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Cardiovascular assays

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Our selection of human cardiovascular intact fresh tissue models offers a unique insight into the likely effects of your test article in the clinic. Our scientists create customized protocols that answer your specific questions about the effects of test drugs on human cardiac or vascular function using fresh intact blood vessels or cardiac muscle donated via our extensive network of clinical partners from across the UK and USA. The functional tissues are transported rapidly to our pharmacology labs in the USA or UK where our experience scientists are on hand to conduct ex vivo experiments. We can also conduct comparative studies in other preclinical species to explore species differences using the same blood vessels or cardiac tissues. 

For regulatory safety pharmacology studies in accordance with ICH S7A, we offer the ability to conduct studies in accordance with Good Laboratory Practice (GLP) and are the only GLP CRO using human fresh, functional, intact tissues.

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Diagram of our myograph system used to measure the tone of small blood vessels, such as resistance arteries. 


Subcutaneous resistance arteries 

Human resistance arteries are our most frequently used blood vessel to predict the effects of test drugs on peripheral vascular resistance and hence systemic blood pressure. Resistance arteries are the primary way by which organ-specific blood flow is regulated and, due to the high number of small resistance arteries and their ability to markedly dilate and constrict, they are key to the overall vascular control of systemic blood pressure. Our expert scientists can isolate resistance arteries from human or animal subcutaneous tissues to assess drug-mediated vasoconstriction and vasodilatation.

  • Assess whether your test articles cause vasoconstriction/dilatation to measure the effect on blood pressure
  • Compare with reference vasodilators and vasoconstrictors
  • Option for studies to be conducted in accordance with GLP regulations
  • Customized protocols are also available 

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One of our scientists dissecting subcutaneous resistance arteries.

Vasoconstriction in subcutaneous resistance arteries

These assays determine whether your test articles cause vasoconstriction in human subcutaneous resistance arteries using phenylephrine, 5-HT or U46619 (thromboxane A2 mimetic) as reference compounds.

Vasoconstriction via adrenoceptors:
Phenylephrine model

This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasoconstriction via adrenoceptors.

Vasoconstriction via 5-HT receptors:
5-HT (serotonin) model

This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors.

Vasoconstriction via prostanoid receptors:
U46619 (thromboxane A2) model

This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasoconstriction via prostanoid (thromboxane) receptors.

Vasodilation in subcutaneous resistance arteries

These assays determine whether your test articles cause vasodilatation (vasodilation) in human subcutaneous resistance arteries. Several reference compounds are available, including acetylcholine, desmopressin, bradykinin, milrinone, or sodium nitroprusside.

Acetylcholine model:
 Vasodilation via ACh receptors

This assay uses subcutaneous resistance arteries to assess the ability of your test article to induce vasodilation via endothelium-dependent mechanisms and provides a comparison with known vasodilators such as acetylcholine.

Sodium nitroprusside (SNP) model:
Vasodilation via NO donors

This assay assesses the effect of your test article to induce vasodilation via endothelium-independent mechanisms and provides a comparison with the effects of a direct nitric oxide (NO) donor such as SNP.

Acetylcholine model:
 Vasodilation via ACh receptors

This assay uses subcutaneous resistance arteries to assess the ability of your test article to induce vasodilation via endothelium-dependent mechanisms and provides a comparison with known vasodilators such as acetylcholine.

Milrinone model:
Vasodilation via PDE3 receptors

This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasodilation via PDE3 receptors.

Vasodilation via vasopressin & oxytocin receptors:
Desmopressin model

This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasodilation via vasopressin & oxytocin receptors.

Diseased arteries

These assays use ischemic subcutaneous resistance or muscular arteries to determine the effects of your test article ex vivo. For ischemic arteries, bradykinin or sodium nitroprusside (SNP) can be used as reference compounds. PDA-angiotensin 1 can be used for atherosclerotic arteries. 

Ischemic arteries (bradykinin):
Ischemic bradykinin model

This assay uses ischemic resistance arteries to assess the effect of your test article on vasodilation via bradykinin receptors.

Ischemic arteries (nitric oxide donors):
Ischemic SNP model

This assay uses ischemic resistance arteries to assess the effect of your test article on vasodilation via nitric oxide (NO) donors.

Atherosclerotic arteries:
Atherosclerotic PDA-angiotensin 1 model

This assay uses atherosclerotic resistance arteries to assess the effect of your test article on vasoconstriction via angiotensin receptors


Cardiac Contractility

Cardiac contractility is of major interest in safety pharmacology, as a number of drugs have been shown to have direct effects on cardiac function that may affect stroke volume and hence cardiac output. Using human isolated fresh cardiac tissues, we can assess your test articles for undesired or off-target effects, or assess their ability to modulate cardiac contractility as potential treatments for heart failure. Our scientists will design studies to answer your specific questions and can provide positive or negative controls to compare your test drug against known modulators of cardiac function.

  1. Heart tissue is dissected to obtain contractile trabeculae muscles
  2. Isolated atrial pectinate muscle or ventricular trabeculae are set up in organ baths
  3. Contractions of the cardiac muscle can be paced with electrical field stimulation. A range of frequencies can be used to mimic the effects of increasing/decreasing heart rate.

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Example of a human heart used to complete our cardiac studies. 

Ventricular trabeculae muscles

Ventricular muscle functions to control the flow of blood into and out of the ventricles, which are responsible for pumping blood to the lungs and systemic circulation. Any alterations to ventricular contractility can affect cardiac output as well as the workload on the heart.

