Conditions: Obesity
Keywords: Bradykinin Obesity Nitric Oxide Donor tissue type plasminogen activator isosorbide dinitrate phosphodiesterase inhibitor Renin-Angiotensin Aldosterone System Fibrinolysis Angiotensin converting enzyme
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The purpose of the study is to determine if giving isosorbide,a drug that is used to treat chest pain, affects blood vessel release of an anti-clotting factor.

Detailed description:
To test the hypothesis that the administration of the NO donor isosorbide dinitrate,but not the phosphodiesterase inhibitor sildenafil, will attenuate stimulated vascular t-PA release whereas both agents will improve glucose uptake.

Arms:
arm 1: Bradykinin (Clinalfa AG, Läufelfingen, Switzerland) arm 2: N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA) arm 3: Isosorbide (NO donor) arm 4: Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor

Interventions: intervention 1: Control (bradykinin) intervention 2: L-NMMA + bradykinin intervention 3: Isosorbide + L-NMMA + bradykinin intervention 4: Sildenafil + L-NMMA + bradykinin
Intervention descriptions: intervention 1: Graded doses of bradykinin (Clinalfa AG, Läufelfingen, Switzerland) will be infused at 50, 100, and 200ng/min. Each dose will be infused for 5 minutes and FBF will measured during the last 2 minutes of infusion. Arterial and venous blood samples will be obtained for measurement of net t-PA release after each dose. intervention 2: Thirty minutes after administration of bradykinin a continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be started started. While continuing the infusion of L-NMMA, baseline measurements and infusion of bradykinin will be repeated. intervention 3: Following the second bradykinin infusion, 12 subjects will receive 5mg isosorbide dinitrate (an exogenous NO donor; Major Pharmaceuticals Inc, Livonia MI). Sixty minutes after the administration of isosorbide the continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be restarted and baseline measurements and bradykinin infusion will be repeated. intervention 4: Following the second bradykinin infusion, 12 subjects will receive 50mg sildenafil (phosphodiesterase type 5 (PDE5) inhibitor to increase cGMP without increasing NO; Pfizer, NY). Sixty minutes after the administration of sildenafil the continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be restarted and baseline measurements and bradykinin infusion will be repeated.

Protocol document: