Hypertension - MBBS Physiology

Reference: Sembulingam's Essentials of Medical Physiology, 6th Edition

Definition

Normal BP: Systolic < 120 mm Hg | Diastolic < 80 mm Hg

Classification of Hypertension

1. Primary (Essential) Hypertension

• Elevated blood pressure in the absence of any underlying disease
• Cause is unknown
• Arterial pressure increases due to increased peripheral resistance from an unknown cause
• Accounts for ~90-95% of all hypertension cases

2. Secondary Hypertension

i. Cardiovascular Hypertension

• Coarctation of aorta
• Arteriosclerosis

ii. Endocrine Hypertension

• Pheochromocytoma - tumor of adrenal medulla causing excess catecholamine secretion
• Hyperaldosteronism - excess aldosterone from adrenal cortex (causes Na+ and water retention)
• Cushing's Syndrome - excess glucocorticoids from adrenal cortex

iii. Renal Hypertension

• Stenosis of renal arteries (Goldblatt hypertension)
• Tumor of juxtaglomerular cells - excess angiotensin II production
• Glomerulonephritis

iv. Neurogenic Hypertension

• Increased intracranial pressure
• Lesion in tractus solitarius (NTS)
• Sectioning of nerve fibers from carotid sinus

Pathophysiology of Primary Hypertension

1. Increased Peripheral Resistance

• Increased sympathetic activity
• Excess circulating catecholamines
• Excess angiotensin II

2. Renin-Angiotensin-Aldosterone System (RAAS) Activation

• Renal ischemia or excess renin secretion triggers angiotensin II formation
• Angiotensin II causes:
  1. Immediate effect - Arteriolar vasoconstriction → raises TPR → raises BP
  2. Long-term effect - Stimulates aldosterone secretion → Na+ and water retention → raises blood volume → raises cardiac output → raises BP
• This two-step mechanism is central to renovascular and endocrine hypertension

3. Impaired Renal Pressure Natriuresis

• Normally, the kidney excretes excess salt and water when BP rises ("pressure natriuresis"), resetting BP toward normal
• In hypertension, this mechanism is blunted - the kidney requires a higher set-point pressure to excrete adequate salt and water
• This is the fundamental long-term mechanism for sustained hypertension (Guyton's concept)

4. Sympathetic Nervous System Overactivity

• Increases heart rate and contractility → raises CO
• Increases arteriolar tone → raises TPR
• Stimulates renal renin release
• Particularly prominent in obesity-related hypertension

5. Volume Loading (Salt-Sensitive Hypertension)

• Excess salt intake → expanded extracellular fluid and blood volume → raised cardiac output → raised BP
• Especially prominent when renal mass is reduced

Effects / Complications of Hypertension (Sembulingam)

1. Renal failure - hypertensive nephropathy
2. Left ventricular failure - from chronically increased afterload
3. Myocardial infarction - accelerated coronary atherosclerosis
4. Cerebral hemorrhage - rupture of cerebral vessels ("stroke")
5. Retinal hemorrhage - hypertensive retinopathy

Treatment Overview (Sembulingam)

• Secondary hypertension - treat the underlying cause
• Primary hypertension - can be controlled but not cured

1. Beta-blockers - block beta-adrenoceptors; reduce cardiac output and vasoconstriction
2. Diuretics - reduce blood volume
3. ACE inhibitors / ARBs - block RAAS
4. Calcium channel blockers - reduce arteriolar tone
5. Alpha-blockers - reduce peripheral resistance

Summary Diagram

Quick Reference Table

• Essentials of Medical Physiology by K. Sembulingam & Prema Sembulingam, 6th Edition - Section 8, Cardiovascular System (Applied Physiology: Hypertension, p. 614 onwards)
• Guyton and Hall Textbook of Medical Physiology, 14th Edition - Chapter 19 (Role of the Kidneys in Long-Term Arterial Pressure Control and Hypertension) - used to supplement and cross-verify mechanism details

Coronary Circulation - MBBS Physiology

Reference: Sembulingam's Essentials of Medical Physiology, 6th Ed. - Chapter 108

Introduction

I. DISTRIBUTION OF CORONARY BLOOD VESSELS

A. Coronary Arteries

1. Right Coronary Artery (RCA)

• Arises from the right aortic sinus
• Runs in the right atrioventricular (AV) groove
• Supplies:
  • Right atrium
  • Right ventricle
  • Posterior wall of the left ventricle (in 80-90% of people - "right dominant")
  • SA node (in ~60% of people) and AV node (in ~80% of people)
• Main branch: Posterior descending artery (PDA)

2. Left Coronary Artery (LCA)

• Arises from the left aortic sinus
• A short left main stem (~2-3 cm) divides into:
  • Left Anterior Descending (LAD) - also called "widow maker"; supplies anterior wall of LV, interventricular septum (anterior 2/3), and apex
  • Left Circumflex (LCX) - runs in left AV groove; supplies lateral and posterior wall of left ventricle and left atrium
• Supplies anterior and left lateral portions of the left ventricle

Clinical Point (Sembulingam): The LAD is the most commonly occluded coronary artery. Its blockage causes extensive anterior wall myocardial infarction.

