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Medical Physiology - Fundamental Mechanism of Muscle Contraction The commencement and implementation of muscular contraction transpire in the subsequent sequential steps: 1. An action potential propagates along a motor neuron to its terminals on muscle fibers, where each terminal releases a minute quantity of the neurotransmitter acetylcholine. 2. Acetylcholine interacts with a specific region of the muscular membrane to activate acetylcholine-gated cation channels, permitting primarily sodium ions, along with calcium ions, to enter the muscle fiber, resulting in localized depolarization. The local depolarization subsequently causes the opening of voltage-gated sodium channels, culminating in an action potential. The action potential propagates over the muscle fiber membrane, prompting the sarcoplasmic reticulum to release calcium ions into the myofibrils that were previously stored in the sarcoplasmic reticulum. 4. Calcium ions instigate attractive interactions between the actin and myosin filaments, resulting in their sliding together; this constitutes the contractile process. 5. Calcium ions are continuously transported back into the sarcoplasmic reticulum, where they are stored until a muscular action potential occurs; this expulsion of calcium ions from the myofibrils results in the cessation of muscle contraction. 
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Medical Physiology - Physiological Anatomy of Skeletal Muscle ZApproximately 40% of body mass comprises skeletal muscle, with an additional 10% consisting of smooth and cardiac muscle. Numerous concepts of contraction are applicable to all three muscle types. Skeletal Muscle Fiber In the majority of muscles, the fibers span the full length of the muscle. Each fiber is innervated by a single nerve terminal. Myofibrils consist of actin and myosin filaments. Each muscle fiber comprises hundreds to thousands of myofibrils, with each myofibril consisting of approximately 1500 myosin filaments and 3000 actin filaments arranged laterally. These filaments are substantial polymerized protein molecules that facilitate muscle contraction. The thick filaments consist of myosin, whereas the thin filaments comprise actin; observe the subsequent characteristics: • light and dark bands. The myosin and actin filaments partially interdigitate, resulting in the myofibrils exhibiting alternating bright and dark bands. The light bands consist solely of actin filaments and are referred to as I bands. The dark regions known as A bands comprise myosin filaments along with the terminal portions of actin filaments. The A band length corresponds to the length of the myosin filament . • Cross-bridges. The diminutive extensions from the myosin filament sides are termed cross-bridges. They extend from the surfaces of the myosin filament over its whole length, with the exception of the core. Myosin cross-bridges engage with actin filaments, resulting in contraction. • Z the disc. The termini of the actin filaments are affixed to Z discs.The Z disc traverses the myofibril, connecting and aligning the myofibrils throughout the muscle fiber. The complete muscle fiber exhibits alternating light and dark bands, resulting in a striated appearance in skeletal and cardiac muscle. • Sarcomere. The segment of a myofibril situated between two consecutive Z discs is referred to as a sarcomere. At rest, actin filaments exhibit ideal interdigitation with myosin filaments in skeletal muscle, while in cardiac muscle, the interdigitation is somewhat less than optimal.  Medical Physiology - Distinctive Features of Signal Transmission in Nerve Trunks Large nerve fibers are myelinated, whereas small nerve fibers are unmyelinated. The axon constitutes the central core of the fiber, and its membrane facilitates the conduction of the action potential. A thick myelin sheath, formed by Schwann cells, encases the bigger axons. The sheath comprises several layers of cellular membrane that include the lipid sphingomyelin, an effective insulator. At the interface between two consecutive Schwann cells, a brief noninsulated segment measuring only 2 to 3 mm in length persists, allowing ions to move freely between the extracellular fluid and the axon. This region is the node of Ranvier. Saltatory conduction transpires in myelinated fibers. Although ions cannot traverse the thick sheaths of myelinated neurons considerably, they can pass with relative ease through the nodes of Ranvier. Consequently, the nerve impulse traverses from node to node along the fiber, which is the basis for the term "saltatory." Saltatory conduction is advantageous for two reasons: • Enhanced speed. This method enhances the pace of nerve transmission in myelinated fibers by facilitating the depolarization process to leap across extensive intervals along the nerve fiber axis, achieving increases of 5 to 50 times. • Energy conservation. Secondly, saltatory conduction conserves energy for the axon as only the nodes undergo depolarization, resulting in a significantly reduced ion loss—potentially a hundredfold less—than would be required otherwise, thereby necessitating minimal energy to restore the sodium and potassium concentration gradients across the membrane following a sequence of nerve impulses. The conduction velocity is highest in large, myelinated nerve fibers. The conduction velocity of action potentials in nerve fibers ranges from a minimum of 0.25 m/sec in diminutive unmyelinated fibers to a maximum of 100 m/sec in substantial myelinated fibers. The velocity increases roughly with fiber diameter in myelinated nerve fibers and about with the square root of fiber diameter in unmyelinated fibers.  