Muscle contraction agents

Smooth muscle contractions are subject to the actions of hormones and related agents. As shown in Figure 17.32, binding of the hormone epinephrine to smooth muscle receptors activates an intracellular adenylyl cyclase reaction that produces cyclic AMP (cAMP). The cAMP serves to activate a protein kinase that phosphorylates the myosin light chain kinase. The phosphorylated MLCK has a lower affinity for the Ca -calmodulin complex and thus is physiologically inactive. Reversal of this inactivation occurs via myosin light chain kinase phosphatase. 

The action of epinephrine and related agents forms the basis of therapeutic control of smooth muscle contraction. Breathing disorders, including asthma and various allergies, can result from excessive contraction of bronchial smooth muscle tissue. Treatment with epinephrine, whether by tablets or aerosol inhalation, inhibits MLCK and relaxes bronchial muscle tissue. More specific bronchodilators, such as albuterol (see figure), act more selec-... 

Botulinum neurotoxins are widely used as therapeutic agents to cause reduction or paralysis of skeletal muscle contraction. They are used to treat cervical dystonia, which causes regional involuntary muscle spasms often associated with pain. Moreover, they are used in strabism, blepharospasm, hemifacial spasm, and... 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Inspection of the retina during an ophthalmoscopic examination is greatly facilitated by mydriasis, or the dilation of the pupil. Parasympathetic stimulation of the circular muscle layer in the iris causes contraction and a decrease in the diameter of the pupil. Administration of a muscarinic receptor antagonist such as atropine or scopolamine prevents this smooth muscle contraction. As a result, sympathetic stimulation of the radial muscle layer is unopposed, causing an increase in the diameter of the pupil. These agents are given in the form of eye drops that act locally and limit the possibility of systemic side effects. 

Delayed constrictor responses in guinea pig smooth muscle preparations following challenge with jute extract have been observed. The response diminishes with successive doses of extract as though some "store" is being depleted, until, finally, constriction is not seen. Cotton extract is a more potent contracting agent than jute. 

Potential etiologic agents in cotton dust that release histamine are shown in Table VII. Some of these are effector molecules having potent biological effects in minute concentrations, i.e. peptides, which may act directly to affect chemotaxis and leukocyte recruitment, and also to release histamine and stimulate respiratory smooth muscle contraction. These bifunctional effector molecules are of major importance in considering pathogenic mechanisms in byssinosis. 

Some agents are bifunctional, causing the release of histamine and recruiting leukocytes. Bifunctional mediators include bacterial peptides, endotoxins, DNA, C3a, C5a and bradykinin. Each of these substances can exert dual effects. This may either occur directly, as in the case of bacterial peptides and bradykinin causing chemotaxis and bronchial smooth muscle contraction, or indirectly, as endotoxin and DNA conversion of complement. C3a and C5a act indirectly as complement fragments to effect histamine release, which in turn contracts bronchial smooth muscle. However, both appear to act directly to effect chemotaxis with C5a, the more potent fragment. 

Cardiotonic agents are sometimes called positive inotropic drags, i.e. substances that enhance the strength of muscle contractions, and in this case those that enhance the strength of myocardium contraction. Cardiotonic drugs are intended for treating cardiac insufficiency. 

In summary, adrenergic receptors can be subclassified according to their location and affinity for specific pharmacologic agents. Table 18-2 summarizes the receptor subtypes that are located on the primary organs and tissues in the body, and the associated response when the receptor is stimulated. Exactly which receptor subtype is located on any given tissue depends on the tissue in question. Note that some tissues may have two or more different subtypes of adrenergic receptor (e.g., skeletal muscle arterioles appear to have alpha-1 and beta-2 receptors). Also, the response of a tissue when the receptor is stimulated is dependent on the specific receptor-cell interaction. Stimulation of the vascular alpha-1 receptor, for instance, results in smooth-muscle contraction and vasoconstriction, whereas stimulation of the intestinal alpha-1 receptor results in relaxation and decreased intestinal motility. This difference is caused by the way the receptor is coupled to the cell s internal biochemistry at each location. As discussed in Chapter 4, the surface receptor at one cell may be coupled to the... 

Artemisia monosperma The relaxant effects of 7-0-methyleriodictyol, a flavone isolated from the aerial parts of A. monosperma, on smooth muscle contraction has been studied. The inhibition of contraction induced by known therapeutic agents such as acetylcholine and oxytocin are consistent with the use of this plant in the treatment of certain gastrointestinal disorders. 

Succinylcholine increases intraocular pressure transiently. It can also cause muscle pain, which may be due to fasciculation and uncoordinated muscle contraction. The prior administration of a competitive blocking agent may prevent both fasciculation and pain. 

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