Lecture 13 Cardiac Excitation and Contraction_2023.pdf

Cardiac Muscle and Excitation-Contraction Coupling MABS Physiology Lecture 13 Reference: Chapter 4 (pp. 144-148) – Physiology 5th ed. Costanzo Jim Mahaney, PhD (With Chevon Thorpe, PhD) 1 Lecture Objectives 1. Recall excitation-contraction coupling in cardiac muscle and relate the relationship be...

Cardiac Muscle and Excitation-Contraction Coupling MABS Physiology Lecture 13 Reference: Chapter 4 (pp. 144-148) – Physiology 5th ed. Costanzo Jim Mahaney, PhD (With Chevon Thorpe, PhD) 1 Lecture Objectives 1. Recall excitation-contraction coupling in cardiac muscle and relate the relationship between the cardiac action potential (excitation) and the contraction of cardiac muscle. 2. Relate the function of the following proteins in cardiac muscle: myosin, actin, tropomyosin, troponin-C, troponin I, troponin-T, Ca2+ release channel, sarcoplasmic reticulum Ca2+ pump, plasma membrane Ca2+ pump, sodium-calcium exchanger, calsequestrin, calreticulin. 3. Relate the process of calcium-induced calcium release in cardiac muscle and the two major proteins involved in this process. 4. Recall the cardiac muscle contraction cycle and relate the sequence from the point where Ca2+ ions interact with the troponin complex to stimulate contraction to the point where Ca2+ dissociates from the troponin complex to allow muscle relaxation. 5. Relate the role of Ca2+ extrusion from the cardiac muscle cytoplasm to promote muscle relaxation. 6. Recall the terms contractility and inotropy / lusitropy (positive and negative) and relate how they pertain to cardiac function. 7. Relate the central relationship between intracellular free [Ca2+] and force generation by cardiac muscle. 8. Recall the four mechanisms that impact contractility and relate the cellular processes involved. 9. Interpret why cardiac muscle cannot remain in a state of sustained (tetanic) contraction. 10. Relate how impaired release or uptake of calcium within cardiac myocytes may lead to systolic or diastolic dysfunction. 2 2 The BIG Picture • Heart exhibits a wide range of activity and functional capacity and performs a tremendous amount of work over the lifetime of an individual. • The heart can function independently of external stimuli BUT performance is influenced by humoral and neural factors. • The strength of the heart’s contraction is determined ultimately by the strength of contraction of all the individual myocardial cells. • The strength (force) of contraction of each cell is determined by excitationcontraction coupling processes AND sarcomere length • Determined by the physical forces acting on the cell, both prior to contraction (preload) and during contraction (afterload) 3 3 Excitation Contraction Coupling 1 ICa Depolarization Millivolts 2 3 0 Ca2+ Release from SR 4 Ca2+ Current OR Contraction Force Objective 1 [Ca2+]i 4 Contraction Myocyte contraction Systole Ca2+ Uptake into SR 200 ms Myocyte relaxation Diastole 4 4 Objective 2 The Myocardial Cell – Uniquely Designed for Optimal Function Several important morphological and functional differences exist between myocardial and skeletal muscle cells, however, the contractile elements are quite similar • Sarcomeres are the basic contractile unit of the myocardial cell • Runs from Z-line to Z-line that contain thick filaments composed of myosin and thin filaments containing actin, troponin and tropomyosin. • Contractile components (actin and myosin) are responsible for active tension • Elastic elements (titin) are responsible for passive tension • Shortening occurs by the sliding filament mechanism Figure 4-1 from Pearson Education Anatomy & Physiology 5 5 Objective 2 The Myocardial Cell – Uniquely Designed for Optimal Function Mitochondria are more numerous in cardiac muscle Cardiac muscle requires a tremendous amount of ATP, which is most efficiently produced by aerobic oxidative phosphorylation. Transverse-tubular (T-tubular) system are deep invaginations of sarcolemma (continuous) into the muscle fiber at the Z-line • T-tubule lumina are continuous with interstitial fluid and play a key role in excitation-contraction coupling • Carry action potentials into the cell interior • Well developed in ventricles, but poorly developed in atria • Adjacent T-tubules are interconnected by longitudinally running or axial tubules that form a lattice of intracellular tubules Sarcoplasmic reticulum is a network of small diameter tubules in close proximity to contractile elements • Site of storage and release of Ca2+ for excitation-contraction coupling. • Form dyads with T-tubules Figure 4-1 from Pappano’s Cardiovascular Physiology 10th Ed 6 6 Excitation-Contraction Coupling Na+ ATP Sarcolemma NCX Sarcolemma L-type calcium channel Ryanodine Receptor (RYR) Ca2+ Ca2+ Sarcoplasmic Reticulum RYR Ca2+ Ca2+ SR SERCA Ca2+ T tubule Dihydropyridine receptors ↑[Ca2+] Na+ ATP K+ Objective 2, 3 1. Cardiac action potential spreads from the cell membrane into the T tubules 2. During the plateau of the action potential, Ca2+ enters cell from extracellular fluid (inward