Muscular contraction effects

For over three decades, laboratory research has shown caffeine to be effective at mobilizing calcium in skeletal muscle. In vitro experiments have amply demonstrated that caffeine lowers the excitability threshold and extends the length of muscular contractions via calcium release from the sarcoplasmic reticulum.1012 Caffeine also inhibits calcium reuptake by the sarcoplasmic reticulum, perpetuating calcium availability for muscle work.1318 Also, caffeine promotes increased twitch tension development in muscles.1718... 

Although research has been suggestive of caffeine modulated increases in muscular contractions leading to hand tremor, it is more likely that the hand tremor response is the result of caffeine s effects on the central nervous system.32 There is even evidence that moderate doses of caffeine may actually diminish muscle tone.32... 

Another important example is the nicotinic acetylcholine receptor, which is activated by the agonist nicotine causing muscular fibrillation and paralysis. Indirect effects can also occur. For example, organophosphates and other acetylcholinesterase inhibitors increase the amount of acetylcholine and thereby overstimulate the receptor, leading to effects in a number of sites (see chap. 7). Alternatively, botulinum toxin inhibits the release of acetylcholine and causes muscle paralysis because muscular contraction does not take place (see chap. 7). 

The control of glycogen phosphorylase by the phosphorylation-dephosphorylation cycle was discovered in 1955 by Edmond Fischer and Edwin Krebs50 and was at first regarded as peculiar to glycogen breakdown. However, it is now abundantly clear that similar reactions control most aspects of metabolism.51 Phosphorylation of proteins is involved in control of carbohydrate, lipid, and amino acid metabolism in control of muscular contraction, regulation of photosynthesis in plants,52 transcription of genes,51 protein syntheses,53 and cell division and in mediating most effects of hormones. 

The use of new transcriptome information for discovery of novel drug candidates is desirable, as the control of schistosomiasis relies mostly on the use of a single drug, praziquantel, a heterocyclic pyrazino-isoquinolone. This drug exerts multiple effects, such as damage to the tegumental membrane, changes in calcium flux and muscular contractions in the parasite by a mechanism or mechanisms that are not... 

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective anti schistosomal and antitapeworm agent, praziquantel (see Chapter 54 Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies. 

Active stresses exerted by smooth muscle cells appear to increase the internal stresses that exist in vessel wall. The effects of passive and active muscular contraction on the residual stress in the wall have been considered. Their results suggest that basal muscle tone, which exists under physiological conditions, reduces the strain gradient in the arterial wall and yields a near uniform stress distribution. Increased muscular tone that accompanies elevated blood pressure tends to restore the distribution of circumferential strain in the arterial wall, and to maintain the flow-induced wall shear stress at normal levels. It appears that the active stresses exerted by smooth muscle cells may balance the tension within the vessel wall in a similar manner to the way that active fibroblast tension balances the stress in the dermis. 

Calcium performs a variety of cellular functions in muscle and nerve that ultimately result in muscular contraction. Excellent descriptions of calcium s function in muscle and nerve are to be found in the reviews by Hoyle (37), Cohen (38), and Robertson (39). At the neuromuscular junction, the excitable cells are very sensitive to changes in extracellular concentrations of calcium. Curtis (40) and Luttgau (41) described a fall in the resting action potential and electrical resistance when the extracellular calcium concentration fell below 10 M. The action potential and electrical resistance returned to normal following addition of calcium to this vitro preparation. The magnitude of the Initial muscle membrane action potential, that which regulates the propagation of further muscle contraction, is also mediated by the extracellular calcium concentration. While the inward flow of sodium ions from the extracellular space remains the dominant factor in the mechanism of muscle membrane depolarization, calcium ion flux appears to mediate the cell s permeability to sodium ions. This effect is particularly true in cardiac tissue (W). 

Praziquantel is indicated for use in the horse in several coimtries as a component of a combination ivermectin product (Mercier et al 2001). The mode of action of praziquantel has been studied extensively in trematodes (Harnett 1998) and the anticestodal effects of this compoimd are assumed to have a similar basis. Praziquantel increases the permeability of tegumental and muscle cells to calcium ions, which results in parasitic muscular contraction and paralysis. In the horse, praziquantel has a narrow spectrum of activity against tapeworm, with 89-100% efficacy at dose rates of 0.75-1 mg/kg (Lyons et al 1992). 

Drug ahsorption from an intramuscular site also may he altered in premature infants. Differences in relative muscle mass, poor perfusion to various muscles, peripheral vasomotor instability, and insufficient muscular contractions in premature infants compared with older children and adults can influence drug absorption from the intramuscular site. The net effect of these factors on drug absorption is impossible to predict phenobarbital has been reported to be absorbed rapidly, whereas diazepam absorption may be delayed." Thus intramuscular dosing is used rarely in neonates except in emergencies or when an intravenous site is inaccessible. 

Studies using "skinned" cardiac fibers indicate that concentrations of Ca2+ substantially less than required for contraction are capable of triggering the release of Ca2+ from the intracellular sarcotubular system (calcium induced calcium release) (ll, 15, 18). When the Ca2+ concentration within myocardial cells increases from resting values of 10 M to 10 5 M, Ca2+ binds to troponin releasing troponins inhibitory effects upon myosin allowing muscular contraction to occur (19) (Figure l). 

Praziquantel (available on a named-patient basis) is a highly effective anthelmintic, which induces muscular contraction and spastic paralysis in trematodes and cestodes by increasing calcium ion fluxes. 

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