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| ID | Type | Description | Link |
|---|---|---|---|
| 2R01HL060906 | U.S. NIH Grant/Contract | View source | |
| HL065193 | Other Grant/Funding Number | NIH | |
| UL1RR024975 | U.S. NIH Grant/Contract | View source | |
| 5R01HL085740-05 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Center for Research Resources (NCRR) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control (bradykinin infusion) | Experimental | Bradykinin (Clinalfa AG, Läufelfingen, Switzerland) |
|
| L-NMMA + bradykinin | Experimental | N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA) |
|
| Isosorbide + L-NMMA + bradykinin | Experimental | Isosorbide (NO donor) |
|
| Sildenafil + L-NMMA + bradykinin | Experimental | Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Control (bradykinin) | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Net Tissue-type Plasminogen Activator (t-PA) Release | Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. | During and after each study drug administration |
| Measure | Description | Time Frame |
|---|---|---|
| Forearm Blood Flow (FBF) | Forearm blood flow was measured by strain gauge plethysmography | During and after each study drug administration |
| Measure | Description | Time Frame |
|---|---|---|
| Net Glucose Uptake | Individual net reuptake rates at each time point were calculated by the following formula: net uptake = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of glucose in the brachial vein and artery, respectively. | At baseline and after maximum dose of bradykinin |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nancy J Brown, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center-GCRC | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19841473 | Result | Pretorius M, Brown NJ. Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. J Pharmacol Exp Ther. 2010 Jan;332(1):291-7. doi: 10.1124/jpet.109.160168. Epub 2009 Oct 19. |
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Subjects with renal, endocrine, hematological or cardiovascular disease (including hypertension defined as an untreated systolic/diastolic blood pressure greater than 140/90 mmHg were excluded. Subjects with a fasting cholesterol greater than 5.7 mmol/L (220 mg/dl) and smokers were excluded. No washout period was required for the study.
Subjects were recruited from a volunteer registry at Vanderbilt University. Subjects who participated in prior studies and requested to be contacted for future studies were included in the recruitment process. Recruitment began on 12/07 and stopped on 1/09.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Participants | 24 subjects received a bradykinin infusion and then a bradykinin + L-NMMA infusion. Subjects were then randomized to receive either isosorbide (N=12) or sildenafil (N=12). The infusion of bradykinin + L-NMMA was then repeated. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Control (Bradykinin Infusion) |
| |||||||||||||
| L-NMMA + Bradykinin |
| |||||||||||||
| Isosorbide + L-NMMA + Bradykinin |
| |||||||||||||
| Sildenafil + L-NMMA + Bradykinin |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Subjects characteristics for all 24 participants |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Net Tissue-type Plasminogen Activator (t-PA) Release | Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. | Twenty four subjects were studied. One subject was excluded because of erroneous drug administration. Analysis was per protocol. Twenty-three subjects receive bradykinin then L-NMMA plus bradykinin infusions. Subjects were then randomized to either isosorbide or sildenafil. Twelve subjects received sildenafil and 11 subjects received isosorbide. | Posted | Mean | Standard Error | ng/min/100ml | During and after each study drug administration |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Participants | Subjects characteristics for all 24 participants |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mias Pretorius | Vanderbilt University | 615-343-0665 | mias.pretorius@vanderbilt.edu |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D001920 | Bradykinin |
| D019323 | omega-N-Methylarginine |
| D007547 | Isosorbide |
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D007705 | Kinins |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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|
| L-NMMA + bradykinin | Drug | 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. |
|
|
| Isosorbide + L-NMMA + bradykinin | Drug | 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. |
|
| Sildenafil + L-NMMA + bradykinin | Drug | 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. |
|
|
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| L-NMMA + Control |
After the intial bradykinin infusion subjects then received a continuous infusion of L-NMMA plus bradykinin at 50, 100 and 200ng/min |
| OG002 | Isosorbide + L-NMMA + Control | Eleven of the twenty-four subjects were randomized to isosorbide after completing the bradykinin and bradykinin plus L-NMMA infusions. The bradykinin plus L-NMMA infusions were then repeated. |
| OG003 | Sildenafil + L-NMMA + Control | Twelve of the twenty-four subjects were randomized to sildenafil after completing the bradykinin and bradykinin plus L-NMMA infusions. After 1 hour, bradykinin plus L-NMMA infusions were repeated. |
|
|
|
| Secondary | Forearm Blood Flow (FBF) | Forearm blood flow was measured by strain gauge plethysmography | Posted | Mean | Standard Error | ml/min/100ml | During and after each study drug administration |
|
|
|
|
| Other Pre-specified | Net Glucose Uptake | Individual net reuptake rates at each time point were calculated by the following formula: net uptake = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of glucose in the brachial vein and artery, respectively. | Posted | Mean | Standard Error | microgram/min/100ml | At baseline and after maximum dose of bradykinin |
|
|
|
| 0 |
| 24 |
| 4 |
| 24 |
| fainted | Nervous system disorders | Systematic Assessment |
|
| unexpected drug response | Vascular disorders | Systematic Assessment |
|
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009479 | Neuropeptides |
| D009842 | Oligopeptides |
| D011506 | Proteins |
| D009419 | Nerve Tissue Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |
| D001120 | Arginine |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |
| D013012 | Sorbitol |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| FBF (bradykinin 50ng/min) |
|
| FBF (bradykinin 100ng/min) |
|
| FBF (bradykinin 200 ng/min) |
|
| Net glucose uptake (bradykinin 200 ng/min) |
|