Ica) through voltage-gated L-type Ca2+ channels (dihydropyridine receptors) 3. Ca2+ entry triggers the release of even more Ca2+ from the sarcoplasmic reticulum (Ca2+-induced Ca2+ release) through the Ca2+ release channels (ryanodine receptors)1 4. As a result of this Ca2+ release, intracellular [Ca2+] increases [0.1 µM to 10µM] 5. Ca2+ binds to TnC and this Ca2+-troponin complex interacts with tropomyosin to unblock actin active sites 6. Actin and myosin bind, the thick and thin filaments slide past each other, and the myocardial cell contracts (systole)2 [The magnitude of the tension developed is proportional to the intracellular [Ca2+]] 7 7 Review: Role of Ca2+ in Stimulating the Contraction of Striated Muscle Objective 4 • Tropomyosin bound to actin filaments physically blocks the myosin binding site on actin – preventing muscle contraction. • Ca2+ ions bind to troponin C, inducing a conformational change that is communicated to troponin T and troponin I, causing them to move and unblock the myosin binding site on actin. • Cardiac muscle troponin C is MUCH more sensitive to Ca2+ compared to skeletal muscle, making cardiac muscle much more sensitive to [Ca2+]in • As Ca2+ is removed from the myoplasm to promote relaxation, Ca2+ ions dissociate from Troponin C, causing the troponin complex to again block the myosin binding site on actin. 8 8 Review: Sliding Filament Model Objective 4 Crossbridge cycling 1. 2. 3. 4. 5. Figure 9-7 from Boron & Boulpaep’s Medical Physiology 2nd Ed Myosin binding ATP binding ATP hydrolysis Power stroke ADP release 9 9 Excitation-Contraction Coupling Na+ ATP Sarcolemma NCX Sarcolemma L-type calcium channel T tubule Ryanodine Receptor (RYR) Ca2+ Ca2+ Sarcoplasmic Reticulum RYR Ca2+ SR SERCA PLN Dihydropyridine receptors Ca2+ ↑[Ca2+] Na+ ATP K+ Objective 2, 5 Relaxation occurs when Ca2+ is removed from the cytoplasm. There are two main mechanisms and three primary agents: 1) Ca2+ is actively transported out of the cell by the Na+-Ca2+ exchanger (NCX), which exchanges 3 Na+ for 1 Ca2+. High capacity-low affinity Ca2+ transport: removes a lot of Ca when [Ca2+] is high. 2) Ca2+ is actively transported out of the cell by the plasma membrane Ca2+ pump (PMCA). High affinity-low capacity Ca2+ transport. 3) Ca2+ is actively transported back into the the SR by an ATP-dependent Ca2+-pump (SERCA). High affinity-low capacity Ca2+ transport. Ca2+ pumps drive the resting [Ca2+] down to the nM range to promote complete relaxation of the muscle. 10 10 Inotropy Objective 6 Contractility – the intrinsic ability of cardiac muscle to develop force at a given muscle length. Related to the intracellular Ca2+ concentration Ionotropy – the contractile strength of cardiac muscle. Positive inotropic agents increase the force of cardiac contractility Negative inotropic agents decrease the force of cardiac contractility 11 11 Lusitropy Objective 6 Relaxation – the cessation of contraction and return to resting state Also related to the intracellular Ca2+ concentration Lusitropy – the rate of myocardial relaxation Positive lusitropic agents increase the rate of cardiac muscle relaxation Negative lusitropic agents decrease the rate of cardiac muscle relaxation 12 12 Objective 7 Contractility is related to Intracellular [Ca2+] ­ Force by ­ [Ca2+]i • Intracellular [Ca2+]i depends on amount of Ca2+ released by the SR during EC coupling Force (% of maximum) 100 • The amount of Ca2+ released from the SR depends on 2 factors: • the size of inward Ca2+ current (trigger Ca2+ that stimulates the Ca2+ Release Channel) • the amount of Ca2+ previously stored in the SR (SR Ca2+ load) 50 0 0 • Therefore, increased Ca2+ permeability 2+], which increases increases intracellular [Ca 1000 2000 contractility Intracellular Free Ca2+ (nM) DM Bers EC Coupling and Cardiac Contractile Force, 1991 13 13 Mechanisms that Impact Contractility Objective 8 Force development during contraction 1) Sympathetic stimulation of cardiac contractility by catecholamines binding to β1 receptors Sympathetic stimulation to the heart • Phosphorylation of key proteins for contraction and relaxation • Increases Ca2+ entry into the cell. • Increases protein’s sensitivity to Ca2+ Control RESULTS • ↑Inotropy (positive) • Increased peak tension and/or maximum force • Increased rate of force development • ↑Lusitropy (positive) • Increased rate of relaxation (for faster cycling) Time 14 14 Mechanisms that Impact Contractility Objective 8 How catecholamine binding to β1 receptors stimulates contractility • Phosphorylation of L-type Ca2+ channels • Increases the rate and magnitude of external Ca2+ entry into the cell • Stimulates Calcium Induced Calcium Release (CICR) • Phosphorylation of Ryanodine Receptors • Enhances rate and magnitude of Ca2+ release from the SR • Much faster rise in [Ca2+]i • Phosphorylation of PLB • Stimulates the activity of SERCA… ↑uptake and storage of Ca2+ by the SR • Faster relaxation (briefer contraction) • Increases the amount of stored Ca2+ for release on subsequent beats • Phosphorylation of TnI • Decrease sensitivity of