Computer simulation experiments of effect of

different autonomic drugs on arterial blood pressure

& heart rate of rats

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Arterial blood pressure Arterial blood pressure (ABP) (ABP)

ABP is directly proportional to cardiac output (COP) & peripheral vascular resistance (PVR)

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COP= HR X SV

PVR depends mainly on diameter of small sized arterioles

11sTsT experiment: effect of different experiment: effect of different doses of norepinephrine (NA) on doses of norepinephrine (NA) on HR & ABPHR & ABP

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Inject 2 , 4 & 8 nmol/kg of NA

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

Explanation of effect of NE on Explanation of effect of NE on ABP & HR: ABP & HR:

NE acts mainly on 1 receptors VSM contraction vasoconstriction (skin, mucous memb., splanchnic area) PVR

With higher doses of NE, it activates also cardiac 1 receptors some increase in the heart rate

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Design an experiment to Design an experiment to prove the suggested prove the suggested

explanationexplanationInject an alpha adrenoceptor blocker and

test the effect of NE on ABP & HR

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What is the effect of prazosin What is the effect of prazosin on ABP and HR? on ABP and HR? It is an alpha blocker it blocks 1

adrenoceptors vasodilation (skin, mucous membrane, splanchnic area) PVRABP

ABP slight reflex tachycardia

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22ndnd experiment: effect of experiment: effect of different doses of epinephrine on different doses of epinephrine on HR & ABPHR & ABP

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Observation: ABP & HR The ABP before returning to base line level

Inject 2 , 4 & 8 nmol/kg

Explanation of the effect of Explanation of the effect of epinephrine on HR & ABPepinephrine on HR & ABP

Epinephrine stimulates 1 , 1, 2 adrenoceptors Beta receptors are more sensitive to the effect of epinephrine

On heart: 1 activation +ve inotropic & chronotropic effects COP leading to increased ABP

On BV : - 2 activation induces vSMC relaxation [sk.m.

vascular bed ) PVR - 1 activation causes vSM contraction

vasoconstriction (skin, mucous memb., splanchnic area) PVR.

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Explanation of the effect of Explanation of the effect of epinephrine on HR & ABPepinephrine on HR & ABP

The net effect of these two opposing effects (1 & 2 ) on vSMC is an in PVR.

At lower epinephrine concentrations, the effect on alpha receptors decreases, while the activity on 2 receptors predominates leading to decrease PVR & lowering ABP before returning to base line level

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Design an experiment to Design an experiment to demonstrate the role of demonstrate the role of 11 receptors in the effect of receptors in the effect of adrenaline on HR & ABP adrenaline on HR & ABP

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Observation: blocking 1 receptors by atenolol blocks the effect of epinephrine on HR & decreases the effect on ABP

What happens if you block alpha What happens if you block alpha & beta receptors & then inject & beta receptors & then inject epinephrine?epinephrine?

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Epinephrine reversal: The pressor effect of epinephrine is reversed due to 1 & 1 blockade, leaving the 2 vasodilating effect acting ABP.

How to confirm the cause of How to confirm the cause of epinephrine reversal? epinephrine reversal? Inject prazosin then propranolol instead of

atenolol followed by injection of adrenaline

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No epinephrine reversal since propranolol blocks not only cardiac 1 receptors but also vascular 2 receptors

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

ABPABP

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Observation:

In equimolar doses of epinephrine & NE :

Only epinephrine increases HR

NE produces higher increase in ABP

Explanation Explanation

NE acts mainly on alpha receptors with minimal effect on beta receptors minimal increase in HR

Absence of 2 dilating effect explains why the PVR and ABP is more by norepinephrine.

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33rdrd experiment: effect of experiment: effect of different doses of isoprenaline different doses of isoprenaline (Beta agonist) on HR & ABP(Beta agonist) on HR & ABP

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

Explanation for the effect of Explanation for the effect of isoprenaline on HR & ABP isoprenaline on HR & ABP

Isoprenaline activates mainly beta adrenoceptor

It activates cardiac 1 receptors leading to increase in HR & force of contraction (which increases COP)

Activation of 2 receptors—Vasodilaton 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 Design an experiment to prove the explanation for the effect of explanation for the effect of isoprenaline on HR & ABPisoprenaline on HR & ABPStep1: Inject 1 blocker & then inject

isoprenaline

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Observation: atenolol abolishes the effect of isoprenaline on HR

The initial ABP-lowering effect of isoprenaline is maintained, while its pressor effect is abolished

Step 2: Step 2: inject propranolol to block inject propranolol to block 2 2 receptors followed again by receptors followed again by isoprenalineisoprenaline

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Observation: Propranolol blocks 1 & 2 receptors thus abolishes the effect of isoprenaline on ABP

Design an experiment to prove the Design an experiment to prove the explanation for the effect of explanation for the effect of isoprenaline on HR & ABPisoprenaline on HR & ABP

44thth experiment: effect of experiment: effect of phenylephrine on HR & ABPphenylephrine on HR & ABP

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Observation:

Small dose phenylephrine leads to slight increase in ABP with no effect on HR

High dose phenylephrine increases markedly ABP with decrease in the HR

Explanation of the effect of Explanation of the effect of phenylephrine on ABP & HRphenylephrine on ABP & HR

Phenylephrine is an alpha adrenoceptor agonist

Activation of 1 receptors VSM contraction vasoconstriction( skin, mucous memb., splanchnic area) PVR

High dose of phenylephrine marked elevation of ABP reflex in sympathetic activity. Parasympathetic activity will take the upper hand HR

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Design an experiment to prove the Design an experiment to prove the explanation of the effect of explanation of the effect of phenylephrine on HR and ABPphenylephrine on HR and ABPInject an alpha blocker followed by

phenylephrine

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

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

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Inject atropine followed by phenylephrine

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

Explanation for the effect of Explanation for the effect of acetylcholine on HR and ABPacetylcholine on HR and ABP

on heart: M2 activation - ve chronotropic effect COP

on BV: endothelial cells M3 activation release of NO from vascular endothelial cells vSMC relaxation PVR

Decrease in heart rate & decrease in PVR lead to ABP

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55thth experiment: experiment: Effect of Effect of different doses of acetylcholine on different doses of acetylcholine on ABP and HR ABP and HR

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Observation: small doses of acetylcholine lower only ABP

Higher doses produce both in the HR & more significant lowering of ABP

Design an experiment to prove Design an experiment to prove the explanation of the effect of the explanation of the effect of acetylcholine on HR & ABPacetylcholine on HR & ABPInject atropine & then test the effect

of acetylcholine

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Design an experiment to Design an experiment to show show acetylcholine acetylcholine reversal reversal 1. Inject a test dose of acetylcholine2. Inject atropine 3. Inject the same dose of acetylcholine4. Inject a dose of acetylcholine which is 10

times the test dose

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Design an experiment to prove Design an experiment to prove the mechanism of action of the mechanism of action of neostigmine neostigmine Inject a test dose of acetylcholine Inject neostigmine Inject the test dose of acetylcholine

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

Explanation for Explanation for acetylcholine acetylcholine reversalreversal

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 post-synaptic 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 What is the effect of propranololpropranolol on ABP and HR?on ABP and HR?

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