ACTION OF CHOLINESTERS ON SENSORY NERVE ENDINGS IN SKIN AND MUSCLE

1. This is a review of the literature on the subject of the effects of cholinesters and their agonists on sensory nerve endings. 2. The present-day view is that acetylcholine (ACh) has an excitatory action on some cutaneous receptors. Responses appear to be limited to receptors served by small myelinated and un-myelinated axons where responsiveness is multimodal; that is, the receptors are activated by noxious thermal and mechanical stimulation. 3. The possible role played by acetylcholine in sensory transduction processes is discussed, as are other explanations for the presence of nicotinic cholinergic receptors on the terminals of cutaneous receptors. 4. The excitatory action of ACh and succinylcholine (SCh) on muscle spindles is described. Two possible mechanisms are considered: a direct depolarizing action on the nerve terminals and indirect excitation, brought about by a contracture of the intrafusal fibres on which the sensory endings lie. 5. The technique of using SCh in combination with fusimotor stimulation is described. This has provided new information about the internal workings of muscle spindles. Brief mention is also made of the action of SCh on tendon organs and joint receptors. 6. It is concluded that a direct action by cholinesters is restricted to receptors served by small axons with multimodal functions. The precise role of such an action remains the subject of speculation. Possible clinical significance is discussed.     

Affinity profiles of pizotifen, ketotifen and other tricyclic antimuscarinics at muscarinic receptor subtypes M1, M2 and M3.

The affinity of pizotifen, ketotifen and other tricyclic antimuscarinic drugs for different muscarinic receptor subtypes was investigated in vitro in functional experiments with field-stimulated vas deferens of the rabbit (M1 and M2 receptors) and with ileum and trachea of the guinea-pig (M3 receptors). All compounds were competitive antagonists in the three tissues. Like the close analogue cyproheptadine (pA2 = 7.99-8.08), pizotifen (pA2 = 7.23-7.81) and ketotifen (pA2 = 6.34-6.99) were devoid of selectivity for the receptor subtypes studied. Thiazinamium, although exhibiting high affinity for muscarinic receptors (pA2 = 7.83-8.51), was found to be non-selective. In contrast, the novel pirenzepine analogue nuvenzepine was selective for M1 receptors (pA2 = 6.63-7.74). The lack of selectivity of cyproheptadine, pizotifen and ketotifen is reflected in the chemical structures of these drugs. All three antagonists are composed of a very similar tricyclic ring system linked to a 1-methyl-4-piperidylene ring. The finding that thiazinamium, pizotifen and cyproheptadine were potent muscarinic antagonists and possessed non-selective affinity characteristics may have therapeutic implications.     

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline induces and inhibits cytochrome P450 from the IA subfamily in chick and rat hepatocytes.

Several heterocyclic amines, found in cooked food, are powerful mutagens in the Ames Salmonella mutagenicity test system. One of these, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is one of the most mutagenic chemicals tested in this assay. In primary cultures of chick and rat hepatocytes, MeIQ, by itself, induced cytochrome P450 from the IA subfamily but was a weak inducer compared to 3-methylcholanthrene. However, in both chick and rat hepatocytes in culture, MeIQ decreased the amount of 3-methylcholanthrene-induced ethoxyresorufin deethylase activity, which is catalyzed by cytochrome P450 IA. The protein moiety of cytochrome P450 IA was decreased at MeIQ concentrations of 2.5 micrograms/ml or greater in chick hepatocytes and 25 micrograms/ml in rat hepatocytes. In hepatic microsomes from methylcholanthrene-treated chicks and rats, MeIQ was a competitive inhibitor of both ethoxyresorufin deethylase activity, a reaction catalyzed mainly by rodent cytochrome P450 IA1, and uroporphyrinogen oxidation, a reaction catalyzed by rodent P450 IA2. In cultured chick hepatocytes, MeIQ also decreased cytochrome P450-mediated oxidation of uroporphyrinogen by intact cells. The ability of MeIQ to inhibit as well as to induce cytochrome P450s of the IA subfamily may be important in assessing the mutagenic and carcinogenic effects of MeIQ in mammals.     

Iron as a co-morbid factor in nonhemochromatotic liver disease.

