There is a Greater Concentration of Na is a Continuous Contraction That Shows No Evidence

Smooth Muscle

Smooth muscle cells are small and arranged in groups to form the contractile wall of hollow organs and blood vessels.

From: Cell Physiology Source Book , 1995

Cardiovascular System

Brian R. Berridge , ... Eugene Herman , in Fundamentals of Toxicologic Pathology (Third Edition), 2018

Smooth Muscle Cells

Smooth muscle cells are spindle-shaped and have single elongated nuclei. As in cardiac muscle cells, the configuration of the nuclear membranes in smooth muscle cells changes during contraction and relaxation. Smooth muscle cells contain thin (actin) and thick (myosin) contractile filaments as well as cytoskeletal filaments. The thin filaments are the most conspicuous feature of smooth muscle cells. They fill most of the cytoplasm, are easily demonstrable in electron microscopic preparations, are 4–8  nm thick, and insert into condensations of electron-dense material (dense bodies) located subjacent to the plasma membranes. The external laminae of smooth muscle cells are well developed with transport vesicles numerous along their surfaces.

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INORGANIC NUTRIENTS

TOM BRODY , in Nutritional Biochemistry (Second Edition), 1999

Smooth Muscles

Smooth muscles are present in tissues requiring sustained contraction, rather than rapid contraction and relaxation. Smooth muscles regulate the flow of blood through arteries, arterioles, and veins, where they control the size of the lumen of the vessel. They occur in the gastrointestinal tract, where they are responsible for movements of the stomach and the peristaltic waves of the intestines. Smooth muscles are present in sphincters, where they control the flow of fluids through ducts. These muscles are involved in the contraction of the uterus. Smooth muscles are stimulated to contract by catecholamines released by nerves in the vicinity of the muscle, as well as by a number of other hormones. Smooth muscles are also stimulated by the catecholamines in the bloodstream that originate in the secretions of the adrenal medulla. These hormones diffuse over the entire smooth muscle cell. Smooth muscle cells are generally quite small, about 200 to 300 μm long and 5 μm wide. The hormone binds to hormone receptors and activates phospholipase C, resulting in the release of calcium from the sarcoplasmic reticulum and contraction. Smooth muscles are different from skeletal muscles in that they tend to be less dependent on depolarization of the plasma membrane. The contraction of smooth muscles may involve both IP3-dependent release of intracellular calcium and depolarization-dependent entry of extracellular calcium through Ca channels in the plasma membrane.

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Green Tea (−)-Epigallocatechin-3-Gallate and its Effects on Pancreatic Stellate Cells

Makoto Otsuki , Hiroshi Asaumi , in Tea in Health and Disease Prevention, 2013

Effects of EGCG on α-SMA Production

α-SMA is an important marker of PSC activation, and activated PSCs are the principal source of collagen in the fibrotic pancreas (Apte et al., 1999, 2000). Control PSCs exhibit weak fluorescence for α-SMA with short processes (Figure 108.7A). Since PSCs generate acetaldehyde via the alcohol dehydrogenase-mediated oxidation of ethanol (Apte et al., 2000), and since ethanol and its metabolite acetaldehyde induce oxidative stress in PSCs, PSCs treated with ethanol show considerable production of α-SMA (strong fluorescence) and have large bodies with remarkable processes (Figure 108.7B). Treatment with EGCG in the presence of ethanol suppresses the fluorescence and abolishes the ethanol-induced morphological alterations of PSCs (Figure 108.7C). In addition, ethanol and application of 80 mmHg pressure significantly increase the gene expression and protein production of α-SMA in PSCs. EGCG significantly suppresses ethanol- and pressure-induced α-SMA production in a concentration-dependent manner (Figure 108.7D) (Asaumi et al., 2007; Watanabe et al., 2004). SB-203580, a p38 MAPK inhibitor, also abolishes the pressure-induced increase in α-SMA expression (Watanabe et al., 2004).

