Excitation-Contraction Lecture Notes (2024-2025)

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer...

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Hassan Haraba Zainab Adel Alali Student explaintion 221-222-223 notes References Deleted ‫بسم هللا الرحمن‬ ‫ال‬ ‫‪29.1.2024‬‬ Excitation-Contraction Dr. Aliya Elamin B1.3, Theme:15 Reference: Guyton 14ᵗʰ edition, Unit 111, Ch 9, PP: 113-117 Chap:6, P: 82-84, 86 & Chap:21, P: 262-263  Learning Objectives At the end of the lecture students should be able to describe: 1 - Name the steps in the excitation- contraction coupling process. -What events occur between the initiation of an action potential in a heart muscle fiber & the final contraction & relaxation of this cell? -What role do Ca++ ions play in the regulation of cardiac muscle fiber contraction &relaxation? Chap:9,114-117 , Chap:6, P: 82-84 2. - What role do extracellular Ca++ ions play in the contraction strength of the heart? Which other calcium sources play a role in excitation –contraction coupling? How does the intracellular calcium concentration modulate the strength of cardiac muscle contraction? Chap:9, P:116-117 3. How do cardiac muscles & skeletal muscles gain strength? Chap:6, P: 86 4.How is the heart muscle supplied with sufficient blood? Chap21, P: 262-263  Rhythmical control system Blood Flow- through heart chambers & valves In some books, it is written as bundle of His The action potential in the atrial muscles and in the ventricular muscles is the same. The conduction system of the heart is also having the same action potential EXCEPT AV node and SA node. Velocity of Signal Conduction in Cardiac Muscle: 0.3 to 0.5 m/sec Each atrium is a weak primer = pump for the ventricle 1/250 the velocity in very large nerve fibers & 1/10 the velocity in (Skeletal Muscle) 70-80% of ventricular filling occurs passively, then the atrium The velocity of large nerve fibers is faster than the velocity of signal conduction in cardiac muscle contracts to fill it 100%  Action potential (AP) in cardiac muscle Fast Na+ channels are AP of a ventricular muscle fiber = 105 mv Starts from resting membrane closed when membrane P ↑ from -85 mv → +20 mv, during each beat potential -85mv to +20mv potential decreases from AP caused by: +20mv. - 1. Voltage-activated fast Na⁺ channels (Phase 0) - Influx Phase 0 = depolarization K + channels are opened ( Transient Channels ) as in skeletal muscle (SM) - 2. K⁺ channels (fast)→ (phase 1)- Efflux Phase 1 = earily repolarization -3. L-type Ca⁺⁺ channels (slow Ca⁺⁺ channels) = Ca⁺⁺ - Na⁺ channels (phase 2) - - (slower to open , remain open (several tenths of a sec) - A large quantity of Ca⁺⁺ & Na⁺ Influx Phase 2 is also called platue phase - Ca⁺⁺ → Activate muscle contractile process It is also called long-lasting Allows Na+ and Ca++ to enter but mainly Ca++ Action potential: AP, potential: P CON… The membrane remains depolarized for about 0.2 sec = (Plateau) Plateau → → repolarization - Slow Ca⁺⁺ - Na⁺ channels close (0.2 to 0.3 sec), influx of Ca⁺⁺ & Na⁺ ceases 4. Then, the membrane permeability for K⁺ ↑ rapidly (efflux) → ending the AP (phases 3,4) To repolarize the cell, the cell must close the depolarization The channels are slow voltage gated channels (slow Calcium channels )this closure will occur after compared to K+ fast channels in phase 1 0.2- 0.3 sec of opening. After theclosure, the potassium channels will open to restore the cell to the resting membrane. Action potential: AP, Skeletal muscle: SM  Phases of AP Phase 0 :(Depolarization): Voltage-gated Na⁺ channels (fast Na⁺ channels), MP→ +20 mv Phase1: (Initial repolarization): Fast Na⁺ channels close, K⁺ efflux through fast K⁺ channels Phase 2: (Plateau): Voltage-gated Ca⁺⁺ Associated ionic currents channels open & fast K⁺ channels close (ᶦNa⁺), (ᶦCa⁺⁺ ) & (ᶦK⁺) (↑ Ca⁺⁺ influx &↓ K⁺ efflux ) In phase 1,3 and 4 K+ is outside Phase 3: (Rapid repolarization): Ca⁺⁺ channels close & slow K⁺ channels open Phase 4: (RMP) = −80 to −90 mv (K⁺ Phase2 : Ca influx efflux) Phase 0: Na+ influx Membrane potential: MP, Resting membrane potential: RMP Refractory period means that we cannot generate an action potential while we already have an action potential. Two periods: 1. Absolute refractory period Refractory Period (RP) 2. Relative refractory period RP: Interval of time during which a normal cardiac impulse cannot re-excite an already excited area of cardiac muscle Absolute RP of ventricle = 0.25 to 0.30 sec = duration of plateau Absolute RP takes tha majority Absolute RP of atria = 0.15 sec duration of action potential Relative RP = 0.05 sec during which the muscle is more difficult to excite than normal, but can be excited by a very strong excitatory signal → Premature contraction Refractory period: RP  Advantages of the long plateau Ventricular contraction to last 15 times as long in cardiac muscle as in (SM) Delay in repolarization → Absolute refractory period (ARP), lasts for nearly the entire duration of contraction Prolonged RP protects the ventricular muscle from too rapid re-excitation The refractory period of th cardiac muscle is longer than skeletal muscles. Why we need it longer? To protect the ventricles from excessive excitation and contraction. Refractory period: RP, CON… So heart muscle Can't tetanus during high-frequency stimulation (Tetanization →lethal) Allows them to relax long enough to be filled with (B) Longer diastole The heart muscle cannot undergo continuous contractions (tetanus) during high-frequency stimulation. It has a refractory period that allows for relaxation and filling with blood before the next contraction, preventing prolonged contraction and maintaining effective pumping of blood. Blood: B  Very important Syncytial interconnecting nature Contractile proteins Both binding sites are in the of cardiac muscle fibers Thick Myosin Filament head of myosine molecule. Myosine acts on actin Gap junctions : are seen between cardiac muscle cells, They rapidly transmit action potential Site for myosin ATPase enzyme - hydrolysis of ATP A collection of tails makes the body A part of the body hands to the site. At the end we see a Cross bridge = head+hand head with the hand 3 subunits of protein ( Troponin ) The hand is from the body Gap junctions are seen in the makes the cross that anchors tropomyosine on actin Important to know intercalated discs bridge Anchors = ‫يثبت‬ Long tape.It is seen between actin molecules. It covers the ACTIVE Gap junctions: are ion channels that are open between two sites of actin molecules neighboring cells ( Rapid transmission of action potential ), the heart works as a one unit ( syncytium ) Double helix The fusion of cell membranes is called intercalated discs. In this intercalated disc, a gap junction is located. The gap junction: provides the fast passage of ions between the cells. Myosin structure: 1. Two heads, each head contains: A. Actin-binding site: myosin interacts with actin during muscle contraction. B. Myosin ATPase site: where ATP binds and is hydrolyzed. 2. Tail. 3. Cross-bridge Thin Filament Structure Tropomyosin : Lie on top of the active sites of the actin strands Troponin ( 3 subunits: I,T,C) I - Has a strong affinity for actin (Inhibitory at rest) T - For tropomyosin C - For Catt (To initiate the contraction in the muscle) This complex attach tropomyosin to actin The strong affinity of troponin for Ca++ initiate the contraction process  Thin Filament Structure There must be an attraction between actin and myosin head to make a In resting state: contraction 1.Tropomyosin : Lie on top of the active sites of the actin strands So attraction cannot occur between the actin & myosin filaments 2. Troponin ( 3 subunits: I,T,C) I = inhibitory I - Has a strong affinity for actin T - For tropomyosin C - For Ca⁺⁺ Driven from platue phase. Important This complex attach tropomyosin to actin The strong affinity of troponin for Ca⁺⁺ initiate the contraction process The binding of troponin C with Ca++: allows tropomysin to go down between 2 actin molecules and open the active sites.  