Smooth muscles contracting

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

Pig. 2. Proposed mechanism of inbition of smooth muscle contraction by P2" gonists, where AMP is adenosine monophosphate, cAMP is cycHc-3 5 adenosine monophosphate, ATP is adenosine triphosphate, and -P is an attached phosphate. 

Calcium and Vascular Smooth Muscle Contraction. Calcium acts on a number of sites associated with the control of the cytoplasmic calcium concentration. Vascular smooth muscle contraction can be initiated by the opening of the slow calcium channel aUowing influx of extraceUular calcium through the sarcolemmal membrane into the cytoplasmic compartment. The iatraceUnlar calcium concentration increases to 1 x 10 Af, a threshold concentration necessary to initiate contraction. 

Another mechanism in initiating the contraction is agonist-induced contraction. It results from the hydrolysis of membrane phosphatidylinositol and the formation of inositol triphosphate (IP3)- IP3 in turn triggers the release of intracellular calcium from the sarcoplasmic reticulum and the influx of more extracellular calcium. The third mechanism in triggering the smooth muscle contraction is the increase of calcium influx through the receptor-operated channels. The increased cytosolic calcium enhances the binding to the protein, calmodulin [73298-54-1]. 

When exposure is repeated, the allergen binds between two adjacent IgE molecules. This causes release of inflammatory mediators (histamine, leukotrienes, chemotactic factors). These act locally and cause smooth muscle contraction, increased vascular permeability, mucous gland secretion, and infiltration of inflammatory cells (neutrophils and eosinophils). However, histamine can also be released by non-IgE-mediated mechanisms (e.g., due to exposure to certain fungi). 463... 

Mammals, fungi, and higher plants produce a family of proteolytic enzymes known as aspartic proteases. These enzymes are active at acidic (or sometimes neutral) pH, and each possesses two aspartic acid residues at the active site. Aspartic proteases carry out a variety of functions (Table 16.3), including digestion pepsin and ehymosin), lysosomal protein degradation eathepsin D and E), and regulation of blood pressure renin is an aspartic protease involved in the production of an otensin, a hormone that stimulates smooth muscle contraction and reduces excretion of salts and fluid). The aspartic proteases display a variety of substrate specificities, but normally they are most active in the cleavage of peptide bonds between two hydrophobic amino acid residues. The preferred substrates of pepsin, for example, contain aromatic residues on both sides of the peptide bond to be cleaved. 

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-... 

FIGURE 5.19 Method of Barlow for measurement of affinity of a partial agonist, (a) Guinea pig ileal smooth muscle contraction to histamine (filled circles) and partial histamine receptor agonist E-2-P (N,N-diethyl-2-(l-pyridyl)ethylamine (open circles). Dotted lines show equiactive concentrations of each agonist used for the double reciprocal plot shown in panel b. (b) Double reciprocal plot of equiactive concentrations of histamine (ordinates) and E-2-P (abscissae). Linear plot has a slope of 55.47 and an intercept of 1.79 x 10s. This yields a KB (1 — tp/ta) = 30.9 pM. (c) Variant of double reciprocal plot according to Equation 5.8. (d) Variant of double reciprocal plot according to Equation 5.10. Data redrawn from [10],... 

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

Somatostatin is a regulatory cyclic peptide, which has originally been described as a hypothalamic growth hormone release-inhibiting factor. It is produced throughout the central nervous system (CNS) as well as in secretoty cells of the periphery and mediates its regulatory functions on cellular processes such as neurotransmission, smooth muscle contraction, secretion and cell proliferation via a family of seven transmembrane domain G-protein-coupled receptors termed sstx 5. 

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