Figure 108.7. Immunofluorescence for α-SMA in Ethanol-Stimulated PSCs in the Absence or Presence of EGCG.

Pancreatic stellate cells (PSCs) were incubated for 24 h in the following conditions: (A) no treatment as control, (B) 50 mM ethanol and (C) 50 mM ethanol plus 5 μM EGCG. Morphological changes characteristic of activated PSCs were assessed after staining with α-SMA. Original magnification 100 × objective.

(D) Effects of EGCG on α-SMA production in ethanol-stimulated PSCs. Total cell lysates were prepared and the levels of α-SMA production were determined by Western blotting. Data are presented as means ± SD. ∗P < 0.05 vs. control, #P < 0.05 vs. ethanol alone. EtOH, ethanol. (Modified from Asaumi et al., 2006, with permission.)

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Smooth Muscle Action Potentials

R. Kent Hermsmeyer , in Cell Physiology Source Book, 1995

VII Summary

Smooth muscle cells are small and arranged in groups to form the contractile wall of hollow organs and blood vessels. In most cases, the muscle cell specialization is for slow, maintained contraction (tone) rather than speed. The action potential phenomenon here is to activate by a multiplicity of stimulatory and inhibitory inputs to a diverse array of receptors on a single cell. Coordination through chemicals released by nerve fibers, secretory cells, or other smooth muscle cells is important. An array of ion conductances with slower inactivation properties allows for long-duration contractions (tone) and continuously graded regulation. Superimposed electrogenic ion transport allows for additional modulatory inputs. With the multiplicity of receptors and response mechanisms found in the deceptively small smooth muscle cell, the complexity of signaling mechanisms possible with the simple smooth muscle spike should be regarded as a compact masterpiece of multiple responsiveness.

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Disorders of the Endocrine System

Stephen M. Reed DVM, Dipl ACVIM , ... Debra C. Sellon DVM, PhD, Dipl ACVIM , in Equine Internal Medicine (Fourth Edition), 2018

Ileus

Smooth muscle cells have more voltage-gated Ca ²⁺ channels and fewer voltage-gated Na⁺ channels than skeletal muscle fibers, and therefore Na⁺ is less important for the action potential and muscle contraction. This results in slower and more sustained contractions (Ca²⁺ channels are slow channels). In skeletal muscle almost all Ca²⁺ required for contraction comes from the sarcoplasmic reticulum, but in smooth muscle cells the sarcoplasmic reticulum is a rudimentary organelle; these cells depend on extracellular Ca²⁺ for contraction. Therefore any pathologic condition that reduces Ca²⁺ affects smooth muscle contractility. This is evident in horses that develop ileus and colic secondary to hypocalcemia (e.g., after exercise, transport, or sepsis). A recent study found that low ionized calcium concentrations were associated with colic in pregnant mares. ¹⁶⁵ Treatment with calcium gluconate may restore gastrointestinal motility.

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Meat: Food and Science of the Animal Kingdom

Mark Gibson , ... Pat Newsham , in Food Science and the Culinary Arts, 2018

12.1.1.6 Smooth muscle

Smooth muscles—sometimes referred to as visceral muscles—can be found in an animal's cardiovascular, gastrointestinal, genitourinary, and respiratory systems. They are mostly composed of hollow organs (tubular or saccular) and facilitate the transport and/or storage of food, fluids, or gases within the body (with the exception of breathing and the beating of the heart). The walls of these organs are composed of smooth muscle, a type of tissue that enables constriction or dilatation. Smooth muscle is so called because of the lack of the appearance of striations (stripes) as seen in both skeletal and cardiac muscles. Striations are caused by the alternating segments of thick and thin muscle proteins that uniformly line up within muscle fibers giving the appearance of stripes. Smooth tissues like the large and small intestines are often used as casings ( Fig. 12.4).

Fig. 12.4. Smooth muscle.

