Drug Discovery Assay Services Assay: Vascular permeability in human subcutaneous resistance arteries (PAR-1, PAR-3 and PAR-4 receptors)

Code: B036
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Assay type:Blood Vessels
Tissue:Human Subcutaneous Resistance Artery (Healthy)
Target:PAR-1, PAR-3 and PAR-4 receptors
Control Compound:Thrombin
Study Type:Perfusion myography
Functional Endpoint:Vascular permeability

Assay Description

The experiment assesses whether test articles cause an increase in vascular permeability in human subcutaneous resistance arteries with thrombin as a reference compound.

Resistance arteries are involved in regulating organ-specific blood flow and offer the greatest resistance to blood flowing into tissues. Resistance arteries therefore play an important role in the regulation of peripheral vascular resistance and arterial blood pressure.

Example assay graph

Image Legend

Graph showing the percentage change in transmittance of blue light in human subcutaneous resistance arteries; over a 30 min infusion period of dye-bovine serum albumin in the presence and absence of 0.5 units/ml thrombin.

Testing Information

Introduction

The specific results that will be provided are the effects of increasing concentrations of test articles on the absorbance of blue light in isolated human subcutaneous resistance arteries.

Turnaround Time

6 weeks from sample receipt for n = 3 donors.

Timelines are a guide based on Biopta's standard tissue criteria; any client imposed deviations to the standard tissue criteria can alter the project timelines.

Test Article Requirements

Test article(s) to be provided by the Sponsor in storable aliquots at required test concentrations with information on diluent vehicle used. Stock solutions are prepared in distilled water unless otherwise requested. Bath volumes are 16 mL; Sponsor to provide sufficient test article to run the entire study.

Suggested Testing

4 point cumulative concentration response curve.

Study Outline

Rationale and Experimental Design

The experiment assesses whether test articles cause an increase in vascular permeability in human resistance arteries with thrombin as a reference compound.

Exclusion Criteria

No specific exclusion criteria are in place other than to reject macroscopically diseased/necrotic tissue. Furthermore, tissues which do not respond to the standard pharmacology checks will be excluded.

Standardisation and Qualification

All individual vessels are initially pressurised to a standard pressure, prior to starting the study protocol.

Following pressurisation, vessels are Òwoken upÓ with 1 high potassium salt solution challenge with washes and recovery periods following the challenge. This process standardises the basal resting tone and ensures robust contractile responses.

Vessels are then challenged with an appropriate vasoconstrictive agent before endothelial function is assessed by the addition of the appropriate endothelial dependent vasorelaxant agent. Test tissues are then washed and the responses allowed to return to baseline.

Vessels which pass the standardisation and qualification pass/fail criteria will then progress to the study protocol.

Permeability Assay

To assess the ability of each test article to change vascular permeability, 4 point cumulative concentration response curves (CCRC's) will be performed for each test article. A positive control and representative test article vehicle CCRC will also be run to allow direct comparison with test articles.

An example of the conditions assessed for 3 test articles are detailed below:

  • Respresentative test article vehicle CCRC
  • Test article 1 CCRC
  • Test article 2 CCRC
  • Test article 3 CCRC
  • Positive control CCRC

Supplementary Option

To assess the involvement of a specific receptor subtype in any observed responses the concentration of test article eliciting the largest response can subsequently (following a wash out and recovery period) be tested in the presence of a specific anatagonist. This supplementary option will incur an extra charge.

Analysis

Responses shall be expressed as a percentage change in absorbance of blue light. Statistical analysis (where appropriate) will be performed using GraphPad Prism, with the results being shown in graphical form in the final report.

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