In smooth muscle, calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates the 20-kDa myosin light chain (MLC20) at Ser19 to initiate contraction. Dephosphorylation of MLC20 by myosin light chain phosphatase (MLCP) relaxes smooth muscle. Rho-kinase (ROCK) inhibits MLCP by phosphorylating its regulatory subunit MYPT1. This mechanism is called calcium sensitization. Which clinical agent exploits this pathway for vasodilation?

• A Fasudil/Y-27632 — directly inhibits ROCK, preventing MYPT1 phosphorylation and thereby reactivating MLCP to dephosphorylate MLC20 ✓
• B Sildenafil — inhibits PDE5 to increase cGMP which activates PKG to phosphorylate MYPT1 and activate MLCP
• C Nitroglycerin — donates NO to activate sGC/cGMP/PKG which directly phosphorylates MLCK to inhibit it
• D Nifedipine — blocks L-type Ca²⁺ channels preventing calmodulin activation of MLCK

Explanation

Fasudil (and the research tool Y-27632) are selective ROCK inhibitors. ROCK normally phosphorylates MYPT1 (regulatory subunit of MLCP) at Thr696 and Thr853, inhibiting phosphatase activity and maintaining MLC20 in the phosphorylated (contracted) state even at low Ca²⁺ — this is calcium sensitization. ROCK inhibitors block this, reactivating MLCP and promoting MLC20 dephosphorylation and smooth muscle relaxation without lowering intracellular Ca²⁺. Fasudil is approved in Japan for cerebral vasospasm after subarachnoid hemorrhage. Sildenafil acts via cGMP/PKG which phosphorylates MYPT1 at Ser695 to activate MLCP, and also targets telokin.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.