🫀 Experimental Pharmacology: Cardiovascular Drugs & Reflexes (CAL)

By Dr. Sk Sabir Rahaman, MBBS, MD (Pharmacology), DFM(Family Medicine), FCFM, CCEBDM, CCLSD

🎯 Purpose of the Session

The purpose of this practical session is to demonstrate experimentally how different drugs and physiological manipulations affect cardiovascular parameters such as mean arterial pressure (MAP) and heart rate (HR) in an anesthetized animal preparation.

Students will:

• Learn the setup and methods for measuring blood pressure and heart rate in real time.

• Observe characteristic drug responses on the cardiovascular system.

• Understand special pharmacological phenomena like vasomotor reversal of Dale, tachyphylaxis, and nicotinic actions of acetylcholine.

• Bridge the gap between basic pharmacology and clinical applications.

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📌 Learning Objectives

At the end of this session, the student should be able to:

1. Explain the principle of invasive blood pressure recording.

2. Describe the effects of important drugs such as epinephrine, norepinephrine, acetylcholine, histamine, and ephedrine on MAP and HR.

3. Understand reflex phenomena such as carotid occlusion reflex and Cushing’s reflex.

4. Demonstrate and interpret:

   • Vasomotor reversal of Dale.

   • Tachyphylaxis with ephedrine.

   • Nicotinic action of acetylcholine.

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🔑 Key Definitions and Abbreviations

• MAP (Mean Arterial Pressure):
  The average arterial pressure during one cardiac cycle. It is the most reliable indicator of tissue perfusion.
  Formulae:

  • MAP = DBP + (1/3)(SBP – DBP)

  • MAP = (1/3) SBP + (2/3) DBP

• HR (Heart Rate): Number of heartbeats per minute.

• SBP (Systolic Blood Pressure): Peak pressure in arteries during cardiac contraction.

• DBP (Diastolic Blood Pressure): Lowest pressure during cardiac relaxation.

• NE (Norepinephrine): Adrenergic neurotransmitter, acts mainly on α1 receptors → vasoconstriction.

• E (Epinephrine): Hormone from adrenal medulla, acts on α and β receptors → biphasic effect on BP.

• ACh (Acetylcholine): Primary parasympathetic neurotransmitter, acts on muscarinic and nicotinic receptors.

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⚙️ Experimental Setup

🐕 Animal Preparation

• Dog or cat anesthetized with α-chloralose (80 mg/kg IV).

• α-Chloralose is preferred because it provides stable long-duration anesthesia while preserving autonomic reflexes (unlike barbiturates, which abolish reflexes).

🩸 Cannulations

• Femoral vein – for administration of drugs and anesthetic.

• Common carotid artery (CCA) – connected to a mercury manometer via cannula to record blood pressure.

🖊️ Recording

• Mercury column movements transmitted to a float and stylus.

• Stylus records on smoked paper of kymograph → upward deflection = rise in BP, downward = fall.

• Heart rate is calculated from pulse tracings.

⚠️ Precautions

• Flush cannulas with sodium citrate or heparinized saline to prevent clotting.

• Remove air bubbles from tubing.

• Flush system between different drugs to prevent cross-effects.

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💊 Effects of Important Drugs on MAP and HR

1. Norepinephrine (NE)

• Mechanism: Strong α1 agonist → intense vasoconstriction → ↑ MAP.

• Reflex: Rise in BP stimulates baroreceptors → reflex bradycardia.

• Net effect: ↑ MAP, ↓ HR.

• Clinical correlation: Used in shock to restore BP.

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2. Epinephrine (Adrenaline)

• Acts on α1, β1, β2 receptors.

• Biphasic Response:

  • Low dose → β2 (vasodilation in skeletal muscle) → ↓ BP.

  • High dose → α1 (vasoconstriction) + β1 (↑ HR, ↑ contractility) → ↑ BP.

• Reflex bradycardia may occur during initial BP rise.

After α-blocker (Phentolamine):

• α1 effect blocked.

• β2 effect predominates → fall in BP.

