RatCVS: Simulated rat cardiovascular system

Purpose: To observe the effects of different drugs on a rat’s heart and cardiovascular system using a
simulated experiment and also to determine the unknown drug “D” using the myriad of known standard
cardiovascular drugs.
Introduction: RatCVS is a simulation of a pithed rat experimental preparation for investigating the
actions of drugs on the heart and cardiovascular system. "Pithing" refers to the destruction of spinal cord
pathways, severing all the nerve connections between the brain and the cardiovascular system. This
greatly simplifies the interpretation of experimental results by removing the central baroreceptor reflexes.
The simulation allows you to observe traces of blood pressure, left ventricular pressure, venous pressure,
heart rate and contractile force on a simulated chart recorder, to apply a variety of different drugs, and to
observe their effects.
Rat Cardiovascular System Preparation:

Figure 1. schematic of virtual rat simulation with the cardiovascular parameters studied.
A rat is anaesthetised and artificially ventilated. Three cannulae are inserted into the femoral artery, vein
and the left ventricle of the heart. The arterial cannula is connected to a pressure transducer to measure
arterial blood pressure. Traces of arterial blood pressure (ABP) and heart rate (HR), computed from ABP,
are recorded on the chart recorder. The left ventricular cannula is connected to a second pressure
transducer and used to produce a trace of left ventricular pressure (LVP). A measure of the contractile
force of the heart (HF) is derived from the LVP. The venous cannula is connected to a third pressure
transducer and used to produce a trace of central venous blood pressure (VBP). Drugs can also be injected
into the animal via the venous cannula. A specially designed pithing rod can be passed down the spinal
cord of the animal destroying all nerve connections with the brain, and hence disabling the central blood
pressure reflexes associated with the carotid artery baroreceptors.
Materials: Rat CVS software
Using the Simulation:
1. Select New Rat from the File menu, to clear the chart.
2. Click the Start button to start the chart recorder running.
3. To inject a drug into the animal’s circulation:
a) Select a drug from the Standard Drugs menu
b) Select the required dose from the list of doses.
c) Click Inject Drug button to add the drug.
4. You can make quantitative measurements from the traces by moving the mouse cursor over the
trace and noting the value in the readout at the bottom of the screen.
5. You can add as many doses and/or drugs as necessary. When you have finished your
experiment, click the Stop button to stop the chart.
 6. To print out a hard copy of the traces shown on the screen, Select Print from the File menu.
7. When you have completed an experiment you can save it to a storage file by selecting Save
Rat ... from the File menu. (To re-load an experiment, select Load Rat).
8. To exit from the simulation program, select Exit from the File menu.

Receptors:

· Heart: The heart has both muscarinic cholinoceptors (mAchR), beta1-adrenoceptors and
adenosine receptors. Muscarinic stimulation results in a reduction in heart rate (H.R.) and stroke
volume (S.V.) and causes a reduction in blood pressure. Adrenergic stimulation results in an
increase in H.R., and S.V. Blocking calcium channels in heart muscle causes a reduction in H.R.
and S.V.

· Blood vessels: Alpha1-adrenoceptors on blood vessels cause vasoconstriction, increasing

· Adrenaline: Alpha+Beta-adrenoceptor agonist (Alpha=Beta).

· Noradrenaline: Alpha+Beta-adrenoceptor agonist (Alpha>Beta).

· Isoprenaline: Beta-adrenoceptor agonist.

· Phenylephrine: Alpha-adrenoceptor agonist.

· Acetylcholine: Cholinoceptor agonist.

· Glyceryl Trinitrate: Nitrovasodilator.

· Cromakalim: Potassium channel opener.

· Angiotensin II: Vasoconstrictor

· Digoxin: Na/K pump inhibitor.

· Milrinone: Phosphodiesterase inhibitor

· Adenosine: Adenosine receptor agonist.

· Propanalol: Beta-adrenoceptor antagonist.

· Atenalol: Beta-1 adrenoceptor antagonst.

· Atropine: Muscarinic cholinoceptor antagonist.

· Phentolamine: Alpha-adrenoceptor antagonist.

· Prazozin: Alpha-1 adrenoceptor antagonist.

· 8-SPT (8-parasulphophenyltheophylline): Adenosine receptor antagonist.

· Captopril: Angiotensin converting enzyme inhibitor.

· Verapamil: Calcium channel blocker.

· Losartan: Angiotension II antagonist.

· Glibenclamide: Potassium channel blocker

Each of these drugs will be injected and the agonists and antagonists’ relationships will be
investigated.
Results: Initially for all the drugs listed, parameters such as ABP, LVP, VBP, HF and HR were studied
individually for each drug. For ease of comparison, 100ug/kg (or 0.1mg/kg) of each drug was injected.
Then, 100ug/kg of unknown drug D was injected into a new rat and the parameters were observed and
recorded. Upon observing the ABP, LVP, VBP, HF and HR evoked by drug D, its behavior seemed
similar to that of adrenergic agonists. It also showed great contrast to phentolamine. To further classify
the selective adrenergic agonist action of the drug D, it was compared to known adrenergic agonists such
as adrenaline, isoprenaline, phenylephrine.

i) D vs phentolamine

Figure 2. ABP, LVP, VBP, HF and HR of a rat after treatment with 100ug/kg of unknown drug D vs
100ug/kg of phentolamine
ii) Noradrenaline and phentolamine:

Figure 2. ABP, LVP, VBP, HF and HR of a rat after treatment with 100ug/kg of Noradrenaline vs
100ug/kg of phentolamine

iii) Phenylephrine and phentolamine:

Figure 2. ABP, LVP, VBP, HF and HR of a rat after treatment with 100ug/kg of phenylephrine vs
100ug/kg of phentolamine

iv) Isoprenaline and phentolamine:

v) Adrenaline and phentolamine:

Figure 2. ABP, LVP, VBP, HF and HR of a rat after treatment with 100ug/kg of Adrenaline vs 100ug/kg
of phentolamine

Conclusion: The agonistic and antagonistic effects of all the above drugs could be seen using the
simulation. The graphical representation shows changes in the rat’s heart rate, its heart flow and its aortic
& ventricular blood pressure. Any changes in these listed parameters that the drug induced can be easily
observed. By comparing and contrasting the parameters observed with various drugs, the pharmacological
class of drug D was assigned and concluding it to be noradrenaline. Furthermore, this simulation enables
to conduct a pharmacological study without the need to sacrifice countless animals.