Unit 3: Circulatory Physiology in Mammals

1. Circulation of Blood Through the Mammalian Heart

Overview of the Mammalian Heart Structure

The mammalian heart is a myogenic, four-chambered muscular organ located in the mediastinum of the thoracic cavity. It consists of two upper receiving chambers (right atrium and left atrium) and two lower pumping chambers (right ventricle and left ventricle). The heart is divided vertically by the interatrial and interventricular septa, preventing the mixing of deoxygenated and oxygenated blood.

Pattern of Blood Flow

Mammals exhibit double circulation, comprising pulmonary circulation and systemic circulation. Blood flows through the heart in a strict, unidirectional sequence dictated by four main cardiac valves.

1. Deoxygenated Blood Return: Systemic deoxygenated blood from the upper and lower body returns via the superior vena cava and inferior vena cava into the right atrium. Coronary sinus drains blood from the heart wall itself into the right atrium.
2. Right Atrioventricular Passage: The right atrium contracts, moving blood through the tricuspid valve into the right ventricle.
3. Pulmonary Pumping: The right ventricle contracts, pumping deoxygenated blood through the pulmonary semilunar valve into the pulmonary trunk, which divides into left and right pulmonary arteries leading to the lungs for gas exchange.
4. Oxygenated Blood Return: Freshly oxygenated blood returns from the lungs through four pulmonary veins into the left atrium.
5. Left Atrioventricular Passage: The left atrium contracts, passing blood through the bicuspid valve (mitral valve) into the left ventricle.
6. Systemic Pumping: The thick-walled left ventricle contracts forcefully, propelling oxygenated blood through the aortic semilunar valve into the systemic aorta, distributing blood to the entire body.

Definition - Double Circulation: A circulatory pathway in which blood passes through the heart twice during a single complete circuit through the body, consisting of pulmonary circulation (heart to lungs to heart) and systemic circulation (heart to body tissues to heart).

Comparison of Circulatory Circuits

Exam Note: Remember that pulmonary arteries are the only arteries in the adult mammal that carry deoxygenated blood, and pulmonary veins are the only veins that carry oxygenated blood.

2. Structure and Working of Conducting Myocardial Fibres

Structure of Conducting Myocardial Fibres

The mammalian heart is myogenic, meaning the initiation of the heartbeat originates within specialized cardiac muscle tissue rather than nerve impulses. Conducting myocardial fibres are specialized, non-contractile or weakly contractile cardiac muscle cells modified for high-velocity impulse generation and conduction.

• Sinoatrial (SA) Node: Located in the upper wall of the right atrium near the entrance of the superior vena cava. It acts as the primary pacemaker because it possesses the highest intrinsic rate of spontaneous depolarization (70-80 impulses per minute).
• Atrioventricular (AV) Node: Situated in the lower interatrial septum near the tricuspid valve. It serves as a secondary pacemaker (40-60 impulses per minute) and introduces an essential conduction delay.
• Bundle of His (Atrioventricular Bundle): A tract of specialized conductive tissue passing from the AV node through the fibrous cardiac skeleton into the interventricular septum. It divides into left and right bundle branches.
• Purkinje Fibres: Large, specialized myocardial fibres extending throughout the subendocardial tissue of the ventricular myocardium. They contain abundant glycogen, fewer myofibrils, and extensive gap junctions, allowing rapid transmission of impulses (2-4 meters per second).

Mechanism of Action (Working)

The conductive tissue functions through spontaneous, rhythmic electrical depolarization driven by specialized pacemaker potentials.

1. Pacemaker Potential Generation: SA nodal cells lack a stable resting membrane potential. They exhibit slow spontaneous diastolic depolarization (pacemaker potential) caused by the inward flow of sodium ions through hyperpolarization-activated cyclic nucleotide-gated channels (funny current, I-f), followed by influx through T-type and L-type calcium channels.
2. Atrial Propagation: Depolarization spreads rapidly across atrial myocytes via gap junctions embedded within intercalated discs, causing synchronized atrial contraction. Internodal tracts carry the impulse directly to the AV node.
3. AV Nodal Delay: The impulse is delayed at the AV node by approximately 0.1 seconds (100 milliseconds). This delay occurs due to smaller cell diameters and fewer gap junctions, ensuring that atrial contraction is fully completed before ventricular contraction begins.
4. Ventricular Propagation: The electrical signal passes rapidly from the AV node through the Bundle of His, down the left and right bundle branches, and into the Purkinje network. This triggers depolarization of the ventricular myocardium from the apex toward the base of the heart, pushing blood upward toward the arterial outlets.