B. Venous Drainage

C. Physiological Shunt

• A small portion of aortic blood flows directly into the myocardium via the thebesian veins (venae cordis minimae), bypassing the coronary arteries
• This represents a right-to-left shunt - it returns deoxygenated blood to the left heart, slightly reducing the oxygen saturation of arterial blood
• This is called the physiological shunt in the heart

II. CORONARY BLOOD FLOW

A. Normal Coronary Blood Flow

• At rest: ~70 mL/min per 100 g of heart weight
• Total resting coronary flow: approximately 225 mL/min (~4-5% of cardiac output)
• During strenuous exercise: increases 3 to 4 times (coronary reserve)
• The heart consumes ~8-10 mL O₂/min/100g of tissue at rest (much higher than most other organs)
• 70-80% of oxygen is extracted from coronary blood (compared to ~25% in skeletal muscle)

B. Measurement of Coronary Blood Flow

• Fick's principle - using oxygen consumption
• Electromagnetic flowmeter on coronary arteries
• Thermodilution method
• Radioactive microspheres

III. PHASIC CHANGES IN CORONARY BLOOD FLOW

Left Ventricle (Sembulingam, Fig. 108.1)

Key Point: The left ventricle receives most of its blood supply during diastole. This is why a fast heart rate (short diastole) or low diastolic BP can critically reduce coronary perfusion.

Right Ventricle

• Right ventricular muscle contracts with much less force than the left
• Intramural pressure rise during systole is smaller
• Therefore, phasic changes in the right coronary artery are less pronounced
• Some flow continues even during systole

Epicardial vs. Subendocardial Blood Flow

• Epicardial coronary arteries lie on the surface and are less affected by myocardial compression
• Subendocardial arteries are most susceptible to systolic compression
• A subendocardial plexus of vessels compensates for the reduced systolic flow
• In disease (e.g., hypertrophy, high diastolic pressure), subendocardial ischemia occurs first - this is why subendocardial MI is more common than epicardial MI in diffuse disease

IV. FACTORS REGULATING CORONARY BLOOD FLOW

1. Need for Oxygen (Most Important - Sembulingam)

• Oxygen is the single most important factor regulating coronary blood flow
• Coronary blood flow is directly proportional to oxygen consumption of cardiac muscle
• Even at rest, 70-80% of oxygen is extracted - almost maximal
• When oxygen demand increases, the only way to supply more O₂ is to increase flow
• Any decrease in O₂ triggers vasodilation immediately

2. Metabolic Factors

Adenosine mechanism (Guyton): When O₂ falls in muscle cells, ATP degrades to AMP, then to adenosine. Adenosine leaks out of cells and causes arteriolar vasodilation, increasing coronary flow to match metabolic needs. This is the primary local regulatory mechanism.

3. Coronary Perfusion Pressure

• Coronary Perfusion Pressure = Aortic Diastolic Pressure - Left Ventricular End-Diastolic Pressure (LVEDP)
• Flow increases when aortic diastolic pressure rises
• Flow decreases when LVEDP rises (e.g., heart failure) - this is why cardiac failure worsens coronary ischemia
• Coronary autoregulation: blood flow remains constant over a mean arterial pressure range of 60-180 mmHg (autoregulatory plateau)

4. Nervous Factors

Sympathetic Stimulation:

• Direct effect: Norepinephrine acts on:
  • Alpha receptors (predominant on epicardial arteries) → vasoconstriction
  • Beta-2 receptors (predominant on intramuscular arteries) → vasodilation
• Indirect (dominant) effect: Increased heart rate and contractility → increased metabolism → metabolic vasodilation overrides direct constriction
• Net result: Coronary flow increases (metabolic override prevails)

Sembulingam: Stimulation of sympathetic nerves increases rate and force of cardiac contraction → liberation of more metabolites → vasodilation → increased coronary flow.

Parasympathetic (Vagal) Stimulation:

• Direct effect: Acetylcholine → mild coronary vasodilation
• Indirect (dominant) effect: Slows heart rate, decreases contractility → less O₂ demand → less metabolites → coronary vasoconstriction
• Net result: Coronary flow decreases

V. SPECIAL FEATURES OF CARDIAC METABOLISM

• At rest, cardiac muscle derives ~70% energy from fatty acids, ~30% from glucose
• During ischemia or anaerobiosis, switches to glucose utilization
• Heart has minimal anaerobic capacity - very sensitive to ischemia
• Energy stored as creatine phosphate (short-term reserve only)
• Capillary density in myocardium is much higher than skeletal muscle - optimises O₂ delivery

VI. APPLIED PHYSIOLOGY - CORONARY ARTERY DISEASE (Sembulingam, Chapter 108)

A. Coronary Occlusion

• Atherosclerosis (most common) - plaque formation narrows lumen
• Thrombosis - clot forms on ruptured atheromatous plaque
• Embolism - thrombus or detached plaque fragment blocks smaller vessels
• Coronary vasospasm - especially with sympathetic excess (Prinzmetal/variant angina)

