WINDSOR UNIVERSITY SCHOOL OF MEDICINE Smooth Muscle Dr.Vishal Surender.MD.

Smooth Muscle: Properties Each fibre is much smaller than in skeletal muscle Found in walls of hollow organs and tubes. Usually found in two different layers: Circular – to squeeze or dilatee.g-blood vessels. Longitudinal – to stretch or shortene.g-GI tract. Metabolic economy-Uses less energy, Low oxygen consumption thus allows to Maintain force for long periods, e.x-urinary and esophageal sphincters. metabolic economy of smooth muscle, which allows it to remain contracted for long periods with little energy consumption, and the small size of its cells, which allows precise control of very small structures, such as blood vessels. A Circular Organization Is Typically Found in Blood Vessels The simplest smooth muscle arrangement is found in the arteries and veins of the circulatory system. Smooth muscle cells are oriented in the circumference of a vessel so that their shortening results in reducing the vessel's diameter. This reduction may range from a slight narrowing to a complete obstruction of the vessel lumen, depending on the physiological needs of the body or organ. In the larger muscular vessels, particularly arteries, there may be many layers of cells and the force of contraction may be quite high. In small arterioles, the muscle layer may consist of single cells wrapped around the vessel. The blood pressure provides the force to relengthen the cells in the vessel walls. This circular arrangement is also prominent in the airways of the lungs, where it regulates the flow of air. A further specialization of the circular muscle arrangement is a sphincter, a thickening of the muscular portion of the wall of a hollow or tubular organ, whose contraction has the effect of restricting flow or stopping it completely. Many sphincters, such as those in the gastrointestinal and urogenital tracts, have a special nerve supply and participate in complex reflex behavior. The muscle in sphincters is characterized by the ability to remain contracted for long periods with little metabolic cost.

Smooth muscle is different:- It has more variety Anatomy is different. It is controlled by hormones, paracrines, and neurotransmitters. Unitary and Multiunit Smooth Muscle There are two distinct categories of smooth muscle determined by the processes they use to coordinate contraction with their neighboring cells The Regulation and Control of Smooth Muscle Involve Many Factors In addition to contraction in response to nerve stimulation, smooth muscle responds to hormonal and pharmacological stimuli, the presence or lack of metabolites, cold, pressure, and stretch or touch, and it may be spontaneously active as well. This multiplicity of factors is vital for the integration of smooth muscle into overall body function. Although skeletal muscle is primarily controlled by the CNS, the control of smooth muscle is much more closely related to the many factors that regulate the internal environment, and many internal and external pathways have as their final effect the control of the interaction of smooth muscle contractile proteins.

Single unit/Visceral smooth muscle This represents the majority Made up of groups of cells joined together by gap junctions FUNCTIONAL SYNCYTIUM may be innervated but does not always require nervous stimulation for contraction Allows for coordinated contractions Uterus, GIT Smooth muscle cells are also coupled electrically. The structure most effective in this coupling is the gap junction. Functionally, this is a region of low electrical resistance that favors current flow from cell to cell. This facilitates the propagation of action potentials throughout the tissue.

Types of Smooth Muscle Figure 12-25a

Multi unit smooth muscle Found in large blood vessels, large airways and ciliary muscle Made up of discrete units Similar to skeletal muscle Must be separately stimulated by nerves Autonomic stimulation

