Nitric oxide (NO) is a key endothelium-derived relaxing factor. The intracellular pathway by which NO causes vascular smooth muscle relaxation is:

• A NO activates soluble guanylyl cyclase → cGMP → PKG activation → MLCK phosphorylation inhibition + K+ channel activation → hyperpolarization and relaxation ✓
• B NO directly nitrosylates calcium release channels on the ER, increasing intracellular calcium to trigger relaxation
• C NO inhibits phospholipase C, reducing IP3-mediated ER calcium release and decreasing Ca-calmodulin-MLCK activation
• D NO activates adenylyl cyclase through Gs protein coupling, raising cAMP to phosphorylate MLCK and cause relaxation

Explanation

NO diffuses from endothelial cells into adjacent smooth muscle, where it binds the heme moiety of soluble guanylyl cyclase (sGC), activating it and raising cGMP. Elevated cGMP activates protein kinase G (PKG), which has multiple relaxant effects: it phosphorylates and inactivates myosin light-chain kinase (MLCK), phosphorylates phospholamban to enhance SR Ca2+ uptake, opens K+ channels causing hyperpolarization (reducing voltage-gated Ca2+ entry), and inhibits IP3 receptor-mediated Ca2+ release. This multifactorial reduction in intracellular Ca2+ and reduction in MLCK activity produces smooth muscle relaxation and vasodilation.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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