Medical Physiology - Re-establishing sodium and potassium ion gradients following action potential completion: significance of energy metabolism By spreading each impulse along the nerve fiber, the concentration variations between the inner and out-side of the membrane are virtually eliminated. Before the ion concentration changes to the point where action potential conduction stops, nerve fibers can send between 100,000 and 50 million impulses. Still, with time it becomes essential to restore the differences in sodium and potassium membrane concentration. The Na+-K+ pump acts to do this.  Medical Physiology - Propagation of the Action Potential Usually activates nearby areas of the mem-brane, an action potential generated at any one site causes propagation of the action potential. The depolarization process thus follows the whole length of the fiber. A nerve or muscle impulse is the depolarization process transmitted along a nerve or muscle fiber. • Propagation direction of interest. An excitable membrane lacks a single direction of propagation; instead, the action potential moves both away from the stimulus in both directions. • All-or-nothing concept. Once an action potential has been generated at any place on the membrane of a normal fiber, the depolarization process travels over the whole membrane if conditions are correct, or it might not travel at all if conditions are not right.  Medical Physiology - Nerve Action Potential Nerve signals are conveyed through action potentials, which are fast alterations in membrane potential. Each action potential commences with an abrupt transition from the typical resting negative potential to a positive membrane potential, followed by a nearly instantaneous return to the resting negative potential. The sequential phases of the action potential are as follows: • Resting phase. This represents the resting membrane potential prior to the initiation of the action potential. • Depolarization phase. At this moment, the membrane abruptly becomes permeable to sodium ions, permitting a substantial influx of positively charged sodium ions into the axon, resulting in a quick increase in potential in the positive direction. • Repolarization phase. Within a few ten-thousandths of a second after the membrane attains high permeability to sodium ions, the sodium channels commence closure while the potassium channels open to a greater extent than usual. The swift efflux of potassium ions to the exterior reinstates the typical negative resting membrane potential. Voltage-gated sodium and potassium channels undergo activation and inactivation throughout the progression of an action potential. The essential element for both depolarization and repolarization of the neuronal membrane during the action potential is the voltage-gated sodium channel. The voltage-gated potassium channel significantly contributes to the acceleration of membrane repolarization. These two voltage-gated channels exist alongside the Na⁺-K⁺ pump and the Na⁺-K⁺ leak channels that determine the membrane's resting permeability. The events that precipitate the action potential can be summarized as follows. • In the resting state, prior to the initiation of the action potential, the conductance for potassium ions is approximately 100 times greater than that for sodium ions. This results from significantly increased leaking of potassium ions compared to sodium ions through the leak channels. • At the initiation of the action potential, the sodium channels rapidly activate, permitting an increase in sodium permeability of up to 5000-fold (also referred to as sodium conductance). The inactivation process subsequently occludes the sodium channels within only fractions of a millisecond. The initiation of the action potential triggers the voltage gating of potassium channels, leading to their gradual opening. Upon conclusion of the action potential, the restoration of the membrane potential to a negative state prompts the potassium channels to revert to their previous configuration, albeit after a delay. A positive-feedback loop initiates the opening of sodium channels. Should any event induce the membrane potential to ascend from 90 millivolts towards the zero level, the increasing voltage itself prompts the opening of many voltage-gated sodium channels. This facilitates the fast influx of sodium ions, resulting in an additional increase in membrane potential, so activating more voltage-gated sodium channels. This mechanism constitutes a positive-feedback loop that persists until all voltage-gated sodium channels are engaged. An action potential is initiated only upon reaching the threshold potential. This occurs when the quantity of sodium ions infiltrating the nerve fiber The quantity of potassium ions exiting the fiber exceeds the influx of potassium ions. An abrupt elevation in the membrane potential of a major nerve fiber from –90 millivolts to around –65 millivolts typically triggers a rapid onset of the action potential. A membrane potential of –65 millivolts is identified as the stimulation threshold. An action potential cannot be generated while the membrane remains depolarized from the preceding action potential. Immediately following the initiation of the action potential, the sodium channels undergo inactivation, rendering any excitatory signal supplied to these channels ineffective in opening the inactivation gates. The sole situation that can reactivate them is when the membrane potential reverts to or nearly to the initial resting membrane potential level. Subsequently, during another brief fraction of a second, the inactivation gates of the channels open, allowing for the initiation of a fresh action potential. • Absolute refractory phase. An action potential cannot be generated during the absolute refractory period, regardless of the stimulus strength. The refractory period for big myelinated nerve fibers is around 1/2500 of a second, allowing for a maximum transmission of about 2500 impulses per second . • Relative refractory phase. This interval succeeds the absolute refractory period. During this period, stimuli of greater intensity than usual can activate the nerve fiber, leading to the initiation of an action potential.  