Ca⁺⁺ Role in regulation of cardiac muscle contraction ↑ Ca⁺⁺ → Inhibit the Inhibitory effect of troponin-tropomyosin on actin filaments Mechanism: 4 Ca⁺⁺ combine with troponin C → tropomyosin molecule moves deeper into the groove between the 2 actin strands → “uncovers” the active sites of the actin → Actin attracts the myosin cross-bridge heads → Contraction to proceed A sliding filament mechanism  The “Walk-Along” Theory of Contraction Myosine ATPase site hydrolyses ATP and gives ADP+energy. What is sarcomere ? The cross-bridge can not detach without The portion of the ATP. whole muscle fiber that lies between two ATP -> detach successive Z disks No ATP - No detach Myosin head attaches & pulls on the thin filament with the energy released from ATP 16:02 14 Tilt = ‫ينحني‬ Tilt of the head is called the power stroke ATP Hydrolysis ATP binds to the ATPase site on the myosin head. ATP is hydrolyzed into ADP and inorganic phosphate (Pi), energizing the myosin head. 2. Myosin-Actin Binding The actin-binding site on the myosin head binds to the actin-active site on the actin filament. Following this binding, ADP dissociates from the myosin head. 3. (Bending of Myosin Head) The myosin head bends or rotates, pulling the thin actin filament toward the center of the sarcomere. 4. ATP Rebinding for Detachment A new ATP molecule binds to the myosin head, causing it to detach from actin. This allows the cycle to repeat for continuous contraction.  Not everything is mentioned Wrap it up ! Wrap 1- The heads of the cross-bridges bind with it upThe ATP. ! ATPase activity of the myosine head immediately cleaves the ATP but leaves the cleavage, ADP plus phosphate ion, bounded to head 2- When the troponin-tropomysin complex binds with calcium ions, active sites on active actin filaments are uncovered and the myosine heads then bind with these sites. 3- The bond between the head of the cross-bridge ,and the active sites of the actin filament causes a conformational change in the head, promoting the head to tilt toward the arm of the cross-bridge and providing the power stroke for pulling the actin filament 4- Once the head tilts, release of the ADP and phosphate ion. At the site of release of the ADP, a new ATP molecule binds. This binding causes detachment of the head from the actin. 5- After the head has detached from the actin, the new molecule of ATP is cleaved to begin the next cycle leading to a new power stroke Guyton P80  Excitation- contraction coupling Mechanism by which the AP → myofibrils of muscle to contract AP passes over the membrane → Interior of Embagination of cell membrane cardiac muscle fiber along the membranes of transverse tubules (TT) Ca++ enters by voltage dependent calcium channel Opens voltage-dependent Ca⁺⁺ channels in the The Ca++ that enters is called calcium ion induce calsium release membrane of (TT) RyR is in the cestirn Ca⁺⁺ influx → activates Ca⁺⁺ release channels Transverse Tubule allows the action ( Ryanodine receptor channels) in the SR potential to occur inside membrane → release of Ca⁺⁺ → sarcoplasm In the periphery of sacroplasmic reticulm, there is cestirn ( flattened ). Cestirn : storage of calcium Action potential: AP, Sarcoplasmic reticulum: SR 1. Action Potential Transmission The action potential travels along the membranes of the transverse tubules (TT) in the muscle fiber. 