Heavy iron overload, in both primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, especially the liver. The toxicity of iron is believed to involve increased oxidative stress, with iron-catalyzed production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Results of recent studies have demonstrated high prevalences (about 60%-80%) of HFE gene mutations in patients with porphyria cutanea tarda. Chronic hepatitis C is another risk factor for porphyria cutanea tarda. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. A role for modest iron overload in increasing severity of alcohol-induced liver disease has been well established from results of experimental studies. However, it is currently unresolved whether mild-to-moderate hepatic iron deposition or heterozygosity for the C282Y mutation plays a role in human alcoholic liver disease or in nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. There is persuasive evidence that iron reduction decreases insulin resistance, and it likely also decreases oxidative stress, two key pathogenic features of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Iron loading has also been described after portosystemic shunts and in end-stage liver disease.     

The effects of exposure to microgravity and reconditioning of the lumbar multifidus and anterolateral abdominal muscles: implications for people with LBP

BACKGROUND CONTEXTOne of the primary changes in the neuromuscular system in response to microgravity is skeletal muscle atrophy, which occurs especially in muscles that maintain posture while being upright on Earth. Reduced size of paraspinal and abdominal muscles has been documented after spaceflight. Exercises are undertaken on the International Space Station (ISS) during and following space flight to remediate these effects. Understanding the adaptations which occur in trunk muscles in response to microgravity could inform the development of specific countermeasures, which may have applications for people with conditions on Earth such as low back pain (LBP).PURPOSEThe aim of this study was to examine the changes in muscle size and function of the lumbar multifidus (MF) and anterolateral abdominal muscles (1) in response to exposure to 6 months of microgravity on the ISS and (2) in response to a 15-day reconditioning program on Earth.DESIGNProspective longitudinal series.PATIENT SAMPLEData were collected from five astronauts who undertook seven long-duration missions on the ISS.OUTCOME MEASURESFor the MF muscle, measures included cross-sectional area (CSA) and linear measures to assess voluntary isometric contractions at vertebral levels L2 to L5. For the abdominal muscles, the thickness of the transversus abdominis (TrA), obliquus internus abdominis (IO) and obliquus externus abdominis (EO) muscles at rest and on contraction were measured.METHODSUltrasound imaging of trunk muscles was conducted at four timepoints (preflight, postflight, mid-reconditioning, and post reconditioning). Data were analyzed using multilevel linear models to estimate the change in muscle parameters of interest across three time periods.RESULTSBeta-coefficients (estimates of the expected change in the measure across the specified time period, adjusted for the baseline measurement) indicated that the CSA of the MF muscles decreased significantly at all lumbar vertebral levels (except L2) in response to exposure to microgravity (L3=12.6%; L4=6.1%, L5=10.3%; p<.001), and CSAs at L3-L5 vertebral levels increased in the reconditioning period (p<.001). The thickness of the TrA decreased by 34.1% (p<.017), IO decreased by 15.4% (p=.04), and the combination of anterolateral abdominal muscles decreased by 16.2% (p<.001) between pre- and postflight assessment and increased (TrA<0.008; combined p=.035) during the postreconditioning period. Results showed decreased contraction of the MF muscles at the L2 (from 12.8% to 3.4%; p=.007) and L3 (from 12.2% to 5%; p=.032) vertebral levels following exposure to microgravity which increased (L2, p=.046) after the postreconditioning period. Comparison with preflight measures indicated that there were no residual changes in muscle size and function after the postreconditioning period, apart from CSA of MF at L2, which remained 15.3% larger than preflight values (p<.001).CONCLUSIONSIn-flight exercise countermeasures mitigated, but did not completely prevent, changes in the size and function of the lumbar MF and anterolateral abdominal muscles. Many of the observed changes in size and control of the MF and abdominal muscles that occurred in response to prolonged exposure to microgravity paralleled those seen in people with LBP or exposed to prolonged bed rest on Earth. Daily individualized postflight reconditioning, which included both motor control training and weight-bearing exercises with an emphasis on retraining strength and endurance to re-establish normal postural alignment with respect to gravity, restored the decreased size and control of the MF (at the L3-L5 vertebral levels) and anterolateral abdominal muscles. Drawing parallels between changes which occur to the neuromuscular system in microgravity and which exercises best recover muscle size and function could help health professionals tailor improved interventions for terrestrial populations. Results suggested that the principles underpinning the exercises developed for astronauts following prolonged exposure to microgravity (emphasizing strength and endurance training to re-establish normal postural alignment and distribution of load with respect to gravity) can also be applied for people with chronic LBP, as the MF and anterolateral abdominal muscles were affected in similar ways in both populations. The results may also inform the development of new astronaut countermeasures targeting the MF and abdominal muscles.