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Calcium Signaling in the Heart and Small Intestine

Tetsuya Watanabe , in Biophysical Basis of Physiology and Calcium Signaling Mechanism in Cardiac and Smooth Muscle, 2018

7.5 Action Potential in Small Intestinal Muscle

Smooth muscle is spindle-shaped cells with one centrally located nucleus and no externally visible striations. It is found mainly in the walls of hollow organs. Muscles of small intestine like other unitary smooth muscles have many gap junctional connections between individual cells and act as one sheet in a coordinated fashion. The outstanding characteristic of the small intestinal muscle is its rhythmicity which is alternate contractions and relaxations at a regular frequency at regularly spaced intervals called segments along a section of the intestine [13]. A sharp spike superimposed upon the small sinusoidal wave activity occurs when the circular muscle contracts. The peristaltic contraction makes a rise in the tone level without any interruption in the rhythm of segmental contractions. Thus, the muscle fiber does not need to have an individual innervation and depolarization of one fiber triggers synchronous depolarization throughout the bundle, which are independent of its nerve supply and cause continuous rhythmic partial contractions. Nerve impulses or neurotropic drugs such as ACh and EPI can modulate its motility.

Each sharp spike may correspond to Na⁺ influx and the circular muscle contraction, and the small sinusoidal wave activity may relate to the cyclic discharge of Ca^{2   +} from intracellular stores in the ER and relate to the tone, but there is no indication of influx of extracellular Ca^{2   +} as seen in the SA node cell. ACh raised the membrane potential and increased spike frequency, resulting in a large increase in the tonic tension and the rate of contraction as shown in Fig. 7.2.

Fig. 7.2. Effects of ACh on the membrane potential of small intestinal smooth muscle in vitro. The sharp spike potential occurs when the circular muscle contracts, and it is superimposed upon the slow wave activity. ACh can modulate the signal by raising the base membrane potential and increasing the spike frequency with a large increase in tonic tension.

ACh secreted from postganglionic parasympathetic nerve terminal binds to the muscarinic cholinergic receptors. The M₃ receptor is a G protein-coupled receptor, and its metabolic function is mediated by interactions with G proteins. G₁₁ and G₁₃ proteins are responsible for stimulation of phospholipase C activity which catalyzes hydrolysis of one of the membrane phospholipids, phosphatidylinositol 4,5 diphosphate. The hydrolysis produces the second messenger, inositol triphosphate (IP₃), that modulates the discharge of Ca^{2   +} from intracellular stores in the ER through IP₃-gated Ca^{2   +} receptor. The second messenger Ca^{2   +} binds to calcium-binding protein, calmodulin (CaM), and the activated CaM diffuses and then activates calmodulin-dependent myosin light chain kinase. This enzyme catalyzes the phosphorylation of the myosin light chain at serine, which induces activation of ATPase on the actin binding site. The cross bridges form between myosin and actin resulting in contraction of smooth muscle.

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Oviduct, Uterus, and Vagina

Darlene Dixon , ... Micheal P. Jokinen , in Boorman's Pathology of the Rat (Second Edition), 2018

7.2.7 Leiomyoma and Leiomyosarcoma

Smooth muscle neoplasms of the uterus are rare; most of those observed probably arise from the myometrium. The benign and malignant forms represent a morphological continuum and are distinguished primarily by the degree of cellularity and cellular differentiation, pleomorphism, and/or atypia. Leiomyomas are usually distinct, well-delineated nodules in the myometrium of the uterus and consist of well-differentiated smooth muscle cells arranged in interlacing bundles ( Figures 27.35 and 27.36). Some collagen may be present between bundles and individual cells but is generally not obvious unless special stains are applied. The cell boundaries are not distinct and the cytoplasm is eosinophilic and fibrillar in appearance. They usually have typical elongated nuclei with rounded ends, aggregated chromatin near the nuclear membrane, and occasionally a prominent nucleolus.

Figure 27.35. Leiomyoma arising from myometrium. The uterine lumen epithelium has undergone squamous metaplasia (arrow).

