Prepotential (Pacemaker Potential) of the SA Node

The Pacemaker Potential vs. Ventricular Action Potential

• Maximum diastolic potential is only about -55 to -60 mV (ventricular is -90 mV)
• No stable phase 4 - the membrane continuously drifts upward
• No rapid Na+ spike - the action potential upstroke is entirely Ca2+-dependent

Ionic Basis of the Prepotential - Three Sequential Events

1. Decline of IK (Repolarizing K+ current decreases)

2. Activation of the "Funny Current" I_h (or I_f)

• Called the "h" channel (activated by hyperpolarization) or "f" channel (because of its funny activation)
• The current it carries = I_h or If (funny current)
• This is responsible for the first, slow part of the prepotential

3. T-type Ca2+ channels open (ICa-T)

4. L-type Ca2+ channels fire the action potential

Note: Evidence also exists that Ca2+ sparks (local Ca2+ release from the sarcoplasmic reticulum) contribute to the prepotential - a "calcium clock" mechanism that works alongside the membrane clock described above.

Summary Table

Autonomic Modulation of the Prepotential

• Increases intracellular cAMP
• cAMP facilitates opening of L-type Ca2+ channels
• The slope of the prepotential steepens → threshold reached faster → heart rate increases (tachycardia)

• Opens K+ channels (I_K-ACh)
• Membrane hyperpolarizes further (maximum diastolic potential more negative)
• Reduces the slope of the prepotential and slows I_h
• Threshold is reached more slowly → heart rate decreases (bradycardia)
• Strong vagal stimulation can temporarily stop SA node firing entirely

Why Only SA and AV Nodes Have Prepotentials

• Ganong's Review of Medical Physiology, 26th Ed., pp. 522-523

Cardiac Output and Factors Affecting It

Definition

"Cardiac output is the quantity of blood pumped into the aorta each minute by the heart. This is also the quantity of blood that flows through the circulation."

• Guyton and Hall Textbook of Medical Physiology

The Basic Formula

• A 70 kg adult male has ~5.6 L/min; women are ~15% lower
• The cardiac index (CO per m² BSA) corrects for body size
• Cardiac index peaks at about 4 L/min/m² around age 10, and falls to ~2.4 L/min/m² by age 80

The Cardiac Output Curve (Guyton)

Factors Affecting Cardiac Output

1. Factors Affecting Stroke Volume

A. Preload (Frank-Starling Mechanism)

• Preload = End-diastolic volume (EDV); the degree of stretch of ventricular muscle before contraction
• The Frank-Starling law states: the more the ventricle fills during diastole, the more forcefully it contracts and the more blood it ejects
• This is based on the length-tension relationship in cardiac muscle - greater fiber stretch = greater overlap of actin-myosin = more force
• In normal physiology, venous return is the primary determinant of preload and thus the primary controller of cardiac output
• Factors that increase preload (and thus CO): increased blood volume, increased venous tone, body position (lying down), exercise (muscle pump), inspiration

B. Afterload

• Afterload = the resistance the ventricle must overcome to eject blood = largely determined by aortic pressure and total peripheral resistance (TPR)
• As afterload increases, stroke volume decreases (harder to eject)
• As afterload decreases (e.g., vasodilation), stroke volume increases
• Guyton shows a reciprocal relationship between TPR and cardiac output - conditions that chronically decrease TPR (Beriberi, AV fistula, hyperthyroidism, anemia) lead to high cardiac output states

C. Contractility (Inotropy)

• Contractility = the intrinsic strength of contraction independent of preload and afterload
• Agents that increase contractility (positive inotropes) shift the Frank-Starling curve upward - more stroke volume for the same EDV
• Agents that decrease contractility (negative inotropes) shift the curve downward

2. Factors Affecting Heart Rate

Note: Very high heart rates can actually reduce CO because diastolic filling time shortens, preload falls, and stroke volume drops enough to offset the rate increase.

3. Peripheral Factors (Venous Return)

• Mean systemic filling pressure (Psf) - the driving pressure from peripheral vessels to right atrium; increased by blood volume expansion
• Resistance to venous return - increased by venous constriction or obstruction
• Right atrial pressure - the back-pressure opposing venous return

1. Beriberi (thiamine deficiency) - inability to use cellular nutrients → compensatory vasodilation → TPR may halve → CO doubles
2. AV fistula - blood bypasses capillary resistance → ↓TPR → ↑CO
3. Hyperthyroidism - ↑metabolism → vasodilation → CO increases 40-80%
4. Anemia - ↓blood viscosity + tissue hypoxia → vasodilation → ↑CO

• Myocardial infarction, severe valvular disease, myocarditis, cardiac tamponade, arrhythmias
• Decreased venous return (hemorrhage, dehydration, obstructed venous return)

CO During Exercise

• Marked sympathetic stimulation → ↑HR + ↑contractility
• Skeletal muscle pump → ↑venous return → ↑preload
• Local vasodilation in active muscles → ↓TPR → ↑venous return
• Increased respiratory movements (respiratory pump)

Summary of Factors

Cardiac Output = Stroke Volume × Heart Rate

Stroke Volume is ↑ by:           Heart Rate is ↑ by:
- ↑ Preload (EDV/venous return)   - Sympathetic stimulation
- ↓ Afterload (↓TPR/aortic P)    - Fever
- ↑ Contractility (inotropes)    - Bainbridge reflex
                                  - Thyroid hormones

• Guyton and Hall Textbook of Medical Physiology
• Costanzo Physiology, 7th Edition, pp. 155-157