Advanced
Mechanisms
A rigorous investigation into eNOS uncoupling, the enterosalivary pathway, and chemoreceptor adaptation.
eNOS Uncoupling
The efficacy of the NO pathway is determined by the coupling state of the eNOS dimer. Oxidative stress can shift enzymatic activity from NO production to superoxide generation .
THE ARGININE PARADOX
Supplementing L-Arginine fails if BH4 is depleted, as it fuels superoxide production instead of NO .
The BH4 Criticality
Tetrahydrobiopterin (BH4) stabilizes the eNOS homodimer. Peroxynitrite ($ONOO^-$) oxidizes BH4 to BH2, causing the dimer to collapse into monomers .
- COUPLED STATEL-Arg + O2 → NO
- UNCOUPLED STATENADPH + O2 → Superoxide
ADMA: Endogenous Inhibition
Asymmetric dimethylarginine (ADMA) competitively inhibits eNOS. It is regulated by DDAH enzymes, which are highly sensitive to oxidative stress .
Enterosalivary Pathway
An oxygen-independent backup system for NO generation. Critical during hypoxia and exercise.
Pharmacokinetics
1. Ingestion
Dietary Nitrate ($NO_3^-$) absorbed in upper GI .
2. Concentration
Salivary glands concentrate nitrate 10x over plasma.
3. Bioactivation (CRITICAL STEP)
Oral commensal bacteria reduce Nitrate → Nitrite ($NO_2^-$) .
WARNING: Antiseptic mouthwash abolishes this step .
4. Acidification
Gastric acid converts Nitrite → NO + Nitrogen Oxides.
CO2 & Chemoreceptors
Going beyond the Bohr effect : How central chemoreceptor sensitivity dictates vascular tone.
Chemoreceptor Resetting
Chronic stress/hyperventilation lowers the CO2 set-point. The brain perceives normal CO2 as "too high," triggering vasoconstriction .
K-ATP Channels
Intracellular acidosis (from CO2) opens ATP-sensitive Potassium channels in smooth muscle, causing hyperpolarization and relaxation .
Actionable Protocol: IHHT
Intermittent Hypoxic-Hypercapnic Training
- Exhale to Functional Residual Capacity (FRC).
- Hold breath until moderate-to-strong air hunger (Hypercapnia + Hypoxia).
- Resume nasal breathing (Recovery).
- Repeat 5-8 cycles, 2x daily.
*Stimulates HIF-1α, upregulates VEGF/eNOS, and resets chemoreceptor tolerance .