Common Mistake: Confusing Purkinje fibres with nerve fibres. Purkinje fibres are modified cardiac muscle cells, not neurons.

3. The Cardiac Cycle

The cardiac cycle encompasses all mechanical and electrical events occurring from the beginning of one heartbeat to the beginning of the next. At a standard rest heart rate of 75 beats per minute, a single cardiac cycle lasts approximately 0.8 seconds.

Phases of the Cardiac Cycle

1. Atrial Systole (0.1 second):

   Atria contract, pushing an additional 20-30% of end-diastolic volume into the ventricles (atrial kick). AV valves are open; semilunar valves are closed.

2. Ventricular Isovolumetric Contraction (0.05 second):

   Ventricles begin to contract, raising intraventricular pressure. The AV valves close rapidly (producing the First Heart Sound, S1). Because all four valves are closed, ventricular volume remains constant while pressure rises sharply.

3. Ventricular Rapid and Reduced Ejection (0.25 second):

   Intraventricular pressure surpasses arterial pressure (aortic and pulmonary pressures). The semilunar valves open, and blood is ejected forcefully into the aorta and pulmonary trunk. Ventricular volume decreases rapidly.

4. Ventricular Isovolumetric Relaxation (0.06 second):

   Ventricles relax, causing intraventricular pressure to drop rapidly below arterial pressure. Backflow of blood closes the semilunar valves (producing the Second Heart Sound, S2). All four valves are closed; ventricular volume remains unchanged.

5. Ventricular Filling Phase (0.34 second):

   Intraventricular pressure falls below atrial pressure, causing AV valves to open. Blood flows passively from atria into ventricles (rapid filling followed by reduced filling/diastasis). Ventricles fill to about 70-80% of capacity before atrial systole occurs.

Heart Sounds

4. Cardiac Output and Its Regulation

Definition - Cardiac Output (CO): The total volume of blood pumped by each ventricle of the heart per unit of time (typically measured in liters per minute).

Mathematical Expression

Cardiac Output is determined by multiplying Heart Rate (HR) by Stroke Volume (SV):

CO = HR x SV

Where:

• HR (Heart Rate): Number of heartbeats per minute (Normal resting average = 72 bpm).
• SV (Stroke Volume): Volume of blood ejected per ventricle per beat (Normal resting average = 70 mL/beat).
• Normal Resting CO: CO = 72 bpm x 70 mL/beat = 5040 mL/min (approximately 5.0 L/min).

Determinants of Stroke Volume

• Preload: The degree of stretch on the ventricular myocardium prior to contraction, directly proportional to End-Diastolic Volume (EDV).
• Contractility: The intrinsic forcefulness of myocardial contraction at any given preload, influenced by inotropic agents (e.g., sympathetic stimulation, calcium ions).
• Afterload: The pressure or resistance against which the ventricles must pump to eject blood into the major arteries (e.g., systemic vascular resistance).

Frank-Starling Law of the Heart: Within physiological limits, the force of ventricular contraction is directly proportional to the initial muscle fibre length (end-diastolic volume). Increased venous return increases EDV, stretching myocardial fibres and leading to a more forceful contraction and increased Stroke Volume.

Regulation of Cardiac Output

1. Neural Regulation

• Sympathetic Stimulation: Releases norepinephrine, which acts on Beta-1 adrenergic receptors in the SA node, AV node, and myocardium. Increases heart rate (positive chronotropy) and myocardial contractility (positive inotropy), thereby increasing CO.
• Parasympathetic Stimulation: Mediated via the Vagus Nerve (CN X), releasing acetylcholine onto Muscarinic (M2) receptors at the SA and AV nodes. Decreases heart rate (negative chronotropy) and slows AV conduction; has minimal effect on ventricular contractility.

2. Hormonal Regulation

• Epinephrine and Norepinephrine: Secreted by the adrenal medulla during stress or exercise; enhance heart rate and contractility.
• Thyroid Hormones (T3/T4): Increase basal metabolic rate and potentiate the cardiac effects of catecholamines, causing a sustained increase in HR and CO.

3. Autoregulation (Intrinsic Mechanism)

• Changes in venous return directly adjust stroke volume beat-by-beat via the Frank-Starling mechanism without neural involvement.

