Activity contractile

If MLCK activates contraction by increasing myosin phosphorylation, then an increase in the activity of myosin light chain phosphatase, MLCP, by decreasing the fraction of myosin which is phosphorylated, should lead to relaxation from the active (contractile) state. Cyclic adenosine monophosphate (AMP) is a strong inhibitor of smooth muscle contraction and it has been suggested that activation of MLCP could result from its phosphorylation via cAMP activated protein kinase (see Figure 5). 

Okadaic acid (OA), being a polyether, presents ionophoretic properties (facilitation of ion transport across membranes) as does CTX. It has been found that OA causes contraction in smooth muscles even in the absence of Ca (Ozaki and Karaki 1987 Shibata 1985). Ozaki and Karaki (1987) studied the mechanism of action of OA compared to calyculin A (another polyether isolated from a marine sponge). The results of this work suggest that OA has two separate effects activation of calcium channels as well as activating contractile elements to induce smooth muscle contraction. Recently, OA, in addition to other compounds from marine sources, has been found to be a tumor promoter that is, an agent that promotes tumor formation on already initiated cells (Fujiki 1988). It has been found that the OA class of tumor promoters bind to their own receptors which are present in particulate as well as cytosol fractions. The mechanism of action of these compounds has been partially elucidated. 

Chiarelli, P. and De Rossi, D. (1988) Determination of mechanical parameters related to the kinetics of swelling in an electrically activated contractile gel. Prog. Coll. Polym. Sci., 78, 4-8. 

Fujiwara N, Asaka K, Nishimura Y et al (1999) Preparation of gold-sohd electrolyte composites as electric stimuli responsive materials. Chem Mater 12 1750-1754 Hamlen RP, Kent CE, Shafer SN (1965) Electrolytically activated contractile polymer. Nature... 

Thrombosis is an often encountered consequence of atherosclerotic alterations of the vessel wall, and there can be no doubt that in its genesis, blood platelets play a predominant role (cf.55)< Platelets in turn are of considerable interest as the model of a metabolically active, contractile cell, capable of reacting to a variety of external stimuli. In the course of their activation, they display a series of morphological and biochemical alterations, in the course of which they aggregate and acquire procoagulant properties. It is of particular interest that lipids and fatty acids are known to interact with platelets and with the blood clotting system, and this again justifies the inclusion of a chapter on thrombosis in this series of articles on diet and atherosclerosis. ... 

Hamlen RP, Kent CE, Sharer SN (1965) Electrolytically activated contractile polymer. Nature 206 1149-1150... 

Skeletal muscles are the only actuators in the human body. A skeletal muscle is composed of two types of structural components active contractile elements and inert compliant materials. The contractile elements are contained within the muscle fibers. The fibers vary in length from a few millimeters to more than 40 cm, and their width is between 1 and 150 im. Approximately, 85% of the mass of a muscle consists of the muscle fibers composed from sarcomeres, while the remaining 15% is largely composed of the connective tissue, which contains variable proportions of collagen, reticular, and elastic fibers. The connective tissues provide an arrangement of simple, spring-like elements (elastic components of the muscle) that exist both in series and in parallel with the contractile elements. 

In the presence of calcium, the primary contractile protein, myosin, is phosphorylated by the myosin light-chain kinase initiating the subsequent actin-activation of the myosin adenosine triphosphate activity and resulting in muscle contraction. Removal of calcium inactivates the kinase and allows the myosin light chain to dephosphorylate myosin which results in muscle relaxation. Therefore the general biochemical mechanism for the muscle contractile process is dependent on the avaUabUity of a sufficient intraceUular calcium concentration. 

The cardiac effects of the calcium antagonists, ie, slowed rate (negative chronotropy) and decreased contractile force (negative inotropy), are prominent in isolated cardiac preparations. However, in the intact circulation, these effects may be masked by reflex compensatory adjustments to the hypotension that these agents produce. The negative inotropic activity of the calcium antagonists may be a problem in patients having heart failure, where contractility is already depressed, or in patients on concomitant -adrenoceptor blockers where reflex compensatory mechanisms are reduced. 

Relatively selective stimulation of Pi-adrenergic receptors can be achieved with dobutamine. This is a racemic drug of which both isomers activate the Pi-receptor, and in addition the (-) isomer activates ( -receptors whereas the (+) isomer activates p2-receptors the simultaneous activation of ai- and p2-receptors results in no major net effect on peripheral resistance, and thus the overall cardiovascular effects are mediated by Pi-stimulation leading to increases in cardiac contractility and output. Dobutamine is used for the short-term treatment of acute cardiac failure and for diagnostic purposes in stress echocardiography. 

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. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Peripheral mAChRs are known to mediate the well-documented actions of ACh at parasympathetically innervated effector tissues (organs) including heart, endocrine and exocrine glands, and smooth muscle tissues [2, 4]. The most prominent peripheral actions mediated by activation of these receptors are reduced heart rate and cardiac contractility, contraction of... 

The major relaxing transmitters are those that elevate the cAMP or cGMP concentration (Fig. 3). Adenosine stimulates the activity of cAMP kinase. The next step is not clear, but evidence has been accumulated that cAMP kinase decreases the calcium sensitivity of the contractile machinery. In vitro, cAMP kinase phosphorylated MLCK and decreased thereby the affinity of MLCK for calcium-calmodulin. However, this regulation does not occur in intact smooth muscle. Possible other substrate candidates for cAMP kinase are the heat stable protein HSP 20, (A heat stable protein of 20 kDa that is phosphorylated by cGMP kinase. It has been postulated that phospho-HSP 20 interferes with the interaction between actin and myosin allowing thereby smooth muscle relaxation without dephosphorylation of the rMLC.) Rho A and MLCP that are phosphorylated also by cGMP kinase I (Fig. 3). 

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