Contractile proteins, sensitization

Other possibiHties include Ot blockers (36) and calcium antagonists (37). Other unproven agents include the P-adrenoreceptor agonists, phosphodiesterase inhibitors that affect movement of sodium and potassium through cellular channels, and calcium contractile protein sensitizers (38). Any of these agents and the appropriate cellular mechanisms that prevent or slow morphologic alteration in the heart or blood vessels should counteract the aging process. 

From this brief summary of excitation-contraction coupling it is obvious that Ca is an important link between the activated membrane and the contractile proteins, and thus a regulator of tension development. Westerblad et al. (1991) defined three factors which explain the force decrease in fatigued muscle reduced Ca " release from the SR, reduced Ca sensitivity of the myofilaments, and reduced maximum Ca -activated tension. 

Fatigue during intermittent tetanic stimulation is caused by three mechanisms (a) decreased maximum Ca activated tension, (b) decreased sensitivity of the contractile proteins, and (c) decreased Ca release from the SR. 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

Many of the biochemical and molecular events that are responsible for uterine smooth muscle contraction are the same as those that control other smooth muscle tissues (Fig. 62.1). Once uterine smooth muscle sensitivity has been augmented, actin and myosin must interact for contraction to occur. This interaction depends on the phosphorylation of the contractile proteins by the enzyme myosin light chain kinase (MLCK). This enzyme requires Ca++ and is active only when associated with calmodulin. Activation of the entire muscle contraction... 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

Ca2+ -free media do not seem to be related to changes in cellular Ca2+ regulation but to an inhibitory effect on the regulation of contractile proteins, an effect probably related to the decreased sensitivity of contractile elements to Ca2+ that apparently resulted from the inhibitory effects of quercetin on protein kinases [110]. 

Myocardial relaxation is an energy-dependent process that is sensitive to episodes of ischemia. Diastolic resequestration of calcium ions by the sarcoplasmic reticulum is an energy-dependent process. In the event of ischemia, the sequestration of calcium is inhibited, allowing the calcium to continue its interaction with the myofibrillar contractile proteins. CCBs have been used with some success in patients with diastolic dysfunction. ... 

Riiegg JC, Pfitzer G (1985) Modulation of calcium sensitivity in guinea pig -taenia coli skinned fiber studies. Experientia 41 997-1001 Riiegg JC, Pfitzer G (1991) Contractile protein interactions in smooth muscle. Blood Vessels 28 159-163... 

The platelets contain a contractile protein (throm-bosthenin), which has solubility properties similar to those of the actomyosin group of proteins. The activity of the protein requires the presence of ATP and metallic ions. The protein has been isolated from human platelets, and like actinomycin, the contractile protein possesses ATPase activity. Electron microscopic examination of isolated thrombosthenin revealed a microfibric structure 80-100 A wide with a possible periodic structure [28]. In the presence of ATP, the contractile protein dissociates into an actinlike protein (thrombosthenin A) and a myosinlike (thrombosthenin M) moiety. ATPase activity is nonexistent in thrombosthenin A and weak in thrombosthenin M. When tested alone, neither thrombosthenin A or M is ATP sensitive, but the mixing of A and M thrombosthenin restores ATP sensitivity and ATPase activity. 

Sauviat, M.-P., Chesnais, J.-M., Choukri, N., Diacono, J., Biard, J.-F., and Verbist, J.-F. (1993) The polyether bistramide A affects the calcium sensitivity of the contractile proteins in frog atrial heart muscle. Cell Calcium, 14, 301-309. 

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). 

Kitazawa T, Kobayashi S, Horiuti K, Somlyo AV, Somlyo AP 1989 Receptor coupled, permeabilized smooth muscle role of the phosphatidylinositol cascade, G proteins and modulation of the contractile response to Ca2+. J Biol Chem 264 5339-5342 Lopez-Lopez JR, Shacklock PS, Balke CW, Wier WG 1995 Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science 268 1042-1045 Marks AR, Fleischer S, Tempst P 1990 Surface topography analysis of the ryanodine receptor/ junctional channel complex based on proteolysis sensitivity mapping. J Biol Chem 265 13143-13149... 

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