Figure 27.36. Higher magnification of Figure 27.35 showing well-differentiated smooth muscle cells arranged in interweaving bundles.

Leiomyosarcomas generally are larger than the benign form, and the borders are not well delineated. Invasive growth of the type seen with malignant epithelial neoplasms is not often seen, but large neoplasms encroach on and destroy normal tissue. The parallel arrangement of the neoplastic cells in interlacing bundles is not as uniform as in leiomyoma and the cells may have less abundant fibrillar cytoplasm; leiomyosarcomas therefore appear more cellular than leiomyomas (Figures 27.37 and 27.38). The nuclei are usually elongated but vary somewhat in size and shape (pleomorphism and atypia); mitoses may be frequent. Degeneration and necrosis are sometimes observed, particularly in the more malignant neoplasms. Leiomyosarcomas seldom metastasize.

Figure 27.37. Leiomyosarcoma of the uterus. Note the greater cellularity.

Figure 27.38. Higher magnification of leiomyosarcoma showing cellular pleomorphism, atypia, and mitotic figures.

Large anaplastic leiomyosarcomas must be distinguished from endometrial stromal sarcomas and fibrosarcomas. Generally, neoplastic smooth muscle cells are arranged in more distinct bundles and the cells are larger and the cytoplasm more fibrillar than that of stromal sarcomas. Leiomyoma and leiomyosarcoma show positive immunolabeling for desmin and actin and are negative for S100, in contrast with the stromal sarcomas; vimentin results are variable.

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Stimulus Transduction in Metabolic Sensor Cells

Stanley Misler , in Cell Physiology Source Book, 1995

IV Vascular Smooth Muscle Cells

A Hypoxic Vasodilation of Coronary and Mesenteric Vessels

Smooth muscle cells of resistance vessels (arteries and arterioles) are very sophisticated metabolic sensors. In fact, they encompass a complete vasodilator reflex system in a single cell. In response to a drop in ambient pO₂, these cells reduce their tension generation (Fig. 9A). This results in vessel relaxation and the local redistribution of O₂ supply to O₂-consuming tissue. A key to the explanation of this phenomenon is the increase in K ⁺ conductance and membrane hyperpolarization, which precedes the fall in tension. However, the joint inhibition of electrical and mechanical activity during metabolic blockage appears to be a fairly general property of vertebrate muscle, including cardiac and skeletal muscle. These are worth exploring before returning to the case of smooth muscle.

FIG. 9. Hypoxia and stimulus-contraction coupling in vascular myocytes. (A) Model of hypoxia-induced vasodilation in cardiac, cerebral, and mesenteric vessels. Under conditions of normal oxygen levels where K⁺(ATP) channels are largely closed and voltage-dependent Ca²⁺ channels open, V _m = −35 mV, and cytosolic Ca^{2 +} is low. With a decrease in pO₂, cytosolic ATP levels drop, resulting in the opening of K ⁺ (ATP) channels and cell repolarization to –50 mV, effecting a drop in cytosolic Ca²⁺ and myocyte relaxation. (B) Model of hypoxia-induced vasoconstriction in pulmonary arteries. Under conditions of normal oxygen levels, V _m = −50 mV with O₂-sensitive K⁺ channels largely open, voltage-dependent Ca²⁺ channels largely closed, and cytosolic Ca²⁺ levels low. With a decrease in pO₂, O₂-sensitive K⁺ channels close, resulting in depolarization, opening of Ca²⁺ channels, Ca²⁺ entry, and Ca²⁺-induced contraction.

