Micturition Reflex

Definition

Anatomy of the Bladder and Sphincters

• Detrusor muscle - smooth muscle that forms the bladder body; gap junctions allow coordinated whole-bladder contraction
• Trigone - smooth triangular area on the posterior wall between the two ureteric orifices and the urethral opening
• Bladder neck (posterior urethra) - 2-3 cm long; contains the internal sphincter (smooth muscle, involuntary)
• External sphincter - skeletal (striated) muscle in the urogenital diaphragm; under voluntary control via the pudendal nerve

Innervation

Bladder Filling and Cystometrogram

• Empty bladder: intravesical pressure ~0 cmH₂O
• 30-50 mL: pressure rises to 5-10 cmH₂O
• 200-300 mL: pressure stays nearly flat (high compliance due to detrusor relaxation - stress relaxation)

• 300-400 mL: steep pressure rise

• First urge to void: ~150 mL; sense of fullness: 400-500 mL

The Micturition Reflex: Mechanism

Afferent Limb

• Bladder stretch activates tension/stretch receptors in the detrusor wall - particularly in the posterior urethra
• Signals travel via myelinated Aδ-fibers in the pelvic nerves to the sacral cord (S2-S4)

Spinal Reflex Arc

• Sacral spinal cord integrates the afferent stretch signals
• Sends parasympathetic efferent signals back through the pelvic nerve to the detrusor → detrusor contraction
• Simultaneously inhibits the external sphincter via the pudendal nerve

Self-Regenerative (Positive Feedback) Cycle

1. Bladder contraction further stretches the posterior urethra
2. This activates more stretch receptors
3. Which increases afferent firing
4. Which increases detrusor contraction further

1. Progressive, rapid pressure rise
2. Sustained peak pressure
3. Return to baseline

Supraspinal Control: The Brain's Role

Pontine Micturition Center (PMC) - "Barrington's Center"

• Located in the pons (dorsomedial tegmentum)
• The PMC acts as a switch: it inhibits parasympathetic output during storage and activates it during voiding
• Coordinates detrusor contraction with sphincter relaxation (prevents detrusor-sphincter dyssynergia)
• Receives integrated afferent information from the periaqueductal gray (PAG), which in turn receives input from cortex, hypothalamus, and bladder afferents
• The PMC threshold is set by GABAergic inhibitory mechanisms and inputs from rostral brain regions

Cerebral Cortex

• Primarily inhibitory - keeps the reflex suppressed until a socially appropriate time
• Can also facilitate the sacral micturition center when voiding is desired

Summary of Higher Control (Guyton & Hall):

1. Higher centers keep the micturition reflex partially inhibited during storage
2. They can prevent voiding (via tonic voluntary external sphincter contraction) even when the reflex fires
3. When ready to void, the cortex facilitates the sacral center and simultaneously relaxes the external sphincter

Two Types of Micturition Reflex

Storage Reflexes (preventing unwanted voiding)

1. Sympathetic storage reflex (vesicospinovesical storage): Bladder distension (Aδ afferents) → lumbar sympathetic (L1-L3) → inhibits parasympathetic ganglia (β3-AR stimulation relaxes detrusor) + contracts bladder neck (α-AR)
2. Somatic guarding/continence reflex (pelvic-to-pudendal): Sudden rise in intra-abdominal pressure (cough, sneeze) → Aδ afferents → sacral cord (Onuf's nucleus) + PAG/PMC → pudendal nerve → external sphincter contraction (rhabdosphincter)

Voluntary Initiation of Voiding

1. Person voluntarily contracts abdominal muscles → raises intravesical pressure
2. Urine enters the bladder neck and posterior urethra under pressure
3. This stretches the posterior urethra → activates stretch receptors
4. Excites the micturition reflex AND simultaneously inhibits the external sphincter
5. Bladder empties completely (normally <5-10 mL residual urine)

