Muscle contraction calcium channels

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. 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

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]. 

The trigger for all musele eontraetion is an increase in Ca eoneentration in the vicinity of the muscle fibers of skeletal muscle or the myocytes of cardiac and smooth muscle. In all these cases, this increase in Ca is due to the flow of Ca through calcium channels (Figure 17.24). A muscle contraction ends when the Ca concentration is reduced by specific calcium pumps (such as the SR Ca -ATPase, Chapter 10). The sarcoplasmic reticulum, t-tubule, and sarcolemmal membranes all contain Ca channels. As we shall see, the Ca channels of the SR function together with the t-tubules in a remarkable coupled process. 

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. 

Systemic and coronary arteries are influenced by movement of calcium across cell membranes of vascular smooth muscle. The contractions of cardiac and vascular smooth muscle depend on movement of extracellular calcium ions into these walls through specific ion channels. Calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia), and verapamil (Calan), inhibit die movement of calcium ions across cell membranes. This results in less calcium available for the transmission of nerve impulses (Fig. 41-1). This drug action of the calcium channel blockers (also known as slow channel blockers) has several effects on die heart, including an effect on die smooth muscle of arteries and arterioles. These drug dilate coronary arteries and arterioles, which in turn deliver more oxygen to cardiac muscle. Dilation of peripheral arteries reduces die workload of die heart. The end effect of these drug is the same as that of die nitrates. 

Sarcoplasmic reticulum Ca -channels. In many smooth muscle cells the rise of intracellular calcium which triggers contraction comes from the flow of calcium from the SR through Ca channels. In others, the SR contributes some unknown fraction of the triggering calcium relative to the amount which comes from the extracellular space through the plasma membrane Ca -channels. There are at least two kinds of Ca -channels in the SR. 

Another possibility is that the antagonist interferes with other post-receptor events that contribute to the tissue response. For example, calcium channel blockers such as verapamil block the influx of calcium necessary for maintained smooth muscle contraction hence, they reduce the contractile response to acetylcholine. Some pharmacologists prefer to describe this as a variant of functional antagonism (see above). 

The action potential easily penetrates all regions of these small cells. Therefore, smooth muscle does not have transverse tubules. Furthermore, smooth muscle cells have very little sarcoplasmic reticulum, so intracellular storage of calcium is limited. Instead, the calcium needed for contraction is obtained primarily from the extracellular fluid. The influx of Ca++ ions through their channels in the cell membrane stimulates the release of a small amount of Ca++ ions from the sarcoplasmic reticulum. 

Arteriolar resistance changes that take place in order to maintain a constant blood flow are explained by the myogenic mechanism. According to this mechanism, vascular smooth muscle contracts in response to stretch. For example, consider a situation in which blood pressure is increased. The increase in pressure causes an initial increase in blood flow to the tissue. However, the increased blood flow is associated with increased stretch of the vessel wall, which leads to the opening of stretch-activated calcium channels in the vascular smooth muscle. The ensuing increase in intracellular calcium results in vasoconstriction and a decrease in blood flow to the tissue toward normal. 

Increases in the concentration of calcium in the cytosol provides a signal that can initiate muscle contraction, vision, and other signaling pathways. The response depends on the cell type. In muscle, a transient rise in the cytosolic calcium levels (from opening calcium channels in the sarcoplasmic reticulum) causes contraction. This signaling in contraction is a direct consequence of electrical activation of the voltage-gated channel. 

Calcium couples muscle membrane excitation to filament contraction. Important work has focused on the proteins present in the T-tubule/SR junction. One protein, an integral component of the T-tubular membrane, is a form of L-type, dihydropyridine-sensitive, voltage-dependent calcium channel. Another, the ryanodine receptor (RyR), is a large protein associated with the SR membrane in the triad that may couple the conformational changes in the Ca2+ channel protein induced by T-tubular depolarization to the Ca2+ release from the SR (Fig. 43-6). 

Fig. 4.2. Effects of triphenylethylene SERMs on spontaneous and depolarization-induced contractions in visceral smooth muscle. Tamoxifen (a) and ethylbromide tamoxifen (EBTx, b) rapidly and reversibly inhibit spontaneous peristaltic activity in duodenal muscle. Both compounds also inhibit depolarization-induced tonic contraction of uterine muscle (c). The inhibition of L-type voltage-dependent calcium channels underlies the relaxing effects illustrated here. Drugs concentrations were 10 xM in all cases. %RA percent of activity related to maximal activity...

Bolton TB, Aaronson PI, MacKenzie I 1988 Voltage-dependent calcium channel in intestinal and vascular smooth muscle cells. Ann NY Acad Sci 522 32 -2 Bolton TB, Prestwich SA, Zholos AV, Gordienko DV 1999 Excitation-contraction coupling in gastrointestinal and other smooth muscles. Annu Rev Physiol 61 85—115 Bramich NJ, Hirst GDS 1999 Sympathetic neuroeffector transmission in the rat anococcygeus muscle. J Physiol 516 101—115... 

Amlodipine is a calcium channel blocker used to treat hypertension and angina pectoris. Calcium channel blockers block the passage of calcium, an essential factor in muscle contraction, into the heart and smooth muscles. Such blockage interferes with the contraction of these muscles, which in turn dilates the veins that supply blood to them. This reduces blood pressure. 

It is now obvious that the contraction of smooth muscle is controlled by the concentration of calcium in the cytoplasm. A basic principle of calcium-channel blocker action is that they disturb diffusion of calcium into muscle cells of the heart and vessels. Reduction of calcium ions entering the cells of the myocardium leads to a reduced use of the energy of phosphate bonds for mechanical heart work. As a result, strength of cardiac contractions and heart work are reduced, which in turn leads to a reduction in the heart s need of oxygen. 

Pharmacology The calcium channel blockers share the ability to inhibit movement of calcium ions across the cell membrane. The effects on the cardiovascular system include depression of mechanical contraction of myocardial and smooth muscle and depression of both impulse formation (automaticity) and conduction velocity. 

Available evidence suggests that a single unifying mechanism does not exist but rather that various vasodilators may act at different places in the series of processes that couple excitation of vascular smooth muscle cells with contraction. For example, the vasodilators known as calcium channel antagonists block or limit the entry of calcium through voltage-dependent channels in the membrane of vascular smooth muscle cells. In this way, the calcium channel blockers limit the amount of free intracellular calcium available to interact with smooth muscle contractile proteins (see Chapter 14). 

It has been known since the late 1800s that calcium influx is necessary for the contraction of smooth and cardiac muscle. The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table... 

Cardiac muscle is highly dependent on calcium influx for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node—so-called slow-response, or calcium-dependent, action potentials—may be reduced or blocked by all of the calcium channel blockers. Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. In some cases, cardiac output may also decrease. This reduction in cardiac mechanical function is another mechanism by which the calcium channel blockers can reduce the oxygen requirement in patients with angina. 

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