B. Myocardial Ischemia and Necrosis

Myocardial Ischemia

• Defined as reaction of myocardium to hypoxia due to severely reduced coronary flow
• Develops when blood flow decreases but cell death has not yet occurred
• Reversible if blood flow is restored quickly (especially within 20-40 minutes)
• Small areas of ischemia may recover via coronary collateral circulation

Myocardial Stunning

• Transient mechanical dysfunction of the heart caused by a mild reduction in coronary blood flow
• Insufficient to cause necrosis but causes brief contractile dysfunction
• Heart recovers completely once flow is restored

Necrosis

• Death of myocardial cells - occurs when ischemia is severe and prolonged
• Irreversible once completed
• Leads to myocardial infarction

C. Myocardial Infarction (Heart Attack) - Sembulingam

1. Cardiac pain (severe, crushing chest pain)
2. Nausea
3. Vomiting
4. Palpitations
5. Difficulty in breathing (dyspnea)
6. Extreme weakness
7. Sweating
8. Anxiety

• ECG changes: ST elevation, Q waves, T-wave inversion
• Cardiac enzymes rise: Troponin I/T (most specific), CK-MB, LDH
• Collateral vessels may develop if occlusion is gradual
• In sudden complete occlusion - no time for collaterals → large infarct

D. Cardiac Pain - Angina Pectoris (Sembulingam)

• Starts beneath the sternum (retrosternal)
• Radiates to the left arm, left shoulder, jaw, and neck
• Described as crushing, tightening, or pressure-like
• Lasts 2-15 minutes (if longer, suspect MI)
• Relieved by rest and nitrates

• The heart and left arm develop from the same dermatomal segment in the embryo (C8-T4)
• Pain impulses from the heart travel via cardiac sympathetic nerves to T1-T5 spinal segments
• The brain interprets these as arising from the somatic areas of the same segments - hence referred to left arm and chest wall

Summary Flow Chart

Coronary Occlusion (Atherosclerosis/Thrombus)
        ↓
Reduced Coronary Blood Flow
        ↓
Myocardial Hypoxia → Release of Adenosine, CO₂, H⁺, K⁺
        ↓
↑ Coronary vasodilation (compensatory) ←→ If inadequate → Ischemia
        ↓                                             ↓
 Restored blood flow                     Angina Pectoris (Pain)
  (Myocardial Stunning)                              ↓
                                           Necrosis → Infarction

Quick Revision Points for Exams

• Essentials of Medical Physiology - K. Sembulingam & Prema Sembulingam, 6th Edition, Chapter 108: Coronary Circulation (pp. 629-633)
• Guyton and Hall Textbook of Medical Physiology, 14th Edition, Chapter 21 - used to cross-verify and supplement regulation details

Conducting System of the Heart - Origin and Propagation of Cardiac Impulse

Reference: Sembulingam's Essentials of Medical Physiology, 6th Ed. - Chapters 90 & 96

Introduction

Components of the Conducting System (Sembulingam)

1. Sinoatrial (SA) node - the primary pacemaker
2. Internodal fibers - connect SA node to AV node
3. Atrioventricular (AV) node - delays conduction
4. Bundle of His (AV bundle) - common bundle
5. Right and Left Bundle Branches - divide at the interventricular septum
6. Purkinje fibers - terminal distribution to ventricular myocardium

1. Sinoatrial (SA) Node - The Primary Pacemaker

Location

• Situated in the right atrium, just below (inferior to) the opening of the superior vena cava
• Also called the Keith and Flack's node

Structure (Sembulingam)

• Spindle-shaped collection of specialized muscle cells
• Cells are small, poorly striated, with fewer myofibrils
• Surrounded by fibrous connective tissue
• Richly supplied by both sympathetic and parasympathetic nerve fibers

Why is the SA Node the Pacemaker?

• All parts of the conductive system can generate impulses spontaneously (automaticity)
• The SA node discharges at the fastest intrinsic rate (70-80/min), outpacing all others
• Because it fires fastest, it depolarizes all other pacemaker tissues before they can fire spontaneously
• Therefore, SA node sets the rhythm for the entire heart

Intrinsic Rates of Different Parts (Sembulingam)

Key concept: If the SA node fails, the next fastest site takes over - this is the escape pacemaker or latent pacemaker.

2. Origin of the Cardiac Impulse

Ionic Mechanism - Pacemaker Potential (Sembulingam + Ganong)

Phases of SA Node Action Potential

Important distinction: The SA/AV node action potential is driven by Ca²⁺ (not Na⁺). That is why:

• There is no sharp spike before the plateau
• Ca²⁺ channel blockers (verapamil, diltiazem) slow the SA and AV nodes
• TTX (Na⁺ channel blocker) does not affect nodal tissue

3. Propagation of the Cardiac Impulse

Step-by-Step Sequence (Sembulingam)

