Malignant Hyperthermia - 5
Normal Excitation-Contraction Physiology

  1. Wave of depolarization along motor nerve causes release of acetylcholine (ACh) from nerve endings.
  2. ACh traverses neuromuscular junction (NMJ) and initiates depolarization of muscle cell membrane (sarcolemma).
  3. Wave of depolarization proceeds internally via transverse tubules (T-tubules) that abut the sarcoplasmic reticuluum (SR).
  4. SR releases calcium ions (Ca+) through a calcium release channel. Dihydropyridine receptors and ryanodine receptors (RYRs) are located in the area where the T-tubule abuts the SR and are near or major parts of the calcium release channel. The RYR, a large protein molecule, is one of (if not the) largest receptors in the body. RYRs are felt to play an important role in transfer of charge to and, especially, release of Ca+ from the SR.
  5. Ca+ in the myoplasm combines with troponin, releasing troponin's inhibition of action-myosin interaction.
  6. Actin and myosin filaments are thus free to slide past one another and muscle contraction takes place while adenosine triphospate (ATP) is used.
  7. Subsequent re-uptake of Ca+ by the SR (also an energy-dependent process!) leads to muscle relaxation.

    Pathophysiologic Excitation-Contraction in MH

    The abnormality in MH is in or near the SR calcium release channel, in at least some families involving an abnormal RYR. This abnormality leads to too much free myoplasmic calcium. This calcium ion excess leads to excessive ATP breakdown, to ATP depletion, lactate production, increased CO2 production, increased VO2, and, eventually, to myonecrosis and rhabdomyolysis with myoglobinemia, myoglobinuria, generalized stress response, hyperkalemia, arrhythmias, renal failure, DIC, and death.
    The effect of the therapeutic agent dantrolene is to decrease the release of Ca+ from the SR and increase re-uptake of Ca+ by the SR. Since dantrolene has become available, mortality from MH has declined from greater than 50% to less than 10%.

Greg Gordon MD