5. Electrocardiogram (ECG)

Definition - Electrocardiogram (ECG): A graphic representation of the electrical voltage changes produced by cardiac muscle depolarization and repolarization over time, recorded from extracellular electrodes placed on the surface of the body.

Standard ECG Components

• P Wave: Represents atrial depolarization spreading from the SA node across both atria.
• QRS Complex: Represents rapid ventricular depolarization. Ventricular muscle mass is large, resulting in a prominent waveform (Q: initial negative deflection, R: tall positive peak, S: negative deflection). Atrial repolarization occurs simultaneously but is masked by the QRS complex.
• T Wave: Represents ventricular repolarization.
• U Wave: (Occasionally seen) Represents repolarization of the papillary muscles or Purkinje fibres.

Key ECG Intervals and Segments

Clinical Diagnostic Significance:

• Elevated S-T Segment: Indicates acute myocardial infarction (heart attack).
• Prolonged P-R Interval: Indicates conduction delay through the AV node (AV heart block).
• Absent P Waves: Indicates atrial fibrillation or SA node block.

6. Blood Pressure and Its Regulation

Definition - Blood Pressure (BP): The lateral force exerted by circulating blood per unit area against the vascular walls of arteries.

Key Parameters

• Systolic Blood Pressure (SBP): Maximum pressure in the arteries during ventricular contraction (Normal: ~120 mmHg).
• Diastolic Blood Pressure (DBP): Minimum pressure in the arteries during ventricular relaxation (Normal: ~80 mmHg).
• Pulse Pressure (PP): The difference between systolic and diastolic pressure. Formula: PP = SBP - DBP (Normal: ~40 mmHg).
• Mean Arterial Pressure (MAP): Average pressure driving blood into tissues throughout the cardiac cycle. Formula: MAP = DBP + (1/3 x PP)

Short-Term Regulation of Blood Pressure (Neural Controls)

Functions within seconds to minutes, primarily targeting total peripheral resistance and cardiac output.

1. Baroreceptor Reflex (Pressure Receptor System):
   • Stretch-sensitive mechanoreceptors are located in the carotid sinus (monitored by Glossopharyngeal nerve, CN IX) and aortic arch (monitored by Vagus nerve, CN X).
   • Response to Increased BP: High BP stretches baroreceptors, increasing action potential firing rates to the Cardiovascular Center (CVC) in the medulla oblongata. CVC increases parasympathetic output and inhibits sympathetic output, lowering heart rate, stroke volume, and systemic vasodilation, returning BP to normal.
   • Response to Decreased BP: Reduced stretch decreases firing rate, leading to increased sympathetic discharge, which induces vasoconstriction, increased heart rate, and elevated contractility.
2. Chemoreceptor Reflex:
   • Sensors in carotid and aortic bodies monitor arterial blood levels of O2, CO2, and H+ ions.
   • Hypoxia, hypercapnia (high CO2), or acidosis stimulate chemoreceptors, signaling the vasomotor center to induce reflex vasoconstriction, thereby raising blood pressure to enhance tissue perfusion.

Long-Term Regulation of Blood Pressure (Hormonal and Renal Controls)

Functions over hours to days by controlling blood volume and fluid-electrolyte balance.

1. Renin-Angiotensin-Aldosterone System (RAAS):
   • A drop in renal perfusion pressure causes juxtaglomerular cells in the kidneys to release the enzyme Renin.
   • Renin cleaves plasma Angiotensinogen (from liver) into Angiotensin I.
   • Angiotensin Converting Enzyme (ACE) in lungs converts Angiotensin I to Angiotensin II.
   • Angiotensin II actions: Potent systemic vasoconstrictor; stimulates thirst; triggers release of Aldosterone from the adrenal cortex.
   • Aldosterone acts on renal distal tubules to increase Na+ and water reabsorption, expanding blood volume and raising BP.
2. Anti-Diuretic Hormone (ADH / Vasopressin):
   • Released by the posterior pituitary in response to dehydration or low blood volume. Increases water reabsorption in renal collecting ducts and induces vasoconstriction at high concentrations.
3. Atrial Natriuretic Peptide (ANP):
   • Secreted by cardiac atrial cells in response to excessive atrial stretch (high volume). Promotes renal excretion of sodium (natriuresis) and water, induces vasodilation, and inhibits RAAS, thereby reducing blood pressure.