Pathophysiology of Micturition

• Guyton and Hall Textbook of Medical Physiology, Chapter 26 (Micturition)
• Medical Physiology (Boron & Boulpaep), Chapter 33
• Smith and Tanagho's General Urology, 19th Ed., Chapter on Neural Control of Bladder

Cardiac Output and Its Regulation

1. Definition

2. Normal Values

Cardiac Index

3. Components: Determinants of CO

A. Preload

• The load on the ventricle at the end of diastole, before contraction begins
• Equivalent to end-diastolic volume (EDV) or end-diastolic fiber length
• Clinically estimated by: Central Venous Pressure (CVP) for right ventricle, Pulmonary Capillary Wedge Pressure (PCWP) for left ventricle
• Increased preload → increased SV (Frank-Starling mechanism)
• Increased by: high venous return, blood transfusion, bradycardia (longer filling time)
• Decreased by: hemorrhage, dehydration, venodilation (nitrates)

B. Afterload

• The systolic load opposing ventricular ejection - wall stress during contraction
• Clinically approximated by systemic vascular resistance (SVR) or systolic blood pressure
• Formally defined using Laplace's Law: Wall stress (σ) = (P × R) / (2h) where P = pressure, R = radius, h = wall thickness
• Increased afterload → decreased SV (harder for ventricle to eject)
• Increased by: hypertension, aortic stenosis, arteriolar vasoconstriction
• Decreased by: vasodilators (e.g., ACE inhibitors, nitroprusside)

Note: The ventricle compensates for chronically increased afterload by hypertrophy (↑ wall thickness h), which reduces wall stress per Laplace's law.

C. Contractility (Inotropy)

• The intrinsic force-generating ability of the myocardium, independent of preload and afterload
• Reflects the number of cross-bridges formed at a given sarcomere length
• Increased by: sympathetic stimulation (β₁-receptors → ↑ cAMP → ↑ intracellular Ca²⁺), digoxin, catecholamines, exercise
• Decreased by: heart failure, myocardial ischemia, β-blockers, acidosis, hypoxia
• On Frank-Starling curves: positive inotropy shifts the curve upward; negative inotropy shifts it downward

D. Heart Rate (Chronotropy)

• CO = SV × HR - directly determines output at any given SV
• Increased by: sympathetic stimulation (β₁), catecholamines, thyroid hormone, fever
• Decreased by: parasympathetic (vagal) stimulation, β-blockers, hypothyroidism
• Extreme tachycardia (>160-180/min) paradoxically decreases CO because diastolic filling time is too short → reduced EDV → reduced SV

4. The Frank-Starling Law (Intrinsic Regulation)

• Increased venous return → ↑ EDV → stretches sarcomeres → more optimal overlap of actin-myosin filaments → stronger contraction → ↑ SV
• Physiological basis: at sarcomere lengths of 1.8-2.2 µm, greater stretch = more cross-bridge formation

1. The left and right ventricles automatically match their outputs - preventing pulmonary congestion
2. Ensures cardiac output equals venous return in steady state
3. Acts as a beat-to-beat self-regulating mechanism

5. The Cardiac Output Curve (Cardiac Function Curve)

• Plots right atrial pressure (RAP) vs. cardiac output
• At normal RAP (~0 mmHg), CO = ~5 L/min
• The curve plateaus at ~13 L/min in a normal heart (2.5× resting CO)
• Hypereffective heart (sympathetic stimulation, hypertrophy): curve shifts upward
• Hypoeffective heart (heart failure, MI, drugs): curve shifts downward and flattens

6. Venous Return and Its Role (Peripheral Regulation)

"The venous return to the heart is the primary controller of cardiac output under normal conditions." - Guyton & Hall

• ↓ TPR (vasodilation) → ↑ venous return → ↑ CO (e.g., exercise, AV fistula, anemia)
• ↑ TPR (vasoconstriction) → ↓ CO (e.g., hypertension)

• Increased blood volume
• Venoconstriction (sympathetic stimulation)
• Skeletal muscle pump (exercise)
• Respiratory pump (negative intrathoracic pressure during inspiration)
• Decreased venous capacitance