In cardiac myocytes, depression of cellular energy levels achieved by inhibition of energy production (e.g., substrate or O₂ deprivation) or by overstimulation of energy use (e.g., repetitive stimulation), all result in a slow but progressive reduction in the duration of the Ca²⁺ _o-dependent plateau phase of the AP. This progressively reduces plasma membrane Ca²⁺ entry, which is needed as a trigger for regenerative release of Ca²⁺ from the sarcoplasmic reticulum. The net result is a reduction in twitch tension. All of this occurs before any detectable change in resting V _m or reduction in Ca²⁺ currents measured by voltage clamping. An early clue linking metabolic blockade to excitability was the finding of increased background K⁺ conductance, induced by metabolic inhibition and, thereafter, abolished by intracellular injection of ATP. The search for the single-channel correlate of the K⁺ conductance resulted in the first identification of a voltage-independent ATP_i-inhibitable K⁺ channel in the excised patch. Recalling that the plateau phase of the AP represents a time of delicate balance between slowly activating outwardly directed K⁺ current, which tends to hyperpolarize the cell, and slowly inactivating inwardly directed Ca²⁺ current, which tends to depolarize the cell, it is surprising that increase in background G _K might tip the balance in favor of earlier repolarization.

Other mechanisms probably contributing to ischemia-induced contractile failure include (1) altered [Ca²⁺]_i "homeostasis" and reduced binding of Ca²⁺ to the contractile apparatus induced by changes in pH_i and ATP_i, and (2) activation of other K⁺ channels such as muscarinic and G-protein-gated K⁺ channels.

In skeletal muscle, failure of neuromuscular transmission of the AP and inhibition of contraction are seen with metabolic blockade or intense exercise. Here, the AP and twitch are both quite brief and not reliant on Ca²⁺ entry. However, under some conditions, large increases in K⁺(ATP) channel activity occur. The increased background K⁺ conductance overwhelms the effect of the increase in G _Na evoked by presynaptic transmitter release. Hence, transmitter release produces little or no depolarizing effect. Failure of impulse conduction into the T-tubule blocks depolarization-activated release of Ca²⁺ from the sarcoplasmic reticulum.

K⁺(ATP) channels in cardiac and skeletal muscle have single-channel conductance, kinetics, and ATP-ADP gating similar to those found in the β-cell. However, in contrast to those in β-cells, muscle K⁺(ATP) channels are closed in the absence of hypoxia or metabolic poisoning. The channels open more dramatically in response to a reduction in glycolytic activity than to a reduction in oxidative phosphorylation, whereas addition of glucose in the presence of a mitochondrial inhibitor recloses the channels. In cardiac myocytes, glycolytic enzymes may be bound to the plasma membrane, thereby preferentially routing ATP to sarcolemmal K⁺(ATP) channels.

Contractile failure, before metabolic exhaustion, is apparently adaptive for skeletal muscle. A drop in tension development by some motor units results in recruitment of other less well-activated motor units. The adaptive advantage for the ventricle is not clear, since it is an electrical syncytium and must contract as a unit. In the ventricle, AP shortening may locally reduce the refractory period and promote reentry or rebound excitation. In addition, the period of reoxygenation may enhance arrhythy-mogenicity by promoting large transient inward currents (I _ti), which result in spontaneous depolarizations. Hence, it would be better for the ventricle to anticipate rather than react to metabolic deprivation. Such "anticipation" could occur through local vasodilation of coronary arterioles.

Systemic resistance vessels, such as mesenteric arteries and coronary vessels, maintain a resting V _m of –40 to –50 mV as well as resting tone. Small changes in resting V _m affects resting tone: a small depolarization of 5–10 mV results in increased vasoconstriction due to increased opening of HVA Ca^{2 +} channels. A small hyperpo-larization of 5–10 mV or addition of dihydropyridine Ca²⁺ channel antagonists drops resting tone and results in vaso-dilation.

Given our understanding of the role of K ⁺ (ATP) channels in skeletal and cardiac muscle relaxation, we might make the following hypothesis: Assuming that myocytes of resistance arterioles, particularly precapillary sphincters, contained a K ⁺ (ATP) channel of lower ATP affinity than that of myocytes, a drop in microenvironmental O₂ level could reduce arteriolar oxidative metabolism and cytosolic ATP, resulting in the opening of K ⁺ (ATP) channels and hyperpolarization of smooth muscle cells. (This might be enhanced by the release of adenosine by active cardiac tissue, since extracellular adenosine has been shown to activate K⁺(ATP) channels via a G-protein-dependent mechanism.) Such a scheme might work for the regulation of local blood supply to the brain and gut as well as the heart.