contractile machinery to Ca2+ (inhibits binding to TnC) • Aids in accelerating relaxation Figure 13-26 from Stanfield Principals of Human Physiology 5th Ed 15 15 Mechanisms that Impact Contractility Objective 8 2) Parasympathetic stimulation: Acetylcholine (ACh) binding muscarinic receptors Stimulation of the parasympathetic nervous system and ACh have a negative inotropic effect on the atria. • ACh decreases inward Ca2+ current during the plateau of the action potential • Closing funny channels and T-type Ca2+ channels through inhibitory G protein • ACh increases IK-Ach, thereby shortening the duration of the action potential and, indirectly, decreasing the inward Ca2+ current (by shortening the plateau phase) • Overall… ↓Ca2+ entering atrial cells…↓trigger Ca2+…↓Ca2+ released from SR Figure 13-24 from Stanfield Principals of Human Physiology 5th Ed 16 16 Mechanisms that Impact Contractility Objective 8 3) Decreasing the Na+ gradient across the sarcolemma cause positive inotropic effects How? Increasing intracellular Na+ OR decreasing extracellular Na+ • Cardiac glycosides increase intracellular Na+ by inhibiting the Na+-K+ ATPase • The elevated cytosolic Na+ reverses the Na+-Ca2+ exchanger so that less Ca2+ is removed from the cell and stored in the SR (positive inotropic effect) 17 17 Mechanisms that Impact Contractility 4) Effect of Heart Rate When more action potentials occur per unit time (↑heart rate), more Ca2+ enters the myocardial cells during the action potential plateaus, more Ca2+ is released and accumulated by the SR, and greater tension is produced during contraction SUMMARY: ↑Heart Rate … ↑ Contractility ↓ Heart Rate … ↓ Contractility Objective 8 2 examples: • Positive Staircase Effect, or Bowditch staircase (or Treppe) Increased heart rate increases the force of contraction in a stepwise fashion as the intracellular [Ca2+] increases cumulatively over several heart beats. • Postextrasystolic potentiation The beat that occurs after an extrasystolic beat has increased force of contraction because “extra” Ca2+ entered the cells during the extrasystole 1 spike = 1 heart beat Figure 4-19A from Costanzo’s Physiology, 5th Ed. 18 18 Remember Tetanus and Skeletal Muscle? Objective 9 Basicphysiology.com In skeletal muscle, rapid succession of action potentials can lead to an additive effect on muscle contraction, leading to one substantial and prolonged contraction event. Does this happen in cardiac muscle? Why or why not? 19 19 Electrical vs. Mechanical Events Objective 9 • Cardiac muscle cannot be tetanized • Why? – Duration of the effective refractory period is approximately equal to the duration of the mechanical event • Because of the slow rise in tension of cardiac muscle, an increase in heart rate does not result in temporal summation of tension and cannot produce tetanic contractions 20 20 Objective 10 Impaired Intrinsic Regulators in Heart Failure Defects in any of the contraction-relaxation components can lead to cardiomyopathies that lead to systolic and/or diastolic dysfunction • Systolic: contractile cells cannot generate sufficient force to pump sufficient blood during contraction. • Diastolic: contractile cells cannot relax sufficiently to allow sufficient blood into the ventricles for subsequent contraction. 21 21 Sample Question A patient has a defect with their sarcolemmal L-type calcium channels where the channels allow extracellular calcium to enter the cell but at only half the rate of a normal L-type calcium channel. What would be the most likely direct effect of this disorder? A. B. C. D. The heart will contract more slowly. The heart will contract more slowly and with less force. The heart will contract more rapidly. The heart will contract more rapidly and with more force. 22 Sample Question A patient has a defect with their sarcolemmal L-type calcium channels where the channels allow extracellular calcium to enter the cell but at only half the rate of a normal L-type calcium channel. What would be the most likely direct effect of this disorder? A. B. C. D. The heart will contract more slowly. The heart will contract more slowly and with less force. The heart will contract more rapidly. The heart will contract more rapidly and with more force. 23 Sample Question 2 A patient has a defect in her sarcoplasmic reticulum Ca pump (SERCA) where it only functions at half the rate as SERCA without the defect. How will this affect the following? Can her heart still relax? How will this affect SR Ca load? Will this affect contractility? 24 Sample Question 2 A patient has a defect in her sarcoplasmic reticulum Ca pump (SERCA) where it only functions at half the rate as SERCA without the defect. How will this affect the following? Can her heart still relax? YES: PMCA and NCX still work, SERCA still works but more slowly How will this affect SR Ca load? Less Ca2+ will be transported into the SR, SR load decreases Will this affect contractility? Less Ca will be released by the SR on the next excitation event, so there Will be a less forceful contraction = decreased contractility 25