Respiratory Waves in the Arterial Pressure

What They Are

Mechanisms (3 Causes)

1. Spillover from the respiratory center to the vasomotor center
   • Breathing signals arising in the medullary respiratory center spill over into the vasomotor center with each respiratory cycle, periodically altering vasomotor tone.
2. Intrathoracic pressure changes during inspiration
   • During inspiration, intrathoracic pressure becomes more negative, causing thoracic blood vessels to expand.
   • This reduces blood return to the left heart, which momentarily decreases cardiac output and arterial pressure.
3. Excitation of vascular and atrial stretch receptors
   • Pressure changes in thoracic vessels during respiration can excite vascular and atrial stretch receptors, which reflexly influence vasomotor activity.

Net Result

• During early expiration: arterial pressure typically rises
• During the remainder of the respiratory cycle: pressure falls

Vasomotor Waves (Mayer Waves) - Related Concept

• Cycle duration: 26 seconds in anesthetized dogs; 7-10 seconds in unanesthetized humans
• These represent oscillations of reflex pressure control systems, not simple respiratory mechanics

Two causes of vasomotor waves:

• High pressure excites baroreceptors -> sympathetic inhibition -> pressure falls a few seconds later
• Reduced pressure removes baroreceptor stimulation -> vasomotor center reactivates -> pressure rises again
• This delayed feedback loop creates cyclical oscillations
• The chemoreceptor reflex oscillates simultaneously; it dominates when pressure is in the 40-80 mm Hg range (where baroreceptor control is weaker)

• When cerebrospinal fluid pressure is elevated (e.g., to 160 mm Hg), cerebral vessel compression triggers the CNS ischemic response, driving arterial pressure up to ~200 mm Hg
• Relief of ischemia at high pressure makes sympathetic activity fall -> pressure drops rapidly
• Brain ischemia recurs -> pressure rises again, and the cycle repeats

Key Principle

1. The feedback intensity is strong enough, AND
2. There is a delay between excitation of the pressure receptor and the subsequent pressure response

Necroptosis - Complete Pathway & Cell Signalling

What is Necroptosis?

The Complete Necroptosis Pathway

Step 1: Trigger Signals

• TNFR1 ligation (most studied model) - by TNF (Tumour Necrosis Factor)
• Fas/CD95 ligation
• Toll-like receptors (TLR3, TLR4) - pattern recognition in innate immunity
• T-cell receptor (TCR) signalling
• Viral DNA/RNA sensors - cytoplasmic sensors detect viral nucleic acids
• DNA damage

Critical condition: Necroptosis preferentially occurs when caspase-8 is inactive or inhibited. Normally, active caspase-8 cleaves RIPK1 and RIPK3, suppressing necroptosis in favour of apoptosis. When caspases are blocked (e.g., by viral caspase inhibitors or pharmacological agents), the necroptotic cascade is unleashed.

Step 2: RIPK1-RIPK3 Complex (Necrosome) Formation

1. TNFR1 is ligated by TNF (trimerized TNF binds to trimerized receptor)
2. Ligation recruits RIPK1 (Receptor-Interacting Protein Kinase 1) into a multiprotein complex at the intracellular death domain of TNFR1
3. RIPK1 is phosphorylated (auto- and trans-phosphorylation)
4. Phosphorylated RIPK1 recruits and activates RIPK3 (Receptor-Interacting Protein Kinase 3)
5. RIPK1 and RIPK3 form the necrosome - a multiprotein signalling complex

Note: RIPK1 is not always required - in some TLR3/4 and viral RNA-triggered necroptosis, RIPK3 can be activated independently of RIPK1.

Step 3: MLKL Phosphorylation (The Executioner Step)

1. Within the necrosome, RIPK3 phosphorylates MLKL (Mixed Lineage Kinase domain-Like protein) at key serine/threonine residues
2. Phosphorylated MLKL undergoes a conformational change
3. MLKL monomers assemble into oligomers (homo-oligomerization)
4. MLKL oligomers translocate from the cytosol to the plasma membrane
5. MLKL functions as an endogenous porin - it inserts into and disrupts the plasma membrane

Step 4: Plasma Membrane Disruption and Cell Death

• Plasma membrane rupture leads to cell swelling (oncosis) - microscopically visible as a "balloon-like structure"
• Cytoplasmic contents are released into the extracellular space
• This release includes DAMPs (Damage-Associated Molecular Patterns) - endogenous danger signals
• Result: Cell death + sterile inflammation

Why Does Necroptosis Occur? (Caspase-8 as the Switch)

• Caspase-8 ACTIVE → cleaves RIPK1 and RIPK3 → necrosome cannot form → apoptosis proceeds
• Caspase-8 INACTIVE (e.g., viral inhibitors, pharmacological blockade) → RIPK1/RIPK3 remain intact → necroptosis proceeds

Downstream Consequences

1. Tissue damage - local destruction
2. Inflammation - DAMP-mediated recruitment of innate immune cells; likely contributes to systemic inflammatory response
3. Release of internalized pathogens into the extracellular space where complement and neutrophils can destroy them

ROS and Metabolic Collapse

• Over-generation of reactive oxygen species (ROS)
• Metabolic collapse (ATP depletion)

Inhibitors

• Necrostatin-1: a specific RIPK1 inhibitor - the key research tool to confirm necroptosis is occurring
• RIPK3 knockout / MLKL knockout mice are used experimentally to study necroptosis

Physiological and Pathological Roles

Key Summary (Robbins & Cotran)

"Necroptosis resembles necrosis morphologically, but like apoptosis is a genetically controlled form of cell death. Necroptosis is triggered by ligation of TNFR1 and by proteins found in RNA and DNA viruses. Necroptosis is caspase independent and depends on the RIPK1-RIPK3 complex. RIPK1-RIPK3 signaling leads to the phosphorylation of MLKL, which then forms pores in the plasma membrane. Release of cellular contents evokes an inflammatory reaction as in necrosis."

• Robbins, Cotran & Kumar - Pathologic Basis of Disease, p. 61
• Medical Physiology (Boron & Boulpaep)
• Scott-Brown's Otorhinolaryngology, Head & Neck Surgery Vol. 1