  • Atrial muscle and coronary arteries from the same donor can also be investigated
  • Inotropic (contractility) or lusitropic (relaxation) effects can be assessed
  • Human healthy or diseased hearts can be sourced 
  • Option for GLP studies
  • Available drug targets include acetylcholine receptors, adrenoceptors, and 5-HT receptors

 

Ventricular trabeculae and organ bath-1

Left: Trabecular muscles are visible in this human heart.
Right: Isolated trabecular muscle suspended in an organ bath.

 

Contractility via adrenoceptors:
Adrenoceptor/isoprenaline model

This model uses ventricular trabeculae muscles to assess the effect of your test article on cardiac contractility on adrenoceptors.

Contractility via 5-HT receptors:
5-HT receptor/5-HT model

This model uses ventricular trabeculae muscles to assess the effect of your test article on cardiac contractility via 5-HT (serotonin) receptors.

Contractility via acetylcholine receptors:
Acetylcholine receptor/ Acetylcholine model

This model uses atrial pectinate muscles to assess the effect of your test article on cardiac contractility via acetylcholine (ACh) receptors.

 

Atrial pectinate muscles

Pectinate muscles are mainly located in the right atrium of the heart and can be used as an isolated intact tissue to assess the potential effects of test drugs on atrial contractility.

  • Ventricular muscle and coronary arteries from the same donor can also be investigated
  • Inotropic (contractility) or lusitropic (relaxation) effects can be assessed
  • Human healthy or diseased hearts can be sourced 
  • Option for GLP studies
  • Available drug targets include adrenoceptors, 5-HT receptors, and PDE3 receptors 

Contractility via adrenoceptors:
Adrenoceptor/isoprenaline model

This model uses atrial pectinate muscles to assess the effect of your test article on cardiac contractility with isoprenaline as a control.

Contractility via 5-HT receptors:
5-HT receptor/5-HT model

This model uses atrial pectinate muscles to assess the effect of your test article on cardiac contractility via 5-HT receptors.

Contractility via adrenoceptors:
Adrenoceptor/Salbutamol model

This model uses atrial pectinate muscles to assess the effect of your test article on cardiac contractility with salbutamol as a control

Contractility via PDE3 receptors:
PDE3/Milrinone model

This model uses atrial pectinate muscles to assess the effect of your test article on cardiac contractility via PDE3 receptors.


Pulmonary Artery Tone

The pulmonary arteries are essential for healthy respiratory function. Using isolated, functional pulmonary arteries, we can measure changes in the vascular tone of these arteries in response to your test articles.

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Isolated pulmonary arteries in a Petri dish.

Pulmonary artery model:
Pulmonary artery tone assay

This model uses human pulmonary arteries to assess the effect of your test article on blood vessel tone.


Coronary arteries 

The coronary arteries supply blood to the myocardium of the heart and are a key consideration in cardiovascular safety assessment; even small drug-mediated changes in the vascular tone of coronary arteries could increase the risk of angina or myocardial infarction. We are able to assess the potential for drug-mediated effects on human isolated coronary arteries and provide comparisons to coronary arteries from commonly used preclinical species. A few key advantages of our coronary artery model:

  • Both IC50 and pA2 values can be determined
  • Customized protocols and options to conduct studies to GLP
  • A variety of reference compounds available on request (angiotensin II, 8-arginine vasopressin, mephedrone, 5-HT)
  • Organ bath or wire myograph studies are possible

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Isolated coronary arteries in a Petri dish.

Angiotensin II assay:
Angiotensin receptors

This model uses coronary arteries to assess the effect of your test article on vasoconstriction via angiotensin receptors or in comparison to AT1 receptor agonists.

5-HT assay:
5-HT (serotonin) receptors

This model assesses the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors, or in comparison to 5-HT (serotonin) receptor agonists.

Mephedrone assay:
Opioid & opioid-like receptors

This model uses coronary arteries to assess the effect of your test article on vasoconstriction via opioid and opioid-like receptors.

8-Arginine vasopressin assay:
Vasopressin & oxytocin receptors

This model uses coronary arteries to assess the effect of your test article on vasoconstriction via vasopressin and oxytocin receptors.


Chorionic plate arteries 

The chorionic plate arteries supply nutrients to the growing fetus and are essential for healthy development. Pre-eclampsia is characterized by reduced maternal-fetal blood flow, which can pose increased health risks for both the mother and fetus. We can assess the effects of your test article on the vasodilation of normal or pre-eclamptic arteries. 

Normal arteries (bradykinin):
Bradykinin model

The model assesses whether your test article causes vasodilatation in human chorionic plate arteries via bradykinin receptors.

Normal arteries (PDE5):
Sildenafil model

The model assesses whether your test article causes vasodilatation in human chorionic plate arteries via PDE5.

Pre-eclamptic arteries (bradykinin):
Pre-eclamptic Bradykinin model

The model assesses whether your test article causes vasodilatation in pre-eclamptic chorionic plate arteries via bradykinin receptors.

Pre-eclamptic arteries (PDE5):
Pre-eclamptic Sildenafil model

The model assesses whether your test article causes vasodilatation in pre-eclamptic chorionic plate arteries via PDE5.


Saphenous veins

Although most assessments of drug-mediated vascular effects are conducted in arteries, it can be important to consider the effects on peripheral veins. The saphenous veins are responsible for returning blood from the legs back to the heart. Through constriction or dilation, these veins can adjust the volume of blood returning to the heart, thereby altering cardiac output. We can assess the effect of your test article on the vasoconstriction of veins, including comparisons to positive control mechanisms such as via 5-HT receptors.

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Isolated saphenous veins in a Petri dish. 

Vasoconstriction via 5-HT receptors:
Vasoconstriction in human saphenous vein

The model assesses whether test articles cause vasoconstriction in human saphenous vein, with sumatriptan (5-HT1B/1D receptor agonist) as a reference compound.


Making an inquiry

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