Computer simulation experiments of effect of different autonomic drugs on arterial blood pressure & heart rate of rats

Arterial blood pressure (ABP)

ABP is directly proportional to cardiac output (COP) & peripheral vascular resistance (PVR) COP= HR X SV
PVR depends mainly on diameter
of small sized arterioles
2

1sT experiment: effect of different doses of norepinephrine (NA) on HR & ABP

Inject 2 , 4 & 8 nmol/kg of NA

Observation: increased ABP with minimal effect on HR, which increases only with high doses 3

Explanation of effect of NE on ABP & HR:  NE acts mainly on E1 receptors VSM contraction vasoconstriction (skin, mucous memb., splanchnic area) PVR  With higher doses of NE, it activates also cardiac F1 receptors some increase in the heart rate
4

Design an experiment to prove the suggested explanation

Inject an alpha adrenoceptor blocker and test the effect of NE on ABP & HR

What is the effect of prazosin on ABP and HR?

It is an alpha blocker it blocks E1 adrenoceptors vasodilation (skin, mucous membrane, splanchnic area) PVR ABP y ABP slight reflex tachycardia
y

2nd experiment: effect of different doses of epinephrine on HR & ABP

Inject 2 , 4 & 8 nmol/kg

Observation: ABP & HR The ABP before returning to base line level
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Explanation of the effect of epinephrine on HR & ABP

Epinephrine stimulates E1 , F1, F2 adrenoceptors Beta receptors are more sensitive to the effect of epinephrine y On heart: F1 activation +ve inotropic & chronotropic effects COP leading to increased ABP y On BV : - F2 activation induces vSMC relaxation [sk.m vascular bed ) PVR - E1 activation causes vSM contraction vasoconstriction (skin, mucous memb., splanchnic area) PVR.
y
8

Explanation of the effect of epinephrine on HR & ABP

net effect of these two opposing effects (E1 & F2 ) on vSMC is an in PVR. y At lower epinephrine concentrations, the effect on alpha receptors decreases, while the activity on F2 receptors predominates leading to decrease PVR & lowering ABP before returning to base line level
y The

Design an experiment to demonstrate the role of F1 receptors in the effect of adrenaline on HR & ABP

Observation: blocking F1 receptors by atenolol blocks the effect of epinephrine on HR & decreases the effect on ABP
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What happens if you block alpha & beta receptors & then inject epinephrine?

Epinephrine reversal: The pressor effect of epinephrine is

reversed due to E1 & F1 blockade, leaving the F2 vasodilating 11 effect acting ABP.

How to confirm the cause of epinephrine reversal?

y

Inject prazosin then propranolol instead of atenolol followed by injection of adrenaline

No epinephrine reversal since propranolol blocks not only cardiac F1 receptors but also vascular F2 receptors12

Compare between the effect of epinephrine and norepinphrine on HR & ABP

Observation: In equimolar doses of epinephrine & NE: Only epinephrine increases HR NE produces higher increase in ABP

13

Explanation
y

NE acts mainly on alpha receptors with minimal effect on beta receptors minimal increase in HR Absence of F2 dilating effect explains why the PVR and ABP is more by norepinephrine.

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3rd experiment: effect of different doses of isoprenaline (Beta agonist) on HR & ABP

Observation: Isoprenaline increases HR Isoprenaline initially decreases ABP. As HR reaches its maximum increase, ABP shows minimal increase before returning to normal

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Explanation for the effect of isoprenaline on HR & ABP

y y y y y

Isoprenaline activates mainly beta adrenoceptor It activates cardiac F1 receptors leading to increase in HR & force of contraction (which increases COP) Activation of F2 receptorsVasodilaton decrease in PVR The net effect of the two factors (COP & PVR) is a decrease in blood pressure initially. However, when force of contraction is markedly elevated, the increase of COP overcomes the effect of decrease in PVR and thus ABP starts to increase.
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Design an experiment to prove the explanation for the effect of isoprenaline on HR & ABP
y

Step1: Inject F1 blocker & then inject isoprenaline

Observation: atenolol abolishes the effect isoprenaline on HR The initial ABP-lowering effect of isoprenaline maintained, while its pressor effect is abolished

of is
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Design an experiment to prove the explanation for the effect of isoprenaline on HR & ABP Step 2: inject propranolol to block F2 receptors followed again by isoprenaline

Observation: Propranolol blocks F1 & F2 receptors thus abolishes the effect of isoprenaline on ABP

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4th experiment: effect of phenylephrine on HR & ABP

Observation: Small dose phenylephrine leads to slight increase in ABP with no effect on HR High dose phenylephrine increases markedly ABP with 19 decrease in the HR

Explanation of the effect of phenylephrine on ABP & HR

Phenylephrine is an alpha adrenoceptor agonist y Activation of E1 receptors VSM contraction vasoconstriction( skin, mucous memb., splanchnic area) PVR y High dose of phenylephrine marked elevation of ABP reflex in sympathetic activity. Parasympathetic activity will take the upper hand HR
y
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Design an experiment to prove the explanation of the effect of phenylephrine on HR and ABP
y

Inject an alpha blocker followed by phenylephrine

Observation: prazosin decreases or abolishes the effect of phenylephrine on ABP & reflex bradycardia disappears21

How to prove that reflex bradycardia is due to relative increase in parasympathetic activity

Observation: decreased HR is abolished by atropine despite of elevation of ABP

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Explanation for the effect of acetylcholine on HR and ABP

y on

heart: M2 activation
COP

- ve

chronotropic effect

y on BV: endothelial cells M3 activation release of NO from vascular endothelial cells vSMC relaxation PVR y Decrease in heart rate & decrease in PVR lead to ABP

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5th experiment: Effect of different doses of acetylcholine on ABP and HR

Observation: small doses of acetylcholine lower only ABP Higher doses produce both in the HR & more significant 24 lowering of ABP

Design an experiment to prove the explanation of the effect of acetylcholine on HR & ABP
y

Inject atropine & then test the effect of acetylcholine

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Design an experiment to show acetylcholine reversal

1. 2. 3. 4.

Inject a test dose of acetylcholine Inject atropine Inject the same dose of acetylcholine Inject a dose of acetylcholine which is 10 times the test dose

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Design an experiment to prove the mechanism of action of neostigmine

Inject a test dose of acetylcholine y Inject neostigmine y Inject the test dose of acetylcholine
y

Observation: Neostigmine increases the ABP- lowering effect of acetylcholine & augments its effect on HR

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Explanation for acetylcholine reversal

y

Atropine injection A parasympatholytic blocks muscarinic receptors. It blocks the effect of small dose of Ach. Ach injection [big dose] Stimulates nicotinic receptors NN after muscarinic receptors have been blocked by atropine Rise in ABP Due to activation of NN at :
Adrenal medulla release epinephrine BP Autonomic ganglia release of catecholamines from postsynaptic adrenergic nerve endings [sympathetic predominance] BP

The BP by Ach [big dose] after muscarinic receptor block [by atropine] Ach reversal

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What is the effect of propranolol on ABP and HR?

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