7. Nervous System Regulation (Extrinsic)

Sympathetic Nervous System

• Chronotropy: ↑ HR via β₁ receptors on SA node
• Inotropy: ↑ contractility via β₁ receptors on ventricular myocardium
• Vasomotor tone: maintains arterial pressure → prevents fall in CO when TPR falls
• During exercise: sympathetic activation raises BP above normal → "pushes" additional blood through active muscles (adds 30-100% to CO above what local vasodilation alone achieves)

Parasympathetic (Vagus)

• Primarily slows HR (negative chronotropy) via M₂ receptors on SA/AV nodes
• Minimal direct effect on ventricular contractility

Bainbridge Reflex

• Stretch of right atrial wall → afferent signals to vasomotor center → sympathetic efferents back to SA node → ↑ HR by 10-15%
• A direct intrinsic response to increased venous return that helps the heart keep up

8. CO During Exercise

• CO rises linearly with oxygen consumption and work output
• Resting CO of ~5 L/min can reach 20-25 L/min in an average adult
• Trained athletes: up to 30-40 L/min (due to cardiac hypertrophy + strong sympathetic drive)
• Mechanism: ↑ skeletal muscle metabolism → local vasodilation → ↓ TPR → ↑ venous return → Frank-Starling ↑ SV + simultaneous sympathetic ↑ HR

9. Hormonal Regulation

10. Pathological Changes in CO

Abnormally HIGH CO (due to ↓ TPR)

Abnormally LOW CO

11. Summary: Regulation of Cardiac Output

CARDIAC OUTPUT = STROKE VOLUME × HEART RATE
                        ↑
          ┌─────────────┴──────────────┐
       PRELOAD               AFTERLOAD (inverse)
    (Frank-Starling)      (SVR, aortic compliance)
          ↑                        ↑
    Venous return           Vascular resistance
    
       CONTRACTILITY
    (Sympathetic, catecholamines,
     digoxin, Ca²⁺)
    
       HEART RATE
    (Sympathetic ↑, Vagal ↓,
     Catecholamines, Thyroid)

• Guyton and Hall Textbook of Medical Physiology, Chapter 20 (Cardiac Output, Venous Return, and Their Regulation)
• Costanzo Physiology, 7th Edition, Chapter 4 (Cardiac Output)
• Medical Physiology (Boron & Boulpaep), Chapter on Regulation of Cardiac Output
• Braunwald's Heart Disease, Chapter 46 (Wall Stress, Preload, Afterload)
• Miller's Anesthesia, 10th Edition, Chapter 13 (Preload and Afterload)

Pacemaker Potential (Prepotential) - Physiology

1. What Is the Pacemaker Potential?

2. SA Node vs. Ventricular Action Potential: Key Comparison

3. Ionic Basis of the Pacemaker Potential (Phase 4)

Step 1 - Declining K⁺ conductance (↓ IK)

• At the end of each action potential (after repolarization), the IK current that caused repolarization gradually declines
• Since K⁺ was driving the membrane toward EK (very negative), as IK falls, there is less outward current holding the membrane at the most negative value
• Maximum diastolic potential (MDP): approximately -65 mV

Step 2 - Activation of the "Funny" Current (If / Ih)

• As the membrane repolarizes and becomes negative, HCN (Hyperpolarization-activated Cyclic Nucleotide-gated) channels open
• These are activated by hyperpolarization (hence "h" channels) and carry a mixed Na⁺ + K⁺ inward current
• This current is called If (funny current) because it is paradoxically activated by hyperpolarization (opposite to most voltage-gated channels)
• If drives the first part of the slow depolarization (roughly -65 mV to -50 mV)

Step 3 - T-type Ca²⁺ channel activation (ICa,T)

• As the membrane depolarizes to around -50 mV, T-type (Transient) Ca²⁺ channels open
• These generate an inward Ca²⁺ current (ICa,T) that completes the prepotential, depolarizing the membrane to threshold (~-40 mV)
• Evidence also exists for Ca²⁺ sparks (local Ca²⁺ release from the SR) contributing at this stage

