SECTION I CELLULAR PHYSIOLOGY Malignant Hyperthermia A patient received succinylcholine (muscle relaxant)and halothane (general anesthetic)for routine gallbladder surgery.Instead of the expected musele relaxation.massive fasciculations (spontaneous motor unit contractions)vere followed by rigidity of muscles (contracture characterized hy hard muscles and unnowable joints).Tachycardia developed along with hypertension.A marked increase in respiration was driven by elevated arterial carbon dioxide tension.The core body temperature them began to rise rapidly (up to 44C).reflecting increased metabolism of skeletal mscle.Hyperthermia and cardiac arrhythmias led to left ventricular failure and resulted in acute pulmoeary edema.Increased muscle metabolisn decreased blood oxygen and blood pl.The acidosis is of both metabolic (increased serun lactate)and respiratory (increased blood carbon dioxide)origin. Serun coecentrations of soluble muscle proteins.such as creatine kinase.lactate dehydrogenase,and myoglobin,increased markedly. The symptoas led to a diagnosis of malignant hyperthermia,and the patient was treated with dantrolene,a drug that blocks release of Ca++from the sarcoplasmic reticulun The crisis passed,but severe muscle pain with swelling lasted for nany days.Muscle weakness and wasting occurred for some weeks.Subsequent investigation showed that the patient had a number of relatives who had experienced malignant hyperthermia during anesthesia or died with similar symptoms without an obious cause. 1.Fasciculation and muscular rigidity reflect pathologic contractions of skeletal muscle cells.What would induce this at the cellular level? 2.What are the clinical signs of a rassive increase in retabolisn? 3.What is the probable tissue source of the increased metabolism? 4.What metabolic pathways are involved in the increase in metabolisa?
SECTION I CELLULAR PHYSIOLOGY Malignant Hyperthermia A patient received succinylcholine (muscle relaxant) and halothane (general anesthetic) for routine gallbladder surgery. Instead of the expected muscle relaxation, massive fasciculations (spontaneous motor unit contractions) were followed by rigidity of muscles (contracture characterized by hard muscles and unmovable joints). Tachycardia developed along with hypertension. A marked increase in respiration was driven by elevated arterial carbon dioxide tension. The core body temperature then began to rise rapidly (up to 44°C), reflecting increased metabolism of skeletal muscle. Hyperthermia and cardiac arrhythmias led to left ventricular failure and resulted in acute pulmonary edema. Increased muscle metabolism decreased blood oxygen and blood pH. The acidosis is of both metabolic (increased serum lactate) and respiratory (increased blood carbon dioxide) origin. Serum concentrations of soluble muscle proteins, such as creatine kinase, lactate dehydrogenase, and myoglobin, increased markedly. The symptoms led to a diagnosis of malignant hyperthermia, and the patient was treated with dantrolene, a drug that blocks release of Ca++ from the sarcoplasmic reticulum. The crisis passed, but severe muscle pain with swelling lasted for many days. Muscle weakness and wasting occurred for some weeks. Subsequent investigation showed that the patient had a number of relatives who had experienced malignant hyperthermia during anesthesia or died with similar symptoms without an obvious cause. 1. Fasciculation and muscular rigidity reflect pathologic contractions of skeletal muscle cells. What would induce this at the cellular level? 2. What are the clinical signs of a massive increase in metabolism? 3. What is the probable tissue source of the increased metabolism? 4. What metabolic pathways are involved in the increase in metabolism?