Medical Physiology - Resting Membrane Potential of Neurons The resting membrane potential is determined by diffusion potentials, membrane permeability, and the electrogenic characteristics of the Na⁺-K⁺ pump. • Potassium diffusion potential. A potassium ion ratio of 35:1 from intracellular to extracellular environments generates a Nernst potential of 94 millivolts, as per the Nernst equation. Sodium diffusion potential. The sodium ion ratio from intracellular to extracellular space is 0.1, resulting in a computed Nernst potential of +61 millivolts. • Permeability of membranes. The nerve fiber membrane's permeability to potassium is approximately 100 times greater than that to sodium, so potassium diffusion significantly influences the membrane potential. The application of this elevated permeability value in the Goldman equation results in an internal membrane potential of 86 millivolts, which approximates the potassium diffusion potential of 94 millivolts. • Electrogenic characteristics of the Na⁺-K⁺ pump. The Na ion K ion pump extrudes three sodium ions from the cell for every two potassium ions it imports, resulting in a persistent reduction of positive charges within the membrane. The Na⁺-K⁺ pump is electrogenic as it generates a net deficit of positive ions within the cell, resulting in an internal negative charge of around 4 millivolts across the cell membrane.  Medical Physiology - Membrane Potentials and Action Potentials Electrical potentials are present across the membranes of nearly all cells in the body. Furthermore, neuron and muscle cells are "excitable," meaning they can autonomously generate electrical impulses at their membranes. This debate pertains to membrane potentials generated at rest and during action potentials in nerve and muscle cells. Fundamental Physics of Membrane Potentials A concentration gradient of ions across a selectively permeable membrane can generate a membrane potential. • Diffusion potential of potassium. Assume a cell membrane is permeable exclusively to potassium ions, while being impermeable to all other ions. Potassium ions often diffuse outward due to the elevated potassium content within the cell. The efflux of positively charged potassium ions from the cell generates a negative potential within the cell. In a matter of milliseconds, the potential difference becomes sufficiently substantial to inhibit further net diffusion of potassium, despite the elevated concentration gradient of potassium ions. In typical big mammalian nerve fibers, the potential difference necessary to halt additional net diffusion is approximately 94 millivolts. Sodium diffusion potential. Assume a cell membrane is permeable exclusively to sodium ions, while being impermeable to all other ions. Sodium ions typically permeate into the cell due to the elevated sodium concentration outside the cell. The influx of sodium ions into the cell generates a positive potential within the cell. The membrane potential increases rapidly within milliseconds to a level that inhibits further net passage of sodium ions into the cell; in this instance, for the big mammalian nerve fiber, the potential reaches around +61 millivolts. The Nernst Equation articulates the relationship between diffusion potential and concentration gradient. The membrane potential that inhibits net diffusion of an ion in either direction across the membrane is referred to as the Nernst potential for that ion. The subsequent expression is the Nernst equation:  EMF denotes the electromotive force. The potential is positive (þ) for negative ions and negative (–) for positive ions. The Goldman Equation calculates the diffusion potential when the membrane is permeable to several ions. The diffusion potential that arises is contingent upon three factors: (1) the polarity of the electrical charge of each ion, (2) the membrane's permeability (P) to each ion, and (3) the concentrations (C) of the corresponding ions on the intracellular (i) and extracellular (o) sides of the membrane. The subsequent equation is the Goldman equation:  Observe the subsequent characteristics and ramifications of the Goldman equation: • Sodium, potassium, and chloride ions play a pivotal role in the establishment of membrane potentials in neurons, muscle fibers, and neuronal cells within the central nervous system. • The significance of each ion in influencing voltage is directly proportionate to the membrane's permeability to that specific ion. • A positive ion concentration gradient from the interior to the outside of the membrane induces electronegativity within the membrane.  