• Known as Vasomotor Reversal of Dale.

After β-blocker (Propranolol):

• Both α and β blocked.

• Epinephrine produces little/no effect. Sometimes BP may rise again (re-reversal).

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3. Acetylcholine (ACh)

• Normal dose:

  • M2 effect on heart → bradycardia.

  • M3 effect on endothelium → NO release → vasodilation.

  • Net: ↓ BP + ↓ HR.

• Short duration due to rapid hydrolysis by acetylcholinesterase.

• After Atropine (muscarinic blocker):

  • No muscarinic effect.

  • ACh broken down → minimal action.

• High dose ACh:

  • Stimulates nicotinic receptors (ganglia + adrenal medulla).

  • Sympathetic predominance → ↑ HR & ↑ BP.

• High-dose atropine + high-dose ACh:

  • Muscarinic blocked.

  • Only nicotinic sympathetic action seen → tachycardia + hypertension.

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4. Ephedrine and Tachyphylaxis

• Ephedrine = mixed-acting sympathomimetic (direct α/β stimulation + indirect NE release).

• Initial doses: ↑ BP & ↑ HR.

• Repeated doses: Response progressively decreases.

• Mechanism:

  • Depletion of NE stores.

  • Receptor desensitization.

  • Enhanced metabolism of catecholamines.

• Clinical correlation: Explains why repeated dosing of indirect sympathomimetics is ineffective.

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5. Histamine

• H1 receptors (vessels): Vasodilation via NO → ↓ BP.

• H2 receptors (heart): ↑ HR and contractility.

• Net effect: Fall in BP + Tachycardia.

• After H1 blocker (Mepyramine): Only ↑ HR remains.

• After H2 blocker (Cimetidine) + H1 blocker: No effect.

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🧠 Reflex Phenomena and Nerve Stimulation

1. Central vagus suppression

• Removes inhibitory control → ↑ sympathetic tone → tachycardia + hypertension.

2. Carotid occlusion

• ↓ Baroreceptor stretch → brain perceives low BP → reflex ↑ HR & ↑ BP.

3. Chemoreceptor reflex

• Hypoxia/hypercapnia/acidosis stimulate carotid & aortic bodies → sympathetic activation → ↑ HR & ↑ BP.

4. Cushing Reflex

• Trigger: ↑ Intracranial pressure → cerebral ischemia.

• Response:

  • Sympathetic storm → severe hypertension.

  • Reflex bradycardia via baroreceptors.

  • Irregular respiration.

• Triad: Hypertension + Bradycardia + Irregular respiration.

5. Peripheral vagus stimulation

• Parasympathetic activation → ↓ HR & ↓ BP (due to muscarinic action and NO release).

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📊 Summary Tables

Epinephrine and Blockers

Condition	BP	HR
Epinephrine alone	↑ then ↓	Reflex bradycardia
+ Phentolamine	↓	Tachycardia
+ Propranolol	Little change or ↑	Bradycardia

Acetylcholine Actions

Condition	HR	BP
ACh (low dose)	↓	↓
+ Atropine (after ACh)	No change	No change
High-dose atropine	↑	Little/no change
High-dose ACh	↑	↑
High-dose ACh + atropine	↑	↑

Histamine

Step	Intervention	Response
1	Histamine	↓ BP, ↑ HR
2	+ H1 blocker	Only ↑ HR
3	+ H2 blocker	No effect

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✅ Key Takeaways

• MAP is the best measure of tissue perfusion in experiments and in clinical practice.

• Autonomic drugs produce characteristic, predictable effects on cardiovascular parameters.

• Classic pharmacological concepts like Dale’s vasomotor reversal, tachyphylaxis, and reflexes are best understood through experimental demonstration.

• These experiments form the foundation for rational clinical use of sympathomimetic and parasympathomimetic drugs. 

📘 Prepared by Dr. Sk Sabir Rahaman

📍 Specialist Family Physician | Consultant Pharmacologist | Lifestyle & Diabetes Expert

📧 dr.sabir.rahaman@gmail.com 

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