SA Node
   ↓  (via internodal fibers)
Atrial Myocardium (simultaneous R and L atria)
   ↓
AV Node (DELAY - 0.09 sec)
   ↓
Bundle of His (common bundle)
   ↓  (at top of interventricular septum)
Left Bundle Branch → Left and Right ventricles
Right Bundle Branch ↗
   ↓
Purkinje Fibers (rapid spread)
   ↓
Ventricular Myocardium (from apex → base)

Internodal Fibers (Sembulingam - Chapter 90)

• Conduction through atrial muscle also occurs but is slower
• The Bachmann bundle provides the fastest inter-atrial conduction

AV Node - The Gatekeeper

• Allows the atria to complete their contraction and empty blood into ventricles first
• Prevents too-rapid ventricular filling and protects against atrial arrhythmias flooding the ventricles

• Fewer gap junctions between cells → high resistance to ionic spread
• Smaller cells with higher internal resistance
• Ca²⁺-dependent action potentials (slower than Na⁺-dependent)

This 0.16 sec = PR interval on ECG

Bundle of His (AV Bundle)

• Direct continuation of the AV node
• Runs along the lower border of the membranous interventricular septum
• Surrounded by fibrous connective tissue - insulated from surrounding myocardium
• Only electrically active connection between atria and ventricles (normally)
• Divides into Right Bundle Branch and Left Bundle Branch at the top of the muscular interventricular septum

Bundle Branches

Right Bundle Branch (RBB)

• Runs down the right side of the interventricular septum
• Reaches the apex
• Enters the moderator band (septomarginal trabecula)
• Reaches the anterior papillary muscle and spreads to the right ventricular wall

Left Bundle Branch (LBB)

• Runs down the left side of the interventricular septum
• Divides into two fascicles:
  • Left Anterior Fascicle (LAF) - supplies anterior and superior wall of LV
  • Left Posterior Fascicle (LPF) - supplies posterior and inferior wall of LV

Purkinje Fibers

• Arise from the terminal ends of the bundle branches
• Spread as a subendocardial network over both ventricular walls
• Largest cells in the conductive system (larger than ventricular myocytes)
• Rich in gap junctions → very high conduction velocity
• First reach papillary muscles and apex, then spread toward the base

4. Conduction Velocities at Different Parts (Sembulingam - Chapter 90)

5. ECG Correlation with Impulse Propagation

6. Applied Physiology - Arrhythmias of the Conducting System (Sembulingam - Chapter 96)

A. Heart Block

i. Sinoatrial (SA) Block

• Failure of impulse transmission from SA node → AV node
• Heart momentarily stops → AV node takes over as pacemaker
• Produces AV nodal rhythm at 40-60/min
• On ECG: P wave absent in affected beats

ii. Atrioventricular (AV) Block

iii. Infranodal Block (Bundle Branch Block)

• Block in branches of Bundle of His (below AV node)
• Purkinje fibers become pacemaker → rate ~35/min
• If ventricular muscle takes over → rate ~20/min
• Right bundle branch block (RBBB): Wide QRS with RSR' pattern in V1
• Left bundle branch block (LBBB): Wide QRS with broad notched R in V5-V6

B. Ectopic Pacemakers

SA node fails
    ↓
AV node (40-60/min) → "Junctional rhythm"
    ↓ (if also blocked)
Bundle of His (40/min)
    ↓
Purkinje fibers (35/min) → "Ventricular escape rhythm"
    ↓
Ventricular muscle (20/min) → "Idioventricular rhythm"

C. Other Important Arrhythmias (Sembulingam)

D. WPW Syndrome (Wolff-Parkinson-White)

• An accessory pathway (Bundle of Kent) bypasses the AV node
• Impulse reaches ventricles earlier (pre-excitation) → delta wave on ECG
• Short PR interval + wide QRS + delta wave
• Can cause re-entrant tachycardia

Summary - Impulse Propagation Sequence

SA Node (70-80/min)
    ↓ 0.03 sec
Internodal tracts (Bachmann, Wenckebach, Thorel)
    ↓
Both Atria depolarize simultaneously → P wave on ECG
    ↓
AV Node (DELAY: 0.09 sec → total PR = 0.16 sec)
    ↓
Bundle of His (common bundle)
    ↓
Right Bundle Branch          Left Bundle Branch
        ↓                          ↓
Right ventricle         Left anterior + posterior fascicles
        ↓                          ↓
                Purkinje fibers (4 m/sec)
                        ↓
        Apex → base ventricular contraction → QRS complex

Quick Revision Table

• Essentials of Medical Physiology - K. Sembulingam & Prema Sembulingam, 6th Edition, Chapter 90 (Conducting System) and Chapter 96 (Arrhythmia)
• Ganong's Review of Medical Physiology, 26th Edition, Chapter 29 - Origin and Spread of Cardiac Excitation
• Guyton and Hall Textbook of Medical Physiology, 14th Edition, Chapter 10 - Rhythmical Excitation of the Heart

Pacemaker Potential

Reference: Sembulingam's Essentials of Medical Physiology, 6th Ed. - Chapter 90

Definition

Sembulingam: "Pacemaker potential is the unstable resting membrane potential in SA node. It is also called prepotential."

