other name: Allegra
other name: Zantac
intervention type: Other
intervention name: Angiotensin-II, Valsartan
description: Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement, and exercise bouts at baseline and following treatment with Angiotensin-II receptor agonist (angiotensin-II) and antagonist Valsartan (Diovan).
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
other name: Diovan
intervention type: Drug
intervention name: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine
description: Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement; vasodilation with nitroglycerin followed by Angiotensin-II and Alpha Adrenergic blockade with infusions of Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine and Phentolamine (Regitine).
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
other name: Regitine
intervention type: Drug
intervention name: BQ-123, MitoQ, BH4
description: Catheter placement in femoral artery and femoral vein and muscle biopsy; Nuclear Magnetic Resonance (NMR) scanning and exercise bouts at baseline and following treatment with BQ-123 with or without oral mitochondria-targeted antioxidant (MitoQ) or oral BH4.
arm group label: Chronic Obstructive Pulmonary Disease patients
arm group label: Coronary Angiography patients
arm group label: Healthy Older Controls (over 65 years)
arm group label: Healthy Young Volunteers (18-30 years)
arm group label: Heart Failure patients
arm group label: Hypertension patients
arm group label: Pulmonary Arterial Hypertension patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Russell Richardson, Ph.D.
role: Principal Investigator
affiliation: George E Wahlen VA Medical Center
last name: Maydeen Ogara
phone: 801-584-2522
email: maydeen.ogara@hsc.utah.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Utah
investigator full name: Russell Richardson
investigator title: Ph.D.
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Pulmonary Arterial Hypertension
mesh term: Hypertension
mesh term: Vitamins
mesh term: Vitamin E
mesh term: Thioctic Acid
mesh term: Fexofenadine
mesh term: Valsartan
mesh term: Nitroprusside
mesh term: Phentolamine
mesh term: cyclo(Trp-Asp-Pro-Val-Leu)
mesh term: Norepinephrine
mesh term: Angiotensin II
mesh term: Giapreza
mesh term: Acetylcholine
mesh term: Ranitidine
mesh term: Angiotensinogen
sharing ipd: No