Types of Smooth Muscle Figure 12-25b

Smooth Muscle Has actin and myosin filaments but Lacks the Regular Sarcomere Structure of Skeletal Muscle. Myosin light chain has regulatory role Have intermediate filaments- dense bodies, analogous to Z-line Has less sarcoplasmic reticulum IP3-receptor channel is the primary calcium channel. Calcium storage function of sarcoplasmic reticulum is supplemented by Caveolae analogous to ….. In skeletal muscle? The most notable feature of smooth muscle tissue organization, in contrast to that of skeletal muscle, is the small size of the cells compared with the tissue they make up. Individual smooth muscle cells (depending somewhat on the type of tissue they compose) are 100 to 300 µm long and 5 to 10 µm in diameter. When isolated from the tissue, the cells are roughly cylindrical along most of their length and taper at the ends. The single nucleus is elongated and centrally located. Electron microscopy reveals that the cell margins contain many areas of small membrane invaginations, called caveolae, which may play a role in increasing the surface area of the cell. Mitochondria are located at the ends of the nucleus and near the surface membrane. In some smooth muscle cells, the SR is abundant, although not to the extent found in skeletal muscle. In some cases, it closely approaches the cell membrane, but there is no organized T tubular system as in other types of muscle. The bulk of the cell interior is occupied by three types of myofilaments: thick, thin, and intermediate. The thin filaments are similar to those of skeletal muscle but lack the troponin protein complex. The thick filaments are composed of myosin molecules, as in skeletal muscle, but the arrangement of the individual molecules into filaments is different; the filaments are called “side-polar,” with one crossbridge orientation on one side of the filament and the opposite orientation on the other. There is no central bare region without crossbridges. The intermediate filaments are so named because their diameter of 10 nm is between that of the thick and thin filaments. Intermediate filaments appear to have a cytoskeletal, rather than a contractile, function. Prominent throughout the cytoplasm are small, dark-staining areas called dense bodies (Fig. 8.22). They are associated with the thin and intermediate filaments and are considered analogous to the Z lines of skeletal muscle. Dense bodies associated with the cell margins are often called membrane-associated dense bodies (or patches) or focal adhesions. They appear to serve as anchors for thin filaments and to transmit the force of contraction to adjacent cells.

Caveolae in Smooth Muscle Figure 12-26

Anatomy of Smooth Muscle Figure 12-27a–b

Molecular Mechanism of Smooth Muscle Contraction. In order for smooth muscle to contract there must be some connection between the myofilaments and the cell (to have the same role as the Z line in skeletal muscle). This connection is provided by the dense bodies found within the smooth muscle cells. The thick filament is made of myosin as in skeletal muscle (though of a different form) and so has two heavy chains, including the crossbridge region with the 4 light chains found on the heads. These light chains have an important role to play in smooth muscle contraction because it is phosphorylation of the regulatory light chains found on the myosin heads that initiate contraction. When the myosin is phosphorylated it binds to the thin filaments and pulls them towards the center of the thick filament moving the two dense bodies connected to the thin filaments closer together, shortening the smooth muscle cell.

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum CaM Pi Active MLCK ADP + Active myosin ATPase Actin P Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. Ca2+ binds to calmodulin (CaM). Ca2+–calmodulin activates myosin light chain kinase (MLCK). MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity. crossbridges slide along actin and create muscle tension. ATP Increased muscle tension Inactive myosin Inactive 1 2 3 4 5 Figure 12-28

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. 1 Figure 12-28, step 1

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum CaM Pi Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. Ca2+ binds to calmodulin (CaM). 1 2 Figure 12-28, steps 1–2

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum CaM Pi Active MLCK Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. Ca2+ binds to calmodulin (CaM). Ca2+–calmodulin activates myosin light chain kinase (MLCK). Inactive 1 2 3 Figure 12-28, steps 1–3

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum CaM Pi Active MLCK ADP + Active myosin ATPase P Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. Ca2+ binds to calmodulin (CaM). Ca2+–calmodulin activates myosin light chain kinase (MLCK). MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity. ATP Inactive myosin Inactive 1 2 3 4 Figure 12-28, steps 1–4

Smooth Muscle Contraction ECF Ca2+ Sarcoplasmic reticulum CaM Pi Active MLCK ADP + Active myosin ATPase Actin P Intracellular Ca2+ concentrations increase when Ca2+ enters cell and is released from sarcoplasmic reticulum. Ca2+ binds to calmodulin (CaM). Ca2+–calmodulin activates myosin light chain kinase (MLCK). MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity. crossbridges slide along actin and create muscle tension. ATP Increased muscle tension Inactive myosin Inactive 1 2 3 4 5 Figure 12-28, steps 1–5