Key Differences: SA Node vs Ventricular Muscle

Phases of the SA Node Action Potential

Graphic Overview

Phase 4 - Pacemaker Potential / Prepotential (Most Important)

Step 1: Decline in K⁺ Outflow (IK decreases)

• At the end of repolarization (end of previous action potential), the K⁺ channels that caused repolarization begin to close spontaneously
• This reduces outward K⁺ current (IK) → less hyperpolarizing force → the membrane potential begins to drift upward (less negative)
• This falling K⁺ conductance is the initial trigger of the pacemaker potential

Step 2: Funny Current - If / Ih (Na⁺ + K⁺ inward current)

• As the membrane repolarizes and becomes hyperpolarized, a special channel is activated - the HCN channel (Hyperpolarization-activated Cyclic Nucleotide-gated channel)
• This channel is activated by hyperpolarization (opposite of most channels) - hence called "funny" (If) or "h-current" (Ih)
• It allows slow inward movement of both Na⁺ and K⁺ (predominantly Na⁺ influx)
• This inward current causes the early slow depolarization of the pacemaker potential (first part)

Sembulingam: "Sodium ions leak into the pacemaker fibers and cause slow depolarization - this forms the initial part of pacemaker potential."

Ganong: "A channel permeable to both Na⁺ and K⁺ is activated because this channel is activated following hyperpolarization, it is referred to as an 'h' channel... the current through h channels is called 'funny current' (Ih/If)."

Step 3: T-type Ca²⁺ Channel Opening (ICa-T)

• As the membrane potential reaches about -50 mV, T-type (Transient) Ca²⁺ channels open
• These allow a slow inward Ca²⁺ current → further depolarization
• This forms the later part of the pacemaker potential

Sembulingam: "Then, the calcium channels start opening. At the beginning, there is a slow influx of calcium ions causing further depolarization in the same slower rate. It forms the later part of the pacemaker potential."

Ganong: "ICa due to opening of T channels completes the prepotential."

Phase 0 - Upstroke (Rapid Depolarization)

• When membrane potential reaches threshold at approximately -40 mV, L-type (Long-lasting) Ca²⁺ channels open
• Massive rapid Ca²⁺ influx → sharp upstroke to approximately +10 to +20 mV
• Important: This is driven by Ca²⁺, NOT Na⁺ (unlike ventricular muscle upstroke)
• Therefore the upstroke is slower and less steep than ventricular upstroke

Sembulingam: "When the negativity is decreased to -40 mV (threshold), the action potential starts with rapid depolarization. The depolarization occurs because of influx of more calcium ions. Unlike in other tissues, the depolarization in SA node is mainly due to influx of calcium ions, rather than sodium ions."

Costanzo: "In the SA nodal cells, the upstroke is the result of an increase in gCa and an inward Ca²⁺ current carried primarily by L-type Ca²⁺ channels."

Phases 1 and 2 - ABSENT in SA Node

• There is no rapid early repolarization (phase 1) and no plateau (phase 2) in the SA node
• This is because there are no fast Na⁺ channels in nodal tissue → no large Na⁺ influx to produce a prolonged plateau
• The action potential has a triangular shape without a plateau

Phase 3 - Repolarization

• L-type Ca²⁺ channels inactivate → Ca²⁺ influx stops
• K⁺ channels open → large outward K⁺ current (IK) → rapid repolarization
• Membrane returns to the maximum diastolic potential (~-60 mV)
• The cycle then repeats automatically

Complete Ionic Sequence Summary

Maximum Diastolic Potential (~-60 mV)
         ↓
1. IK declines (K⁺ channels close) → membrane drifts up
         ↓
2. If/Ih activates (HCN channels open) → Na⁺ inward → early slow depolarization
         ↓
3. ICa-T activates (T-type Ca²⁺) → further slow depolarization (later prepotential)
         ↓
Threshold reached (~-40 mV)
         ↓
4. ICa-L activates (L-type Ca²⁺) → rapid upstroke to +10 mV (Phase 0)
         ↓
5. ICa-L inactivates + IK activates → repolarization (Phase 3) back to -60 mV
         ↓
Cycle repeats → next pacemaker potential begins

Significance of the Rate of Phase 4 Depolarization

Autonomic Modulation of Pacemaker Potential (Sembulingam + Ganong)

Sympathetic Stimulation (Increases Heart Rate - Positive Chronotropy)

1. Increases the slope of phase 4 - by enhancing If (funny current) and ICa-T → threshold reached faster
2. Increases ICa-L → faster, stronger upstroke
3. Enhances IK → faster repolarization → shorter action potential → cycle repeats sooner

Parasympathetic (Vagal) Stimulation (Decreases Heart Rate - Negative Chronotropy)

1. Hyperpolarizes the cell (opens K⁺ channels → K⁺ efflux → MDP becomes more negative, e.g., -65 mV instead of -60 mV) → starts further from threshold
2. Decreases slope of phase 4 - reduces If and ICa-T → slower drift toward threshold
3. Decreases ICa-L → slower upstroke

Strong vagal stimulation may completely abolish SA node firing (sinus arrest)