2. Calcium Channel Activation The action potential triggers the opening of calcium ion (Ca++) channels in the TT membrane, allowing calcium ions to enter the muscle fiber. 3. Calcium-Induced Calcium Release The influx of calcium ions activates ryanodine receptor channels in the sarcoplasmic reticulum (SR), leading to the release of stored calcium ions into the sarcoplasm. 4. Calcium Binding to Contractile Proteins Released calcium ions bind to specific sites on contractile proteins, exposing actin’s binding sites. 5. Cross-Bridge Formation Myosin heads from thick filaments bind to the exposed actin binding sites, forming cross-bridges. 6. Filament Sliding and Contraction Myosin-actin interaction causes the actin filaments to slide over the myosin filaments, leading to muscle contraction.  Role extracellular Ca⁺⁺ play in the contraction strength of the heart Without the extra Ca⁺⁺ from (TT) , strength of cardiac muscle contraction ↓ SR of cardiac muscle: Less well developed than that of (SM) & does not store enough Ca⁺⁺ → full contraction (TT) of cardiac muscle have a D 5 times > (SM) (TT) = a volume 25 times as great ECF Ca++ The contraction of heart needs extracellular Ca++ driven from action potential = Contractivity of heart The contraction of skeletal muscle depends on the Ca++ stored in the cestirn To reduce contractivity -> block calcium ions in T tubule Transverse tubule: TT, Skeletal muscle: SM CON…. In both cardiac and skeletal muscles (TT) has a large quantity of mucopolysaccharides (electronegatively charged), bind an abundant store of Ca⁺⁺ Diffuse → interior of the cardiac muscle fiber when a (TT) AP appears Strength of contraction of cardiac muscle depends to a great extent on ECF [Ca⁺⁺ ] Without ECF Ca++ from TT. The strength of the heart DECREASES Con… Openings of the (TT) pass directly through → cardiac muscle cell membrane → extracellular spaces surrounding the cells Quantity of Ca⁺⁺ in the (TT) system—depends to a great extent on ECF [Ca⁺⁺ ] Strength of (SM) contraction is hardly affected by moderate changes in ECF [Ca⁺⁺ ], It depends on Ca⁺⁺ released from SR Any change in the ECF Ca++ will affect the heart contractivity. In contrast, Skeletal muscles will not be affected because it depends on Ca++ stored in cestirn. Transverse tubule: TT, Skeletal muscle: SM, Sarcoplasmic reticulum: SR  Ca⁺⁺ Role in regulation of cardiac muscle relaxation At the end of plateau, Ca⁺⁺ influx stop Ca⁺⁺ in sarcoplasm, rapidly pumped back out of muscle fibers: 1. Ca⁺⁺ → SR by a calcium–adenosine Ca++ then returns by ATPase pump triphosphatase (ATPase) pump (Sarcoplasmic endoplasmic reticulum calcium ATPase, SERCA2) 2. Ca⁺⁺ → TT– ECF by (Na⁺ - Ca⁺⁺ exchanger) Na+ enters Ca++ leaves Na⁺ efflux by Na⁺ - K⁺ ATPase pump Contraction ceases, until a new AP comes along Na+ that entered makes a disturbance. 3Na+ leaves and 2K+ enters Na+ that enters will leave by Na+\K+ pump ( K+ enters ) Balancing the electrolytes allows another action potential to happen Sarcoplasmic reticulum: SR, Transverse Tubule: TT, Extracellular fluid: ECF, Action potential: AP  Sources of Energy (E) for muscle contraction Muscle contraction depends on E supplied by ATP Most of this E to activate the walk-along mechanism Also for: (1) Pumping Ca⁺⁺ from the sarcoplasm → SR (2) Pumping Na⁺ & K⁺ through the muscle fiber membrane → maintain appropriate ionic environment for propagation The importance of energy for contraction and relaxation, but it is mainly for the contraction.