Step 4 - Upstroke: L-type Ca²⁺ channels (ICa,L)

• Once threshold (~-40 mV) is reached, L-type (Long-lasting) Ca²⁺ channels open
• This generates the action potential upstroke in SA nodal cells
• Note: There is no fast Na⁺ current (INa) contributing to the SA node upstroke - this is why SA node action potentials are "slow response" action potentials

Step 5 - Repolarization (IK)

• K⁺ conductance increases → outward IK repolarizes the membrane back to ~-65 mV (MDP)
• The cycle then repeats automatically

4. Summary of Ionic Events in the SA Node Action Potential

Membrane potential
     +10 mV ─────────────────┐ (upstroke: ICa,L opens)
                             │
      -40 mV ─ ─ ─(threshold)│
             T-Ca²⁺ opens ↑  │
                          ↑  │
      -50 mV ─────If(funny)  │
             starts here     │
                          ↑  │  (repolarization: IK↑)
      -65 mV ─────(MDP)──────────────── (IK declines)
              ← Phase 4 →   └────────────────────
              (Pacemaker potential)
              IK declines → If activates → ICa,T → reaches threshold → ICa,L fires

5. Phases of SA Node Action Potential (No Phase 0,1,2)

6. Latent Pacemakers and Overdrive Suppression

1. SA node firing rate decreases (vagal stimulation, disease)
2. Intrinsic rate of a latent pacemaker increases (ischemia, digoxin toxicity)
3. Conduction block from SA node to rest of heart

7. Autonomic Nervous System Control of Pacemaker Potential

Sympathetic Stimulation (↑ Heart Rate - Positive Chronotropy)

• Norepinephrine binds β₁ receptors on SA node → activates Gs protein → ↑ adenylyl cyclase → ↑ cAMP
• ↑ cAMP has two effects:
  1. ↑ If (funny current) → steeper, faster Phase 4 depolarization
  2. ↑ ICa,L → threshold potential decreases (less depolarization needed to fire)
• Result: threshold reached faster → more action potentials per minute → ↑ HR

Parasympathetic Stimulation (↓ Heart Rate - Negative Chronotropy)

• Acetylcholine binds M2 (muscarinic) receptors on SA node → activates Gi protein (Gk) → ↓ adenylyl cyclase → ↓ cAMP
• Three combined effects:
  1. ↓ If → slower Phase 4 depolarization (less steep slope)
  2. ↑ IKACh (K⁺-Ach channels open via Gk directly) → hyperpolarizes MDP further from threshold
  3. ↓ ICa → threshold potential increases (more depolarization needed to fire)
• Strong vagal stimulation → complete cessation of SA node firing (vagal arrest)

8. How Autonomic Inputs Change Heart Rate: Summary Table

9. Clinical Relevance

10. Quick Revision Summary

PACEMAKER POTENTIAL (Phase 4) ionic sequence:
1. ↓ IK (K⁺ conductance falls after repolarization)
2. ↑ If = funny current (HCN channels: Na⁺+K⁺ inward) ← main driver
3. ↑ ICa,T (T-type Ca²⁺) ← completes prepotential to threshold
4. ↑ ICa,L (L-type Ca²⁺) ← ACTION POTENTIAL upstroke (NO fast Na⁺)
5. ↑ IK → repolarization → cycle repeats

Rate determined by: slope of Phase 4, level of MDP, and threshold potential
Sympathetic → ↑ slope + ↓ threshold → FASTER rate
Parasympathetic → ↓ slope + lower MDP + ↑ threshold → SLOWER rate

• Costanzo Physiology, 7th Edition, Chapter 4 (Cardiac Action Potentials, Phase 4, Latent Pacemakers, Autonomic Effects)
• Ganong's Review of Medical Physiology, 26th Edition, Chapter 29 (Pacemaker Potentials)
• Medical Physiology (Boron & Boulpaep), Chapter on Autonomic Modulation of Pacemaker Activity