Other Factors Modifying Pacemaker Potential

Clinical Relevance

Quick Revision Summary

• Essentials of Medical Physiology - K. Sembulingam & Prema Sembulingam, 6th Edition, Chapter 90 (Properties of Cardiac Muscle - Electrical Potential in SA Node)
• Ganong's Review of Medical Physiology, 26th Edition, Chapter 29 - Pacemaker Potentials
• Costanzo Physiology, 7th Edition, Chapter 4 - Action Potentials in the SA Node

How the Pacemaker Potential is Developed

Reference: Sembulingam's Essentials of Medical Physiology, 6th Ed. - Chapter 90

The Core Concept

Step-by-Step Development of the Pacemaker Potential

STEP 1 - The Starting Point: End of Repolarization (~-60 mV)

• After each action potential, K⁺ channels open and K⁺ flows outward → the cell repolarizes back to its most negative value, the Maximum Diastolic Potential (MDP) of approximately -60 mV
• At this point, the K⁺ channels that drove repolarization begin to close progressively
• As K⁺ efflux decreases (↓IK), the outward current that was keeping the cell negative is lost → the membrane potential starts to drift upward
• This is the very first trigger of the pacemaker potential

STEP 2 - Funny Current / If activates (early slow depolarization)

• As the membrane repolarizes and becomes more negative (hyperpolarized), a special type of channel called the HCN channel (Hyperpolarization-activated Cyclic Nucleotide-gated) opens
• This channel is unusual because most channels open when the cell depolarizes, but this one opens when the cell hyperpolarizes - hence it is called the "funny" channel, and its current is If (funny current) or Ih
• The HCN channel allows slow inward movement of Na⁺ (and some K⁺) into the cell
• This inward Na⁺ current is a slow current - very different from the fast Na⁺ current of ventricular muscle
• The net result: positive charges enter the cell → membrane potential rises slowly from -60 mV upward
• This forms the EARLY (initial) part of the pacemaker potential

Sembulingam: "Sodium ions leak into the pacemaker fibers and cause slow depolarization. This slow depolarization forms the initial part of pacemaker potential."

Ganong: "A channel permeable to both Na⁺ and K⁺ is activated following hyperpolarization... the current is called funny current (If/Ih). As Ih increases, the membrane begins to depolarize, forming the first part of the prepotential."

STEP 3 - T-type Ca²⁺ Channels open (late slow depolarization)

• As the membrane potential rises to approximately -50 mV, voltage-sensitive T-type (Transient) Ca²⁺ channels begin to open
• T-type channels are low-voltage activated - they open at a more negative potential than L-type channels
• Ca²⁺ flows inward down its concentration gradient → further slow depolarization
• This forms the LATER (terminal) part of the pacemaker potential
• The combined effect of If + ICa-T pushes the membrane from -60 mV all the way up to threshold at -40 mV

Sembulingam: "Then, the calcium channels start opening. At the beginning, there is a slow influx of calcium ions causing further depolarization in the same slower rate. It forms the later part of the pacemaker potential."

Ganong: "ICa due to opening of T channels completes the prepotential."

STEP 4 - Threshold Reached → Action Potential fires (Phase 0)

• Once the membrane potential reaches -40 mV (threshold), L-type (Long-lasting) Ca²⁺ channels open rapidly
• A large surge of Ca²⁺ rushes into the cell → rapid upstroke (depolarization) to approximately +10 to +20 mV
• This is the action potential of the SA node
• Note: The upstroke is driven by Ca²⁺, NOT Na²⁺ - this is unique to nodal tissue

STEP 5 - Repolarization → Cycle Repeats

• L-type Ca²⁺ channels inactivate → Ca²⁺ influx stops
• K⁺ channels open → K⁺ flows outward → repolarization back to -60 mV (MDP)
• HCN channels reactivate (triggered by the new hyperpolarization)
• The entire pacemaker potential cycle begins again automatically

Visual Summary of the Development

-60 mV  ─────────────────────────────────────────────────────────
(MDP)        │
             │  ① IK closes (K⁺ outflow ↓)
             │     → membrane drifts upward
             │
             │  ② If / Ih activates (HCN channels)
             │     Na⁺ enters slowly → early slow depolarization
             │
-50 mV  ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─
             │
             │  ③ ICa-T activates (T-type Ca²⁺ channels)
             │     Ca²⁺ enters slowly → later slow depolarization
             │
-40 mV  ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ THRESHOLD ─ ─ ─ ─ ─ ─
             │
             │  ④ ICa-L activates (L-type Ca²⁺ channels)
             │     Rapid Ca²⁺ influx → UPSTROKE (Action Potential)
             │
+10 mV  ─────────────────────────────────────────────────────────
             │
             │  ⑤ IK opens → repolarization → back to -60 mV
             │     Cycle restarts automatically

Ionic Basis at a Glance

Why this Mechanism is Self-Sustaining

• Repolarization → hyperpolarization → activates HCN (funny) channels
• HCN channels start depolarizing the cell again → T-type → L-type → action potential → repolarization
• This is an endless self-perpetuating loop - the basis of the heart's automaticity

This is why the heart can beat even when completely removed from the body and placed in a physiological saline solution - as long as the SA node cells are alive, they will continue generating pacemaker potentials and action potentials on their own.