Medical Physiology - “Active Transport” of Substances Across Membranes Active transport can transport a substance against an electrochemical gradient. An electrochemical gradient is the cumulative effect of all diffusion forces at the membrane, resulting from concentration, electrical, and pressure differentials. Substances cannot distribute in an upward manner. Active transport refers to the movement of a material across a cell membrane against a concentration gradient (or against an electrical or pressure gradient). Active transport is categorized into two types based on the energy source utilized for the transport process. In all cases, transport relies on carrier proteins that traverse the membrane, a characteristic also applicable to assisted diffusion. • Primary active transport. The energy is obtained directly from the decomposition of adenosine triphosphate (ATP) or another high-energy phosphate molecule. • Secondary active transport. The energy is obtained secondarily from energy stored as ionic concentration gradients across a membrane, initially established by primary active transport. The sodium electrochemical gradient facilitates the majority of secondary active transport mechanisms. Primary Active Transport The Sodium-Potassium (Na⁺-K⁺) pump facilitates the transport of sodium ions out of cells and potassium ions into cells. This pump is ubiquitous in all body cells, responsible for maintaining the concentration gradients of sodium and potassium across the cell membrane and establishing a negative electrical potential within the cells. The pump functions as follows. Three sodium ions attach to a carrier protein within the cell, whereas two potassium ions bind to the carrier protein externally. The carrier protein has ATPase activity, and the concurrent binding of sodium and potassium ions activates the ATPase function of the protein. This subsequently cleaves one molecule of ATP, resulting in the formation of adenosine diphosphate (ADP) and releasing a high-energy phosphate bond. This energy is thought to induce a conformational alteration in the protein carrier molecule, expelling sodium ions outside and transporting potassium ions within. The Na-K pump regulates cellular volume. The Na⁺-K⁺ pump translocates three sodium ions outside the cell for every two potassium ions transported inside. The persistent net loss of ions from the cell interior generates an osmotic force that drives water out of the cell. Moreover, when the cell starts to inflate, this inherently triggers the Na⁺-K⁺ pump, expelling additional ions that transport water with them. Consequently, the Na⁺-K⁺ pump executes a constant monitoring function in preserving normal cell volume. Active transport exhibits saturation analogous to that of facilitated diffusion. When the concentration gradient of the material to be transported is minimal, the transport rate increases roughly in direct proportion to concentration increases. At elevated concentrations, the transport rate is constrained by the velocities of the chemical reactions involved in binding, release, and carrier conformational alterations. Co-transport and counter-transport are two modalities of secondary active transport. When sodium ions are extruded from cells by primary active transport, a significant concentration gradient of sodium often forms. This gradient signifies a reservoir of energy, as the surplus sodium outside the cell membrane consistently seeks to permeate into the cell core. • Cotransport. The diffusion energy of sodium can transport other molecules in the same way across the cell membrane via a specific carrier protein. • Counter-transportation. The sodium ion and the material undergoing counter-transport migrate to opposing sides of the membrane, with sodium consistently migrating into the cell interior. A protein carrier is necessary once more. Glucose and amino acids can be transported into most cells via sodium co-transport. The transport carrier protein possesses two binding sites on its external surface—one for sodium and another for glucose or amino acids. Once more, the concentration of sodium ions is quite Elevated externally and much reduced within, supplying the energy for transportation. A distinctive characteristic of the transport protein is that the conformational alteration facilitating sodium influx into the cell interior transpires only upon the binding of a glucose or amino acid molecule. Calcium and hydrogen ions can be extruded from cells via the sodium counter-transport mechanism. Calcium counter-transport transpires in the majority of cell membranes, wherein sodium ions migrate into the cell and calcium ions are expelled, both associated with the same transport protein in a counter-transport mechanism. Hydrogen counter-transport predominantly transpires in the proximal tubules of the kidneys, where sodium ions migrate from the tubule lumen into the tubular cells, while hydrogen ions are concurrently transported into the lumen.  Medical Physiology – Diffusion The constant movement of molecules in liquids or gases is known as diffusion. The two subtypes of diffusion via the cell membrane are as follows: Simple diffusion is the passage of molecules across a membrane without the need for carrier protein binding. There are two ways that simple diffusion can happen: (1) through the lipid bilayer's interstices, and (2) through watery channels in transport proteins that cross the cell membrane. A carrier protein is necessary for facilitated diffusion. The carrier protein helps molecules move across the membrane, most likely by chemically attaching to them and facilitating their transit in this form. The diffusion rate of a substance across the cell membrane is directly proportional to its lipid solubility. The lipid solubilities of oxygen, nitrogen, carbon dioxide, anesthetic gases, and most alcohols are sufficiently high to enable direct dissolution in the lipid bilayer and diffusion across the cell membrane. Lipid-insoluble molecules, including water, diffuse through protein channels in the cell membrane. Water easily permeates the cell membrane and can also traverse transmembrane protein channels. Other lipid-insoluble molecules, primarily ions, can traverse the water-filled protein channels similarly to water molecules, if they are suitably diminutive. Protein channels exhibit selective permeability for the transport of one