Smooth muscle activation intracellular calcium concentration

Calcium homeostasis is also affected by an overload in peroxides. In some instances, this may be due to activation of so-called calcium channels. In the presence of extracellular calcium, exposure of smooth muscle cells to 0.3 mM H2O2 was shown to induce a rapid increase in intracellular calcium concentration, followed by a decrease to a new constant level approximately twice higher than the initial one [140]. Subsequent treatment of the cells with Ca2+-channel blockers, with disulfide-reducing agents or with antioxidants such as trolox, prevented the stabilization of intracellular calcium at the high steady-state concentration. These results suggest that an increased disulfide/thiol ratio activates voltage-dependent calcium channels of the outer cell membrane. 

Q13 Calcium channel blockers decrease the opening of L-type calcium channels in the plasma membrane of vascular smooth muscle cells, and so reduce intracellular calcium concentration and contractile activity. The blood vessels therefore dilate. Calcium channel blockers act mainly on the arterial side of the circulation, and the dihydropyridines, such as nifedipine, are useful coronary arteriolar dilator agents. These agents are usually the treatment of choice for Prinzmetal angina. 

In an alternative pathway, acetylcholine stimulates a smooth-muscle cell-membrane receptor to enhance the activity of adenyl cyclase. Adenyl cyclase increases the conversion of cyclic adenosine triphosphate to cAMP, a potent muscle relaxant. Similarly to cGMP, cAMP decreases intracellular calcium concentrations to produce smooth-muscle relaxation in cells of the arteries and cavernosal sinuses. Arterial blood flow to and blood filling of the corpora are enhanced, and a penile erection results (see Fig. 81-2). ... 

The mechanism of cardiac contraction involves a G-protein signal transduction pathway, which regulates intracellular calcium concentrations. Activation of the Gs-protein involves the formation of intracellular cAMP, which thereby increases intracellular calcium, stimulating cardiac muscle contraction (see Chapter 4). Relaxation occurs when the released cAMP is hydrolyzed by cytosolic cAMP-dependent PDE3, one of the phosphodiesterase isofoms. Therefore, inhibition of PDE3 increases intracellular cAMP, promoting cardiac muscle contraction but vasodilation of vascular smooth muscle. (See Chapter 17 for more information about phosphodiesterases.)... 

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. 

All of these factors (ANS stimulation, blood-borne and locally produced substances) alter smooth muscle contractile activity by altering the intracellular concentration of calcium. An increase in cytosolic calcium leads to an increase in crossbridge cycling and therefore an increase in tension... 

Nitric oxide, and perhaps 5-nitrosothiol, activates soinble gnanylate cyclase to increase intracellular concentrations of cyclic GMR Increased cychc GMP induces a sequence of protein phosphorylation associated with rednced intracellular calcium release from the sarcoplasmic reticulum or reduced permeability to extracellular calcium and, conseqnently, smooth muscle relaxation. 

The maintenance of physiologic calcium concentrations in the intracellular and extracellular spaces is vital for the preservation and function of cell membranes propagation of neuromuscular activity regulation of endocrine and exocrine secretory functions blood coagulation cascade platelet adhesion process bone metabolism muscle cell excitation/contraction coupling and mediation of the elec-trophysiologic slow-channel response in cardiac and smooth-muscle tissue. 

The more classic pathway of smooth muscle contractile activation is illustrated in the right-hand side of this panel, where activation leads to an increase in intracellular ionized calcium concentration ([Ca +jj) by virtue of Ca + entry through channels or exchangers (Lyu et al, 1992 van Breemen et al, 1985 Khalil et al, 1987) or the release of Ca2+ from the sarcoplasmic reticulum. [Ca +J in combination with calmodulin activates myosin light chain (MLC) kinase to cause phosphorylation of the 20-kDa MLC, which in turn results in increased actin-activated myosin AT-Pase activity, increase cross-bridge cycling velocity, and, as a result, an increase in contractile force (Aksoy et al, 1976 Sobieszek, 1977). 

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