• Essentials of Medical Physiology - K. Sembulingam & Prema Sembulingam, 6th Ed., Chapter 90
• Ganong's Review of Medical Physiology, 26th Ed., Chapter 29
• Costanzo Physiology, 7th Ed., Chapter 4

Properties of Cardiac Muscle - MBBS Physiology

Reference: Sembulingam's Essentials of Medical Physiology, 6th Ed. - Chapter 90

Classification of Properties

PROPERTIES OF CARDIAC MUSCLE
├── A. Electrical Properties
│   ├── 1. Resting Membrane Potential
│   ├── 2. Action Potential
│   ├── 3. Automaticity
│   ├── 4. Rhythmicity
│   └── 5. Conductivity
│
└── B. Mechanical Properties
    ├── 6.  Contractility
    ├── 7.  All-or-None Law
    ├── 8.  Long Refractory Period
    ├── 9.  Incomplete Tetanus
    ├── 10. Infatiguability
    ├── 11. Extrasystole & Compensatory Pause
    ├── 12. Staircase Phenomenon (Treppe)
    ├── 13. Frank-Starling Law
    └── 14. Tonicity

A. ELECTRICAL PROPERTIES

1. Resting Membrane Potential (RMP)

• The stable resting potential in ventricular muscle is maintained primarily by high resting K⁺ conductance (IK1 channels)
• The SA node has an unstable resting potential - this is the basis of its automaticity

2. Action Potential of Cardiac Muscle

Key feature: The plateau (Phase 2) caused by L-type Ca²⁺ channel opening is unique to cardiac muscle. It:

• Prolongs the action potential to 250-350 ms
• Keeps the cell refractory (prevents tetanus)
• Provides the Ca²⁺ that triggers contraction (excitation-contraction coupling)

3. Automaticity (Self-Excitability)

• The SA node, AV node, Bundle of His, and Purkinje fibers all have this property
• They are called autorhythmic cells or pacemaker cells
• The mechanism is the pacemaker potential (prepotential) - the spontaneous diastolic depolarization driven by If (funny current), then T-type Ca²⁺ channels
• This is why the heart is myogenic - its beat originates from within the muscle itself, not from nerves

Contrast with skeletal muscle: Skeletal muscle requires nerve stimulation to contract and has no automaticity. If its nerve is cut, it stops contracting.

Practical importance: The isolated heart (placed in oxygenated physiological saline) continues to beat rhythmically for hours.

4. Rhythmicity (Autorhythmicity)

• The SA node fires impulses rhythmically at 70-80 per minute under resting conditions
• This regular rhythm ensures the heart pumps blood in a coordinated, regular pattern
• Rhythmicity is intrinsic to the nodal tissue - it does not depend on the nervous system
  • Cutting the vagus and sympathetic nerves does not stop the heartbeat - it continues at ~100/min (intrinsic SA node rate without autonomic influence)

• SA node is the pacemaker because it fires the fastest

5. Conductivity

• Impulses generated in the SA node spread through the entire heart via:
  • Intercalated discs with gap junctions → electrical syncytium
  • Specialized conducting system (internodal tracts, AV node, Bundle of His, Purkinje fibers)
• The heart functions as a functional syncytium - the atria form one syncytium and the ventricles another, separated by the fibrous AV ring
• Because of this, a stimulus applied anywhere in the atrium causes all atrial fibers to contract (all-or-none basis)

B. MECHANICAL PROPERTIES

6. Contractility

• The response to a stimulus takes about 300 msec, which is just enough time for the chamber to pump blood before the next stimulus arrives
• Strength of contraction depends on:
  • Concentration of Ca²⁺ in extracellular fluid (ECF)
  • End-diastolic fiber length (Frank-Starling law)
  • Sympathetic stimulation (positive inotropy)
• Increased contractility → increased cardiac output

• Sympathetic stimulation / catecholamines
• Digitalis (inhibits Na⁺/K⁺ ATPase → ↑ intracellular Ca²⁺)
• Increased heart rate (Bowditch/Treppe effect)
• Increased extracellular Ca²⁺

• Parasympathetic stimulation
• Beta-blockers
• Hypoxia, acidosis
• Heart failure

7. All-or-None Law

• If the stimulus is below threshold → no contraction (none)
• If the stimulus is at or above threshold → maximum contraction (all)
• Increasing stimulus strength beyond threshold does not increase the force of contraction (as long as conditions remain the same)

• Because the heart is a functional syncytium via gap junctions - depolarization spreads to all fibers simultaneously
• Either all fibers in the syncytium depolarize, or none do

Contrast with skeletal muscle: Skeletal muscle shows graded response - stronger stimulus recruits more motor units. This is NOT possible in cardiac muscle.

Note: The all-or-none law applies under same conditions. If conditions change (e.g., more Ca²⁺, more preload), the same stimulus can produce greater contraction - this is explained by the Frank-Starling law and contractility changes.

