Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers (Protocol 3)
Condition: Vascular Disease; Heart Disease
MeSH terms: Heart Diseases; Vascular Diseases
Study type: Interventional

Summary: 
      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 on forearm
      blood flow and release of natural blood clot dissolving factors in the forearm circulation of
      healthy volunteers. In particular, we look at the endothelial mechanisms of vasodilatation of
      Urocortin 2 and 3.

      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.
    


Intervention name(s): NO clamp; Saline; Fluconazole; Aspirin; Combined
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence or the absence of the 'nitric oxide clamp' that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study.
Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent calculation of net release of t-PA and PAI-1.; After a 20 minute saline washout, incremental doses of Urocortin 2, Urocortin 3 and Substance P (in doses as per Protocol 2) will be infused in the presence of saline placebo.
Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent calculation of net release of t-PA and PAI-1.; After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of Fluconazole (which serves to inhibit the EDHF pathway) that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study.
Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function, plasma Ucn 2 and 3 and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at after the top dose of Ucn2/Ucn3 infusion and before and after each dose of Substance P for subsequent calculation of plasma Ucn 2/ Ucn 3 and net release of t-PA and PAI-1.; Oral Aspirin (600mg stat) will be administered 30 minutes before start of the study. After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of saline.
Baseline blood samples will be taken from both forearms at the start of the study for full blood count, cholesterol, glucose, renal function, plasma Ucn 2 and 3 and t-PA and PAI-1 activity and antigen concentrations. Bilateral venous blood samples will be taken at after the top dose of Ucn2/Ucn3 infusion and before and after each dose of Substance P for subsequent calculation of plasma Ucn 2/ Ucn 3 and net release of t-PA and PAI-1.; Oral Aspirin (600mg stat) is administered 30 minutes before start of the study. After a 20 minute saline washout period, ascending doses of Urocortin 2, Urocortin 3 and substance P (doses as per Protocol 2) will be infused intra-arterially in the presence of the 'nitric oxide clamp' that will be commenced prior to the infusion of Urocortin 2, Urocortin 3 and substance P, and will be continued throughout the study. Intra-arterial Fluconazole is also commenced at the time of the Nitric oxide clamp.
This serves to inhibit the cyclooxygenase, EDHF and NO pathways of endothelial vasodilatation.
Blood samples are taken as per previous arms.
Other intervention name(s): Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P; Forearm vascular study - Bilateral forearm blood flow will be measured at baseline and after each dose of Ucn 2, 3 and Substance P.
Intervention MeSH terms: Aspirin; Fluconazole; Substance P; Neurokinin A
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Urocortin 2; Urocortin 3; Nitric Oxide; Plethysmography; Forearm blood flow; Vascular; Heart failure; endothelium; Cyclo-oxygenase pathway; EDHF