ًThe ATP need the myosin head to hydrolyze the ATP for of APs contraction to bind and disassociate. The relaxation process need ATP as well, to pump the Ca to the sarcoplasmic reticulum bv Sarcoplasmic reticulum: SR, Action potential : AP  Sources of E Heart & (SM), use chemical E → work of contraction [ATP] in muscle fiber = 4 millimolar, only 1 to 2 s ATP →ADP → E → contracting machinery ADP is rephosphorylated → new ATP There are several sources of E for this rephosphorylation Skeletal muscle: SM, Energy:E  Source of E used to reconstitute the ATP 1.Phosphocreatine cleaved → high E Pi ADP + Pi= ATP Total amount of phosphocreatine in muscle = only 5 times as great as the ATP Stored ATP & phosphocreatine in muscle → Maximal muscle contraction for only 5 to 8s  2. Glycolysis Reconstitute both ATP & phosphocreatine Breakdown of glycogen previously stored in muscle cells Glycogen → Pyruvic acid + lactic acid → E → ADP + E→ ATP ATP → Energize additional muscle contraction & re- form the stores of phosphocreatine  3.Oxidative metabolism O2 + end products of glycolysis + various cellular foodstuffs → ATP > 95% of E used by muscles for sustained, long-term contraction 70% - 90 % from Fats 10% - 30% from glucose & lactate Rate of O2 consumption by the heart is an excellent measure of the chemical E liberated while the heart performs its work  Regarding Excitation Contraction Coupling A. Cardiac cells AP directly trigger Ryanodine channel Ca⁺⁺ release B. Ca⁺⁺ is mainly reuptaken by mitochondria C. Relaxation begins when Ca⁺⁺ diffuses out of the myofibrils D. Mucopolysaccharides store large amounts of Na⁺  Blood supply of the heart muscles The heart is supplied by right and lift coronary arteries that lies on the surface of the heart and their branches supplies the coronary tissue of the heart muscle by nutrient. Coronary arteries: Lie on the surface of the heart Smaller arteries then penetrate from the surface → cardiac muscle mass Arteries → Nutritive B supply Only the inner 1/10 mm of endocardial surface obtain nutrition directly from B inside cardiac chambers Venous Blood Most of coronary venous B : From left ventricular muscle → RA by coronary sinus = 75% of total coronary BF Most of venous B from the right ventricular muscle → small anterior cardiac veins → RA A very small amount through very minute thebesian veins → empty directly into all chambers of the heart Left ventricular do more effort than right ventricular because The oxygenation they leaves the heart is not 100% it pump the blood to all system. The venous return of the left oxygenated because part of it is venous blood ventricle come from the coronary sinus that do the venous drainage pump 75% of coronary blood flow to the right atrium. Blood flow: BF, Right atrium: RA  Normal Coronary BF Resting coronary BF: Averages 225 ml/min = 4 to 5% of total cardiac out put (CO) Strenuous exercise: CO ↑ 4 to 7 fold & it pumps this B against higher arterial Pressure Coronary BF ↑3 to 4 fold to supply the extra nutrients needed by the heart The cardiac output must increase during exercise, because the blood supply must be increased during exercise. During exercise, the heart blood flow will be greater by 3 to 4 times. Blood flow: BF  Subendocardial portion of the left ventricle [LV] We have right and left coronary artery and their branches in the inner surface. The subendocardial portion of the left ventricle only supplied during diastole because it pump all theblood to the aorta during systole. Both of the atrium and righ ventricle are supplied during systole and diastole. The heart compresses its BVs when it Superficial area of the left ventricle is supplied during systole and diastole. contracts Pressure inside Left Ventricle is slightly > aorta during systole So flow occurs in the arteries supplying the subendocardial portion of the LV only during diastole. If HR↑??? …………….. Coronary flow to other chambers NOT appreciably ↓ during systole No blood supply during systole Increase heart rate, this area will not take a supply, so it is an area that ischemia may occur. Blood vessels: BVs, left ventricle: LV, Heart rate: HR  team Wishes you the best