8. Long Refractory Period

• Due to the plateau phase (Phase 2) maintained by L-type Ca²⁺ channels
• During the plateau, the membrane remains depolarized → Na⁺ channels remain inactivated → cannot fire a new action potential

• The long ARP coincides with the entire period of contraction (systole)
• A new stimulus cannot cause contraction until the heart has almost fully relaxed (diastole)
• This prevents cardiac tetanus (sustained contraction) which would be fatal as the heart could not fill with blood
• Ensures alternating contraction and relaxation essential for pumping

• Absolute Refractory Period (ARP): No stimulus, however strong, can produce a response (~200 ms)
• Relative Refractory Period (RRP): Only a very strong stimulus can produce a response (~50 ms) - this is when extrasystoles can occur
• Effective Refractory Period (ERP): ARP + early portion of RRP

9. Incomplete Tetanus

• In skeletal muscle, repeated rapid stimuli can fuse contractions into a sustained tetanus
• In cardiac muscle, this is impossible because the refractory period lasts almost as long as the entire contraction
• By the time the muscle becomes excitable again, it has already started to relax
• Therefore, the heart can produce incomplete tetanus at most but never complete tetanic contraction
• This is physiologically vital - complete tetanus would prevent the heart from relaxing and filling with blood, causing immediate cardiac death

10. Infatiguability (Non-Fatigability)

• The heart beats continuously throughout life (~100,000 times per day) without fatigue
• Reasons for infatiguability:
  1. Rich blood supply via coronary circulation - constant O₂ and nutrient delivery
  2. Abundant mitochondria in cardiac muscle cells (~35% of cell volume vs 2% in skeletal muscle) → sustained aerobic energy production
  3. High myoglobin content → acts as O₂ store
  4. Uses fatty acids as primary fuel (70%) - high-energy, efficient source
  5. Alternating contraction and relaxation - diastolic rest period allows recovery

Clinical note: Fatigue does occur in heart failure and severe ischemia - when O₂ supply is compromised, the heart's reserve capacity is exhausted.

11. Extrasystole and Compensatory Pause (Sembulingam)

• When a stimulus falls during the relative refractory period of the cardiac cycle, an extra contraction occurs before the next normal beat - called an extrasystole (premature beat / ectopic beat)
• It is weaker than normal (muscle not fully recovered)
• The SA node fires at its regular time but finds the ventricles still refractory (from the extrasystole) → this beat is missed (blocked)

• After an extrasystole, the next normal impulse from the SA node arrives before the heart has recovered → this impulse cannot produce a contraction
• The heart then waits for the next normal SA node impulse → a longer-than-normal pause occurs before the next contraction
• This pause is called the compensatory pause
• After the compensatory pause, the heart returns to its normal rhythm

• The beat after the compensatory pause is often stronger than normal (due to increased Ca²⁺ loading during the longer diastole)

12. Staircase Phenomenon (Treppe / Bowditch Effect)

• Rapid stimulation → less time between beats → less Ca²⁺ removed from cell between beats
• Intracellular Ca²⁺ accumulates progressively with each beat
• More Ca²⁺ available for troponin → stronger contraction
• Also: increased temperature with activity → decreased viscosity of cell components → easier cross-bridge cycling

1. Increased intracellular Ca²⁺
2. Increased temperature
3. Decreased viscosity

13. Frank-Starling Law of the Heart

• Length = End-Diastolic Volume (EDV) (preload)
• Tension = Pressure developed by ventricles
• As EDV increases → fibers are stretched more → more optimal overlap of actin and myosin → stronger contraction → higher stroke volume
• This is called heterometric autoregulation of cardiac output

• Ensures that the right and left ventricles always eject equal stroke volumes - if right ventricle pumps more, more blood returns to left ventricle → left ventricle is more stretched → left ventricle contracts more forcefully to match
• Allows the heart to adjust its output automatically to match venous return

Mechanism at sarcomere level: Optimal sarcomere length for maximum cross-bridge formation is 2.0-2.2 μm. Stretching up to this length increases overlap of actin and myosin → stronger contraction. Overstretching decreases overlap → weaker contraction (descending limb).

14. Tonicity (Resting Tone)

• Unlike skeletal muscle, cardiac muscle maintains a constant baseline tension
• Functions of tonicity:
  1. Prevents overdistension of cardiac chambers - if the heart lacked tone, the chambers would balloon out with each filling
  2. Builds pressure within the chambers necessary for efficient ejection
  3. Maintains the structural integrity of the cardiac chambers
• Tonicity depends on the structural integrity of the myofibrils and the normal ionic environment
• Reduced by: hypoxia, acidosis, myocardial disease
• Enhanced by: sympathetic stimulation, digitalis

Summary Table - Properties of Cardiac Muscle

• Essentials of Medical Physiology - K. Sembulingam & Prema Sembulingam, 6th Ed., Chapter 90 (Properties of Cardiac Muscle)
• Costanzo Physiology, 7th Ed., Chapter 4 - Cardiac Action Potentials
• Ganong's Review of Medical Physiology, 26th Ed., Chapter 29 - Properties of Cardiac Muscle