7. Hemostasis and Mechanism of Blood Coagulation

Definition - Hemostasis: The localized, highly regulated physiological process that stops bleeding from an injured blood vessel, preventing excessive blood loss while maintaining normal blood fluid state elsewhere.

Three Main Steps of Hemostasis

1. Vascular Spasm (Vasoconstriction): Smooth muscle in the damaged vessel wall contracts immediately. Triggered by direct vascular injury, local pain receptors, and chemical release (e.g., Endothelin, Thromboxane A2). Reduces blood flow through damaged area.
2. Platelet Plug Formation:
   • Adhesion: Platelets bind to exposed subendothelial collagen via von Willebrand factor (vWF).
   • Activation and Secretion: Adhered platelets change shape and release ADP, Serotonin, and Thromboxane A2.
   • Aggregation: Released chemicals recruit additional platelets, forming a temporary platelet plug (primary hemostasis).
3. Blood Coagulation (Secondary Hemostasis): Formation of an insoluble fibrin meshwork that stabilizes the platelet plug.

Mechanism of Blood Coagulation

Coagulation involves a cascade of enzyme zymogen activations divided into Intrinsic, Extrinsic, and Common Pathways.

1. Intrinsic Pathway (Contact Activation Pathway):
   • Initiated by blood exposure to traumatized vascular wall collagen or foreign negatively charged surfaces.
   • Sequential activation: Factor XII -> Factor XIIa; Factor XIIa converts Factor XI -> Factor XIa; Factor XIa converts Factor IX -> Factor IXa.
   • Factor IXa, together with activated Factor VIIIa, Calcium ions (Ca2+), and phospholipids, forms the tenase complex, activating Factor X to Factor Xa.
   • Slower cascade (takes several minutes).
2. Extrinsic Pathway (Tissue Factor Pathway):
   • Initiated by external tissue trauma exposing Tissue Factor (TF / Factor III).
   • TF complexes with circulating Factor VIIa in the presence of Ca2+ to form the TF-VIIa complex.
   • This complex directly activates Factor X to Factor Xa.
   • Rapid, explosive cascade (takes seconds).
3. Common Pathway:
   • Factor Xa from either pathway combines with Factor Va, Ca2+, and membrane phospholipids to form the Prothrombinase Complex.
   • Prothrombinase converts Prothrombin (Factor II) into the active enzyme Thrombin (Factor IIa).
   • Thrombin cleaves soluble plasma Fibrinogen (Factor I) into insoluble Fibrin Monomers.
   • Fibrin monomers polymerize spontaneously into loose threads.
   • Thrombin also activates Fibrin-Stabilizing Factor (Factor XIII), which covalently crosslinks fibrin strands into a stable, permanent blood clot.

Comparison of Coagulation Pathways

8. The Fibrinolytic System

Following tissue repair, the blood clot must be removed to restore normal blood vessel patency and prevent vascular occlusion or thrombosis. The physiological breakdown of a fibrin clot is known as fibrinolysis.

Components and Cascade of Fibrinolysis

1. Plasminogen Activation:

   Plasminogen is an inactive plasma proenzyme trapped within the fibrin clot during coagulation. Damaged endothelial cells slowly release Tissue Plasminogen Activator (tPA) or Urokinase-type Plasminogen Activator (uPA), which converts inactive Plasminogen into active Plasmin.

2. Fibrin Degradation:

   Plasmin is a powerful proteolytic enzyme that cleaves insoluble fibrin polymer networks into soluble fragments termed Fibrin Degradation Products (FDPs), including D-dimers.

3. Regulation and Inhibitors:

   To prevent premature clot dissolution or systemic breakdown of fibrinogen, the fibrinolytic system is tightly controlled by specific physiological inhibitors:

   • Plasminogen Activator Inhibitor-1 (PAI-1): Inhibits the activity of tPA and uPA.
   • Alpha-2-Antiplasmin: Circulates in plasma and rapidly inactivates free plasmin in the bloodstream, restricting plasmin action strictly to the clot surface.

Important Summary Formula - Coagulation vs Fibrinolysis:
Coagulation: Fibrinogen --- (Thrombin) ---> Fibrin Mesh (Clot)
Fibrinolysis: Fibrin Mesh --- (Plasmin) ---> Fibrin Degradation Products (FDPs)