or more specific molecules. This permeability arises from the attributes of the channel, including its diameter, shape, and the nature of the electrical charges along its internal surfaces. The gating of protein channels facilitates the regulation of their permeability. The gates are considered to be gatelike extensions of the transport protein molecule, capable of closing over the channel opening or being removed from it through a conformational change in the protein molecule. The operation of gates is regulated through two primary method: Voltage gating - The molecular conformation of the gate reacts to the electrical voltage across the cell membrane. The typical negative charge within the cell membrane prevents the sodium gates from opening. When the inside of the membrane loses its negative charge (becomes less negative), these gates open, permitting sodium ions to enter through the sodium channels. The initiation of sodium channel gate opening is the fundamental cause of action potentials in neurons. Chemical gating-Certain protein channel gates are activated by the binding of an additional molecule to the protein, resulting in a conformational alteration that opens or closes the gate. This phenomenon is referred to as chemical (or ligand) gating. A significant example of chemical gating is the influence of acetylcholine on the "acetylcholine channel" at the neuromuscular junction. Facilitated diffusion is often referred to as carrier-mediated diffusion. A chemical conveyed in this manner typically cannot traverse the cell membrane without the aid of a specific carrier protein. • Facilitated dispersion comprises two distinct steps: The molecule designated for transport enters a closed channel and attaches to a specific receptor, resulting in a conformational alteration in the carrier protein, which subsequently opens the channel to the opposite side of the membrane. Facilitated diffusion is distinct from simple diffusion in a significant manner. The rate of simple diffusion increases in direct proportion to the concentration of the diffusing substance. In assisted diffusion, the diffusion rate approaches a maximum as the substance concentration rises. The maximal rate is determined by the speed at which the carrier protein molecule can undergo conformational change. Glucose and the majority of amino acids are among the most significant molecules that traverse cell membranes via facilitated diffusion. Determinants Influencing the Net Rate of Diffusion Substances can permeate the cell membrane in both directions. Consequently, the net diffusion rate of a drug in the intended direction is typically paramount. The net rate is ascertained by the subsequent factors: • Permeability. The permeability of a membrane for a specific substance is defined as the net diffusion rate of that substance per unit area of the membrane, corresponding to a unit concentration gradient across the membrane, in the absence of electrical or pressure differentials. • Disparity in concentration. The rate of net diffusion across a cell membrane is directly proportional to the concentration gradient of the diffusing substance between the two sides of the membrane. • Electric potential. When an electrical potential is supplied across a membrane, ions traverse the membrane according to their electrical charges. When substantial quantities of ions traverse the membrane, a concentration gradient of those ions forms in the direction opposite to the electrical potential difference. When the concentration gradient reaches a sufficiently elevated level, the two effects counterbalance, resulting in a condition of electrochemical equilibrium. The electrical potential that equilibrates a specific concentration gradient can be calculated using the Nernst equation. Osmosis via Selectively Permeable Membranes “Net Water Diffusion” Osmosis is the net movement of water resulting from a concentration gradient of water. Water is the most prevalent material to permeate the cell membrane. Nevertheless, the quantity that diffuses in each direction is so meticulously adjusted under standard conditions that not even the slightest net displacement of water transpires. Consequently, the cell's volume stays invariant. A concentration gradient for water may arise across a cell membrane. When this occurs, there is a net movement of water across the cell membrane, resulting in the cell either swelling or shrinking, contingent upon the direction of the net movement. The pressure differential necessary to halt osmosis is termed osmotic pressure. The osmotic pressure exerted by solute particles in a solution is dictated by the particle concentration per unit volume of the solvent, rather than the mass of the particles. The average kinetic energy of each molecule or ion that impacts a membrane is approximately consistent, irrespective of its molecular size. Thus, the of a solution's osmotic pressure is the concentration of particles per unit volume, rather than the mass of the solute. The osmole quantifies concentration based on the number of particles. One osmole is equivalent to 1 gram of the molecular weight of undissociated solute. Consequently, 180 g of glucose, corresponding to 1 g molecular weight, equates to 1 osmole of glucose, as glucose does not dissociate. A solution containing 1 osmole of solute per kilogram of water is characterized as an osmolality of 1 osmole per kilogram. 1/1000 osmole dissolved per kilogram results in an osmolality of 1 milliosmole per kilogram. The typical osmolality of external and intracellular fluids is approximately 300 milliosmoles per kilogram, while the osmotic pressure of these fluids is around 5500 mm Hg.  |
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