Calcium Plays a Critical Role in Smooth Muscle Activation This diagram (taken from your text, Fig. 8-23) gives examples of how myoplasmic calcium levels may be increased in order to produce a contraction. Calcium may enter the myoplasm via voltage dependent calcium channels via an action potential or depolarization. Calcium may also enter via ligand-gated channels and the “leak” channel. This calcium may act on the SR to release more calcium or directly bind to calmodulin. The SR also may be stimulated to release calcium via the IP3/DAG second messenger system. This system is stimulated by an agonist binding to a receptor on the plasma membrane (eg. Norepinephrine binding to α1-receptors in vascular smooth muscle causing vasoconstriction). The “leak” channel is believed to be a store-operated calcium channel on the plasma membrane that is stimulated when SR calcium levels become low to replenish stores of calcium. The mechanism underlying the activity of this channel remains unknown. Relaxation will be discussed later.

Smooth Muscle Contraction Activating MLCK Ca2+ myosin-Pi myosin +ATP/actin CONTRACTION

Relaxation in Smooth Muscle Ca2+ ECF Na+ CaM Inactive myosin Myosin ATPase activity decreases. ADP + Myosin phosphatase P ATP Decreased muscle tension Sarcoplasmic reticulum Free Ca2+ in cytosol decreases when Ca2+ is pumped out of the cell or back into the sarcoplasmic reticulum. Ca2+ unbinds from calmodulin (CaM). Myosin phosphatase removes phosphate from myosin, which decreases myosin ATPase activity. Less myosin ATPase results in decreased muscle tension. 1 2 3 4 Figure 12-29

Relaxation in Smooth Muscle Ca2+ ECF Na+ Sarcoplasmic reticulum Free Ca2+ in cytosol decreases when Ca2+ is pumped out of the cell or back into the sarcoplasmic reticulum. 1 ATP Figure 12-29, step 1

Relaxation in Smooth Muscle Ca2+ ECF Na+ CaM Sarcoplasmic reticulum Free Ca2+ in cytosol decreases when Ca2+ is pumped out of the cell or back into the sarcoplasmic reticulum. Ca2+ unbinds from calmodulin (CaM). 1 2 ATP Figure 12-29, steps 1–2

Relaxation in Smooth Muscle Ca2+ ECF Na+ CaM Inactive myosin Myosin ATPase activity decreases. ADP + Myosin phosphatase P ATP Sarcoplasmic reticulum Free Ca2+ in cytosol decreases when Ca2+ is pumped out of the cell or back into the sarcoplasmic reticulum. Ca2+ unbinds from calmodulin (CaM). Myosin phosphatase removes phosphate from myosin, which decreases myosin ATPase activity. 1 2 3 Figure 12-29, steps 1–3

Relaxation in Smooth Muscle Ca2+ ECF Na+ CaM Inactive myosin Myosin ATPase activity decreases. ADP + Myosin phosphatase P ATP Decreased muscle tension Sarcoplasmic reticulum Free Ca2+ in cytosol decreases when Ca2+ is pumped out of the cell or back into the sarcoplasmic reticulum. Ca2+ unbinds from calmodulin (CaM). Myosin phosphatase removes phosphate from myosin, which decreases myosin ATPase activity. Less myosin ATPase results in decreased muscle tension. 1 2 3 4 Figure 12-29, steps 1–4

Smooth Muscle Relaxation Myosin light chain phosphatase predominates Deactivating MLCK Ca2+ myosin-Pi myosin RELAXATION

Smooth Muscle Regulation Many smooth muscles have dual innervation Controlled by both sympathetic and parasympathetic neurons Hormones and paracrines also control smooth muscle contraction Histamine constricts smooth muscle of airways Nitric oxide affects regulation of diameter of blood vessels

Muscles: Summary