Smooth muscle activation mechanisms

Once the intracellular Ca " concentration begins to rise, calmodulin-calcium binding also rises and MLCK, which is dependent on calmodulin activation, rises in turn. The next step in this cascade is the phosphorylation of myosin. Finally, the phosphorylation of myosin results in the activation of the crossbridges and the accompanying transduction of ATP energy into mechanical work. Despite its differences in regulation, smooth muscle behaves mechanically much like other muscles. 

Kannan MS, Prakash YS, Brenner T, Mickelson JR, Sieck GC 1997 Role of ryanodine receptor channels in Ca2+ oscillations of porcine tracheal smooth muscle. Am J Physiol 272 L659-L664 Kirber MT, Walsh JVJ, Singer JJ 1988 Stretch-activated ion channels in smooth muscle a mechanism for the initiation of stretch-induced contraction. Pfliig Arch Eur J Physiol 412 339-345... 

Kirber MT, Walsh JV Jr, Singer JJ. Stretch-activated ion channels in smooth muscle A mechanism for the initiation of stretch-induced contraction. Pflugers Arch. 1988 412 339-345. 

The mechanism underlying the selective phosphorylation of Thr s is not clear, but it suggests the activity of an unidentified kinase. Based on these experiments and studies characterizing the mechanical properties of arterial smooth muscle activated by phor-bol esters (Fulginiti et al., 1993), it was concluded that phorbol ester-stimulated contraction in smooth muscle can occur by a mechanism that is independent of LC20 phosphorylation. 

F5. Foda, H. D., George, S., Rollo, E., et al.. Regulation of gelatinases in human airway smooth muscle cells Mechanism of progelatinase A activation. Am. J. Physiol. 227, L174-182 (1999). 

Chapter 14 shows how modeling can propose mechanisms to explain experimentally observed oscillations in the cardiovascular system. A control system characterized by a slow and delayed change in resistance due to smooth muscle activity is presented. Experiments on this model show oscillations in the input impedance frequency spectrum, and flow and pressure transient responses to step inputs consistent with experimental observations. This autoregulation model supports the theory that low-frequency oscillations in heart rate and blood pressure variability spectra (Mayer waves) find their origin in the intrinsic delay of flow regulation. 

There are two dynamic effects that must be accounted for to accurately model the physiological control mechanism. First, the change in peripheral resistance is delayed. This represents a delay from the time that the flow changes to when the vascular smooth muscle activity actually initiates the process of correcting the flow. This time delay in the change of peripheral resistance is denoted tq. To account for this effect, the change in peripheral resistance determined from the steady value was written as ARs(t — tq). 

Apelins and the Apelin Receptor. Figure 3 Scheme illustrating the hypothesised mechanisms of control of human (a) vasculartone and (b) cardiac contractility by apelin peptides ( ). In the vasculature, apelins (released via the small vesicles of the constitutive pathway) may act directly to activate apelin receptors on the underlying smooth muscle to produce vasoconstriction. This response may be modified by apelin peptides feeding back onto apelin receptors on endothelial cells to stimulate the release of dilators, such as nitric oxide. In heart, apelin peptides, released from endocardial endothelial cells, activate apelin receptors on cardiomyocytes to elicit positive inotropic actions. 

Bronchial Asthma. Figure 2 Mechanisms of bronchial hyperresponsiveness. Toxic products from eosinophils [cationic peptides, reactive oxygen species (ROS)] cause epithelial injury. Nerve endings become easily accessible to mediators from mast cells, eosinophils [eosinophil-derived neurotoxin (EDN)], and neutrophils, and to airborne toxicants such as S02. Activation of nerve endings stimulates effector cells like mucosal glands and airway smooth muscle either directly or by cholinergic reflexes. 

Prostacyclin (epoprostanol) is one of the few drugs effective for the treatment of Primary Pulmonary Hypertension (PPH) a rare but frequently fatal illness of young adults. Increased blood pressure in the pulmonary circulation leads to right-heart failure. Continuous infusion of epoprostanol leads to a decrease in blood pressure however, it is unclear whether this is due to direct dilator activity of the IP receptor acting on smooth muscle, or a more indirect mechanism. 

Vasopressin (Rtressin Synthetic) and its derivatives, namely lypressin (Diapid) and desmopressin (DDAVP), regulate the reabsorption of water by the kidneys. Vasopressin is secreted by the pituitary when body fluids must be conserved. An example of this mechanism may be seen when an individual has severe vomiting and diarrhea with little or no fluid intake. When this and similar conditions are present, die posterior pituitary releases the hormone vasopressin, water in die kidneys is reabsorbed into die blood (ie, conserved), and die urine becomes concentrated. Vasopressin exhibits its greatest activity on die renal tubular epithelium, where it promotes water resoqition and smooth muscle contraction throughout die vascular bed. Vasopressin has some vasopressor activity. 

The regulation of smooth muscle and nonmuscle myosin-II is substantially different from the mechanism described above for two important reasons. First, there is no troponin in smooth muscle and nonmuscle cells. Second, although the rate of hydrolysis of ATP by these myosins is low in the presence of physiological concentrations of Mg % the addition of actin does not necessarily result in the stimulation of ATP hydrolysis by smooth muscle or nonmuscle myosin-II. These observations suggest the presence of a unique mechanism for Ca " regulation in smooth and nonmuscle cells, and that these myosins require an activation process before actin can stimulate ATP hydrolysis. 

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