Makindo Medical Notes

About

• Nitric Oxide (NO) is a gaseous signalling molecule and potent endogenous vasodilator 🌬️.
• Discovered as the “endothelium-derived relaxing factor (EDRF)” in 1987, work on NO won the Nobel Prize in 1998. 🏆
• Functions widely across systems:
  • Regulates vascular tone and blood pressure (cardiovascular system)
  • Acts as a neurotransmitter in CNS & PNS (learning, memory, neurovascular coupling)
  • Plays an immune role — modulating inflammation, macrophage microbicidal activity
  • Contributes to platelet inhibition (antithrombotic effect)
• Its biological activity is tightly controlled because of its very short half-life (seconds) and high reactivity.

Mechanism of Action 🔬

NO has a half-life of only a few seconds, so its actions are localised to nearby cells. The pathway is a central pharmacology favourite:

1. Production: Synthesised by nitric oxide synthase (NOS) from the amino acid L-arginine, oxygen, and NADPH. Cofactor: tetrahydrobiopterin (BH4).
2. Diffusion: Lipid soluble → diffuses rapidly into adjacent vascular smooth muscle cells.
3. Activation: Stimulates soluble guanylate cyclase → ↑ cyclic GMP (cGMP).
4. Effect: cGMP activates protein kinase G → ↓ intracellular calcium → smooth muscle relaxation → vasodilation.
5. Termination: Broken down by phosphodiesterase type 5 (PDE5) — the target of sildenafil (Viagra). 💊

Forms of Nitric Oxide Synthase (NOS)

Three isoforms of NOS exist, each with distinct regulation and roles:

• eNOS (Endothelial NOS): Calcium-dependent, continuously active at low levels to maintain basal vascular tone. 🫀
• nNOS (Neuronal NOS): Present in neurons, important in synaptic plasticity, learning, memory, and regulation of cerebral blood flow. 🧠
• iNOS (Inducible NOS): Calcium-independent; upregulated during sepsis and inflammation. Produces large amounts of NO → beneficial in microbial killing, but excessive levels → vasoplegia, septic shock. ⚠️

Pathophysiological Roles ⚡

• Cardiovascular protection: Endothelial NO prevents vasospasm, platelet aggregation, and leukocyte adhesion.
• Endothelial dysfunction: In atherosclerosis, diabetes, and hypertension, ↓ eNOS activity → impaired vasodilation → ↑ risk of angina, MI, stroke.
• Sepsis: Overexpression of iNOS → massive vasodilation, distributive shock, refractory hypotension.
• Neurological disease: Dysregulated nNOS implicated in stroke (excitotoxicity) and neurodegeneration.

Clinical Relevance 💉

• Nitrates (nitroglycerin, isosorbide dinitrate): Release NO → vasodilation, preload reduction, symptom relief in angina and heart failure.
• Sildenafil (Viagra): PDE5 inhibitor → prevents cGMP breakdown → potentiates NO effect in erectile tissue and pulmonary arteries.
• Inhaled Nitric Oxide (iNO): Used in persistent pulmonary hypertension of the newborn (PPHN) and ARDS → selective pulmonary vasodilation, improves oxygenation without systemic hypotension.
• Septic shock: Excess iNOS activity → vasoplegia. Research into NOS inhibitors for sepsis is ongoing but limited by risk of impairing organ perfusion.
• Stroke and CNS: Both neuroprotective and neurotoxic roles depending on timing and concentration.

Exam Pearls ✨

• 🧪 Biochemistry: NO is produced from L-arginine by NOS with oxygen + NADPH.
• ❤️ Pharmacology: Nitrates → NO → cGMP; Sildenafil → prevents cGMP breakdown (synergistic → dangerous hypotension if combined!).
• ⚡ Pathology: ↓ eNOS → endothelial dysfunction; ↑ iNOS → septic shock.
• 👶 Therapeutics: Inhaled NO in neonates = high-yield paediatric question.