Contractures

Contraction is a general term that refers to the mechanically activated state of myofibrils which is usually caused by action potentials). Contracture means muscle shortening or tension development, which is not triggered by action potentials), e.g. K+ contracture, and caffeine or halothane contracture. The word is also used for deformity or distortion of fingers, hand or limb, such as Dupuytren s or Volkmann s contracture. 

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

Ryanodine is a neutral plant alkaloid from Ryania speciosa and was used as an insecticide. It also has been well known by the characteristic action on mammalian skeletal muscle of slowly developing, and intensive and irreversible contracture. Ryanodine binds specifically to the open RyR channel at the stoichiometry of 1 mol/mol homotetramer with a high affinity (ATD nM) and leads the channel to ryanodine modified state characteristic of long-lasting subconductance ( 50% of normal) opening. At higher concentration, it blocks the channel. 

Ryanodine leads to contracture of mammalian skeletal muscle, whereas it causes negative inotropism in cardiac muscle. This apparent opposite effects are due to difference in the Ca2+ extruding activity the released Ca2+ remains within cytoplasm in skeletal muscle because of low Ca2+ extruding activity, whereas the increased cytoplasmic Ca2+ is rapidly excluded out of the cytoplasm in cardiac muscle via Na+ -Ca2+ -exchange. 

EDMD is another X-linked muscular dystrophy, clinically and genetically completely distinct from DMD and BMD. Affected boys usually have onset in childhood of contractures (especially involving the Achilles tendons, elbows, and spinal muscles), humeroperoneal muscle weakness, and cardiac conduction defects, which tend to be mostly a problem in adult life and may necessitate insertion of a pacemaker. The gene for EDMD is known to map to Xq28, but this localization is... 

Juvenile dermatomyositis (JDM) is perhaps the most uniform, in terms of clinical and histopathological features, of the whole PM/DM disease complex. Presentation may be before 5 years of age with peak incidence between 8 and 12 years. The disease may remit and recur until well into young adult life. The skin lesions include a facial rash in butterfly distribution across nose and cheeks. Erythematous skin changes are seen over extensor surfaces of joints, especially knees, knuckles and elbows. Muscle involvement is generally evident some time later and takes the form of weakness and stiffness, particularly affecting shoulder and pelvic musculature. Proximal muscles are often worse affected than distal muscles and extensors worse than flexors. In the absence of prompt and effective treatment contractures may occur at elbows, ankles, knees, and hips. Subcutaneous calcification and skin ulceration may be found calcification of deeper-lying connective tissue may be apparent on X-ray. 

Hypothyroid myopathy occurs in about 30% of patients with hypothyroidism irrespective of its cause. Muscle pain, cramps, and stiffness may be seen, and are often exacerbated by cold weather. Pseudomyotonic features of delayed muscle contraction and relaxation are common. Myoedema (the mounding phenomenon) is due to the painless, electrically silent contracture produced on direct percussion. Muscle biopsy often shows a predominance of type 1 (slow-twitch) fibers, again analogous to that seen in experimental hypothyroidism (Figure 22). Muscle hypertrophy with weakness and slowness of movement occurs in the Debre-Semelaigne syndrome seen in severely hypothyroid children, and Hoffman s syndrome is a similar condition seen in adults with hypothyroidism, but is also accompanied by painful spasms. 

The caffeine contracture test involves exposing viable muscle fibers to incremental doses of caffeine from 0.5-32 mM, the concentration being increased every four min if no contraction develops. A positive caffeine contracture test is defined as the development of 0.2 g tension at 2 tiM caffeine, or > 7% tension change from baseline with 2 mM caffeine. 

In a joint halothane-caffeine contracture test, both caffeine and halothane are used. A positive test is defined as the development of 1 g contracture after exposure of viable muscle fibers to a concentration of 1 mM or less caffeine in the presence of 1% halothane. 

False negative muscle contraction tests are very rare. To date, a negative muscle contraction test rules out MH. A false negative test can be explained by the presence of two types of muscle fibers in a MH susceptible patient the response being dependent on the proportion of the two types of muscle fibers. The K-type designation is used to describe a patient who has a positive joint halothane-caffeine contracture, but a negative separate halothane or caffeine contracture. Whether K-type individuals are MH-susceptible or not is a controversial issue. 

Mackenzie, A.E., Allen, G., Lahey, D., Crossen, M.L., Nolan, K., Mettler, G., Worton, R.G., MacLen-nan, D.H., Korneluk, R. (1991). A comparison of the caffeine halothane muscle contracture test with the molecular genetic diagnosis of malignant hyperthermia. Anesthesiology 75,4-8. 

Fagrell, D. et al. Capsular contracture around saline-filled fine textured and smooth mammary implants A prospective 7.5 year follow-up. Blast. Reconstr. Surg., 108, 2108, 2001. 

Figure 2. Potency of anatoxin-a analogs to induce contracture in frog rectus abdominis muscle. The data from two experiments are combined in this figure. In one, anatoxinmethylester was found to be equipo-tent with carbamylcholine. In the other, the anatoxin isomers were assayed against ACh [after cholinesterse inhibition by diisopropylfluoro-phosphate (DFP) followed by washing of the preparation] (19). Maximal contracture was measured by depolarization with KCl at the end of each experiment.

Sea urchin toxins extracted from spines or pedicellariae have a variety of pharmacological actions, including electrophysiological ones (75). Dialyzable toxins from Diadema caused a dose-dependent increase in the miniature end-plate potential frequency of frog sartorius muscle without influencing membrane potential (76). A toxin from the sea urchin Toxopneustes pUeolus causes a dose-dependent release of histamine (67). Toxic proteins from the same species also cause smooth muscle contracture in guinea pig ileum and uterus, and are cardiotoxic (77). 

Aplysin has marked effects in mammalian tissue and produces hypotension, bradycardia, neuromuscular paralysis, and contracture of intestinal smooth muscle (85). Aplysiatoxin causes an elevation in blood pressure resistant to adrenoceptor blockade (86). 

Table 4.1 Effect of selected thiols, disulphides, amino acids and antioxidants on the time to the onset and the time to reach maximal ischaemic contracture in isolated perfused rat hearts. Hearts were perfused for a control period of 10 min at the end of which global low-flow (10% of control) ischaemia was initiated. The interventions described above were included in the perfusion fluid 5 min prior to the onset and throughout the ischaemic period. The data are shown as means standard errors of the means (n = 6)...

Haddock, P.S., Hearse, D.J. and Woodward, B. (1989). Effect of anti-oxidants and verapamil on noradrenaline release and contracture in the ischaemic/reperfused rat heart. Br. J. Pharmacol. 78, 745 (abstract). 

Dupuytren s contracture is a contraction of the palmar fascia that usually affects the fourth and fifth digits.27 It is not specific to cirrhosis and can be seen in repetitive use injuries. 

Ffuerta, M. and Stefani, E., Potassium and caffeine contractures in fast and slow muscles of the chicken, Journal of Physiology, 318, 181, 1981. 

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