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Impairment of the heart's pumping capacity (heart failure) remains a major clinical problem with a poor prognosis and the search for novel treatments remains an important area of research.
Urocortins are proteins that appear to increase blood flow and heart pumping activity. There has been particular interest in the role of Urocortins 2 & 3 (subtypes of Urocortins) in heart failure.
In this study, we will examine the effects and mechanisms of Urocortins 2 & 3 and the Corticotrophin Releasing Hormone Receptor Type 2 (CRH-R2) receptor (through which urocortins act) on forearm blood flow and release of natural blood clot dissolving factors in the forearm circulation of healthy volunteers.
In this study, we will look at the role of the lining of the blood vessel (endothelium) in response to urocortin types 2 and 3. We hypothesise that urocortins 2 & 3 act via the endothelium to cause dilatation of the blood vessels and release of tissue-plasminogen activating factor (blood clot dissolving factor). We also hypothesise that urocortins have a role in maintaining the normal baseline level of blood flow in forearm arteries. In addition to the above, we will also look at the effect of temporarily blocking the effect of urocortins, using a specially designed blocker drug (Astressin 2B).
Utilising the well-established technique of 'forearm venous occlusion plethysmography', we will be able to focus on the local effects of urocortins on arterial blood flow in forearm vessels, without affecting this system in the body as a whole.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Astressin 2B | Experimental | Healthy volunteers will receive incremental doses of intra arterial Astressin 2B (a selective and potent Urocortin 2 & 3 antagonist). This serves as a dose finding Protocol for Astressin 2B, which will be used in subsequent protocols. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Astressin 2B | Drug | After an initial saline washout, increasing doses of Astressin 2B (at 0.032, 0.32, 3.2, 32, 320 and 3200 pmol/min) will be infused, for 10 minutes at each dose,intra arterially using forearm venous occlusion plethysmography. Forearm blood flow will be measured with each incremental dose of Astressin 2B. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in forearm blood flow | Absolute change in forearm blood flow with respect to baseline forearm blood flow resulting from infusion of the study drugs, using forearm venous occlusion plethysmography | 3 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Principle safety assessment, heart rate and blood pressure | 3 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David E Newby, PhD FRCP | University of Edinburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wellcome Trust Clinical Research Facility, Royal Infirmary of Edinburgh | Edinburgh | Mid Lothian | EH16 4SA | United Kingdom |
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| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D006331 | Heart Diseases |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
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