Recent evidence supports this hypothesis. First, lowering ambient pO₂ or treatment with the K⁺(ATP) channel opener diazoxide results in hyperpolarization and relaxation of mesenteric vessel smooth muscle; the effect of either maneuver is inhibited by sulfonylureas. Second, K⁺(ATP) channels have been demonstrated in in situ patches or vessels prepared from the membrane of these myocytes. The K _d value (μM) for ATP-induced channel closure is roughly double that of cardiac myocytes.

B Hypoxic Vasoconstriction of Pulmonary Vessels

In contrast to coronary, mesenteric, and cerebral vessels, pulmonary arteries constrict in response to a drop in pO₂ (Fig. 9B ). Acutely, this constitutes an adaptive response in the lung bed because it ensures that areas of the lung that are poorly oxygenated will receive less blood flow; the extra blood flow is "redirected" toward better oxygenated areas to optimize gas exchange. With chronic hypoxia (such as at high altitudes or alveolar destruction), chronic vasoconstriction with smooth muscle proliferation ensues. The end result is the development of increased resistance and pressure in the total pulmonary vascular bed, which is usually a very low-pressure and low-resistance system. This "pulmonary artery hypertension" poses an increased "after-load" for the right ventricle and a stimulus for its hypertrophy. Pulmonary artery myocytes maintain a low resting tension, a V _m of ~–40 mV, and a resting cytosolic Ca²⁺ of < 100 nM. They respond to progressive hypoxia (e.g., a slow fall in p0₂ from 150 to 15 mm Hg) with a 15–mV depolarization, which is not influenced by [Ca²⁺]_o. Given that V _m in these cells shows a Nernstein relationship to [K ⁺]_o, these results suggest that membrane depolarization is due to a large decrease in Ca²⁺ _o-independent resting membrane K⁺ conductance (e.g., G _K). However, depolarization results in a small increase in G _Ca ²⁺, which results in Ca²⁺ entry and a rise in cytosolic Ca²⁺ sufficient to trigger contraction. Tension is maintained so long as Ca²⁺ entry through voltage-gated Ca²⁺ channels exceeds Ca²⁺ efflux via the Na⁺–Ca²⁺ exchanger. Recent whole-cell voltage-clamp experiments have provided evidence for a voltage-activated K⁺ channel that is open at rest and is significantly inhibited by hypoxia. Hence, as in the carotid chemoreceptor, hypoxia-induced reduction in a voltage-dependent I _Kdel, in a cell with a very low background G _m appears to be responsible for depolarization of an oxygen-sensing, smooth muscle cell.

An important paradox that remains to be explained is how pulmonary artery myocytes manage to "hide" their K⁺ (ATP) channels during hypoxia. In these cells, K⁺(ATP) channel openers abort high [K ⁺]_o-induced tension increase, whereas sulfonylureas enhance tension generation. There is no evidence for a hypoxia-induced rise in cytosolic ATP or ATP/ADP ratio.

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CAFFEINE

M.J. Arnaud , in Encyclopedia of Human Nutrition (Second Edition), 2005

Effects on the Gastrointestinal System

Caffeine relaxes smooth muscle of the biliary and gastrointestinal tracts and has a weak effect on peristalsis. However, high doses can produce biphasic responses, with an initial contraction followed by relaxation. Caffeine seems to have no effect on the lower oesophageal sphincter. The increase in both gastric and pepsin secretions is linearly related to the plasma levels obtained after the administration of a dose of 4–8  mg   kg⁻¹. In the small intestine, caffeine modifies the fluid exchange from a net absorption to a net excretion of water and sodium.

The role of caffeine in the pathogenesis of peptic ulcer and gastrointestinal complaints remains unclear, and no association has been found in clinical and epidemiological studies.

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