5.Will muscle ATP levels be maintained? 6.Elevated cell Catt is typically associated with cell death.What are potential causes of pathologically elevated cell Ca++and subsequent cell death? 7.What is the evidence for a defective membrane component in the skeletal muscle of patients experiencing malignant hyperthermia? ANSVER 1.A sudden rise in cell Ca++is required to imitiate crosshridge cyeling and contraction.This inference is supported by research showing that druzs that increase cell Catt.such as caffeine,lidocaine,and cardiac glycosides,increase the severity of the symptoms of malignant hyperthermia.Drugs that lower cell Ca++, whether by preventing release from the sarcoplasmic reticulum (dantrolene)or by blocking influx through the sarcolemma (local anesthetics.Cat+channel blockers). improve survival. 2.Clinical signs inelude the fall in blood oxygen and pH,the rise in blood carbon dioxide.and the rise in body temperature,despite the tachyeardia and increase in ventilation. 3.Skeletal musele constitutes about 40%of the body mass,and the transition fron relaxation to comtraction involves a very large increase in metabolisn Therefore the contractures that result in muscle rigidity are the principal cause of increased metabolisn. 4.Both oxidative pathsays (increase in carbon dioxide and decrease in oxygem) and glycolytic pathays (increase in lactate)are imvolved 5.Normally yes,and muscle cells cease to contract (fatigue)before ATP concentrations decline.Bowever.this is an abnormal situation where there is a failure to inactivate the tissue and reduce cell Ca++.Thus glycogen depletion should be associated with reductions in creatine phosphate and ATP in fast fibers.Muscle rigidity and blood vessel compression impair blood flow,contribute to the changes in blood gases,and limit oxidative ATP synthesis
5. Will muscle ATP levels be maintained? 6. Elevated cell Ca++ is typically associated with cell death. What are potential causes of pathologically elevated cell Ca++ and subsequent cell death? 7. What is the evidence for a defective membrane component in the skeletal muscle of patients experiencing malignant hyperthermia? ANSWER 1. A sudden rise in cell Ca++ is required to initiate crossbridge cycling and contraction. This inference is supported by research showing that drugs that increase cell Ca++, such as caffeine, lidocaine, and cardiac glycosides, increase the severity of the symptoms of malignant hyperthermia. Drugs that lower cell Ca++, whether by preventing release from the sarcoplasmic reticulum (dantrolene) or by blocking influx through the sarcolemma (local anesthetics, Ca++ channel blockers), improve survival. 2. Clinical signs include the fall in blood oxygen and pH, the rise in blood carbon dioxide, and the rise in body temperature, despite the tachycardia and increase in ventilation. 3. Skeletal muscle constitutes about 40% of the body mass, and the transition from relaxation to contraction involves a very large increase in metabolism. Therefore the contractures that result in muscle rigidity are the principal cause of increased metabolism. 4. Both oxidative pathways (increase in carbon dioxide and decrease in oxygen) and glycolytic pathways (increase in lactate) are involved. 5. Normally yes, and muscle cells cease to contract (fatigue) before ATP concentrations decline. However, this is an abnormal situation where there is a failure to inactivate the tissue and reduce cell Ca++. Thus glycogen depletion should be associated with reductions in creatine phosphate and ATP in fast fibers. Muscle rigidity and blood vessel compression impair blood flow, contribute to the changes in blood gases, and limit oxidative ATP synthesis
6.Either the systems that normally reduce intracellular Cat+content have failed,or increases in membrane permeability with resulting Ca++diffusion into the myoplasm have overwhelmed the pumps.Increases in ATP consumption caused by crossbridge cyeling and ion purping exceed ATP production capacity.Elevated cell Na+and reduced cell K+would result,with sarcolemmal depolarization further exacerbating Cat+accumulation.Cell perneability gradually increases.This causes an carly loss of magnesium,phosphate.and small metabolites,followed later by the loss of soluble proteins,such as creatine kinase and myoglobin:the loss of these proteins is diagnostic of necrotic cells. 7.The syndrone was triggered by agents that ordinarily inhibit Catt mobilization by blocking acetylcholine receptors at the motor end plate,thereby preventing the generation of action potentials in the sarcoleama (succinylcholine). or hy a more general menbrane stabilization effect (halothane).The family history suggested a genetic basis for a presuned faulty element in the excitation-contraction coupling pathways.These faulty elements include the serbranes of the end plate,sarcoleaa.T-tubules,and/or sarcoplasaic reticulun
6. Either the systems that normally reduce intracellular Ca++ content have failed, or increases in membrane permeability with resulting Ca++ diffusion into the myoplasm have overwhelmed the pumps. Increases in ATP consumption caused by crossbridge cycling and ion pumping exceed ATP production capacity. Elevated cell Na+ and reduced cell K+ would result, with sarcolemmal depolarization further exacerbating Ca++ accumulation. Cell permeability gradually increases. This causes an early loss of magnesium, phosphate, and small metabolites, followed later by the loss of soluble proteins, such as creatine kinase and myoglobin; the loss of these proteins is diagnostic of necrotic cells. 7. The syndrome was triggered by agents that ordinarily inhibit Ca++ mobilization by blocking acetylcholine receptors at the motor end plate, thereby preventing the generation of action potentials in the sarcolemma (succinylcholine), or by a more general membrane stabilization effect (halothane). The family history suggested a genetic basis for a presumed faulty element in the excitation-contraction coupling pathways. These faulty elements include the membranes of the end plate, sarcolemma, T-tubules, and/or sarcoplasmic reticulum