MPP2 2025 Lecture 5 Cardiac ECC-mechanics PDF

Cardiac Excitation-Contraction Coupling and Muscle Mechanics Lecture 05 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Define myofibrils, myofilaments, sarcomere, thick and thin fil...

Cardiac Excitation-Contraction Coupling and Muscle Mechanics Lecture 05 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Define myofibrils, myofilaments, sarcomere, thick and thin filaments 2. Describe the cellular components, the sequence of excitation-contraction coupling in cardiac muscle, and important sites for regulating contraction 3. Describe distinguishing characteristics of EC-coupling in cardiac muscle compared to skeletal muscle 4. Define preload, afterload, and inotropy 5. Contrast how isometric vs. isotonic contractions are altered by preload, afterload and inotropy as depicted through the following relationships: a. Tension and length changes vs. time b. Length-tension relationship c. Force-velocity relationship 6. Summarize how autonomic nerves, hormones, heart rate, and hypoxia alter inotropy 2 Recommended resources Klabunde, Cardiovascular Physiology Concepts, Wolters Kluwer: 3e, Ch 2: 9-17; Ch 4: 74-88 Links found on slides 3 Cardiac Cell Structure 4 Myofibrils, myofilaments, and sarcomeres Cardiac myocytes ○ Relatively short (~100μ), branching cells connected by intercalated discs Myocytes are comprised of myofibrils, which contain bundles of myofilaments Sarcomeres are the contractile units ○ Contain contractile and regulatory proteins ○ Span distance between Z-lines Klabunde, Cardiovascular Physiology Concepts, 3e ○ Sarcomere length: 1.6 – 2.2 µ 5 Excitation-Contraction Coupling 6 Overview of cardiac EC-coupling Contractile proteins within myofilaments Klabunde, Cardiovascular Physiology Concepts, 3e 7 Contractile proteins: thin filaments Actin Globular proteins arranged as repeating units that form 2 helical strands Myosin binding site located on the actin (colored green in figure) Tropomyosin Rod shaped protein associated with 7 actin molecules Tropomyosin obstructs myosin binding to Klabunde, Cardiovascular Physiology Concepts, 3e actin in the relaxed state 8 Contractile proteins: thick filaments (myosin) Myosin Comprised of a long tail region made up of hundreds of myosin molecules bundled together in each filament Each myosin molecule has two heads which contain myosin ATPase and a binding site for actin Klabunde, Cardiovascular Physiology Concepts, 3e 9 Regulatory proteins Troponin (TN) Inhibits actin-myosin interactions in the absence of Ca++ TN-T binds to TM TN-C binds to Ca++ TN-I inhibits myosin binding to actin Klabunde, Cardiovascular Physiology Concepts, 3e 10 Cardiac E-C coupling – sequence 1. Action potentials move across sarcolemma and down into T-tubules 2. Membrane depolarization opens dihydropyridine (DHP) receptors (L-type Ca++ channels), leading to Ca ++ entry into the cell (“trigger” Ca++) 3. Ryanodine-sensitive calcium-release channels on sarcoplasmic reticulum (SR) open to permit release of Ca++ into the cytoplasm (cytoplasmic Ca++ increases from ~10-7 to 10-5 M) 11 Cardiac E-C coupling – sequence cont. 4. Ca++ binds to troponin C (TN-C), inducing a conformational change in the troponin complex, which causes the tropomyosin (TM) to shift position and expose the myosin binding site on the actin 5. Myosin heads bind to actin, leading to cross-bridge formation and movement (requires ATP hydrolysis) that shortens the sarcomere length 6. Ca++ is resequestered by the SR via the SERCA pump 7. Ca++ unbinds from TN-C, and myosin unbinds from actin (requires ATP); this allows the sarcomere to resume its original, relaxed length 12  Distinguishing characteristics of EC-coupling in cardiac muscle compared to skeletal muscle Cell-to-cell depolarization through gap junctions generates action potentials in adjacent cells ○ Nerves do not activate cardiac muscle contraction TN-C has a low binding affinity for Ca++ and therefore binding can be graded ○ Contractile force depends on the amount of Ca ++ bound to TN-C (3 Ca++/TN-C) Autonomic nerves acting through beta and muscarinic receptors modulate contractile force and rate of relaxation ○ Ca++ release and reuptake by SR are regulated by autonomic nerves 13 Sliding filament theory of contraction Ca++ release by SR and binding to TN-C, results in cross-bridge formation Cycles of attachment and detachment of cross-bridges cause the thin filaments to move inward, thereby reducing the sarcomere length Reuptake of Ca++ by SR causes cross-bridge detachment and relaxation Klabunde, Cardiovascular Physiology Concepts, 3e 14 Time-course of cardiac EC-coupling 15 Mechanical Properties of Cardiac Muscle 16 Preload Preload is the resting cardiac fiber length (initial sarcomere length) before contraction 17 Cardiac muscle length-tension relationship (isometric contractions) Increasing sarcomere length from 1.6 to 2.2 μ increases active tension generation This “length-dependent activation” is thought to be primarily related to stretch-activated binding of Ca++ to TN-C Lmax is the length that yields maximal active tension (~2.2 μ) 18 How does sarcomere length affect muscle fiber shortening (isotonic contractions)? Increasing muscle preload length (A to B) at the same afterload: ○ Increases magnitude of shortening (∆L) to same minimal length ○ Increases velocity of shortening (dL/dt) Klabunde, Cardiovascular Physiology Concepts, 3e 19 Summary: Increased preload Increases the force of contraction Increases velocity of shortening Increases the magnitude (ΔL) of shortening (minimal contracted length does not change) 20 Afterload The force that a muscle fiber (sarcomere) must generate to shorten against a load 21 Isotonic contractions – afterload effects Increased afterload: Leads to increased isometric force (tension) generation before shortening (moving the load) Prolongs the duration of the isometric contraction phase Decreases shortening velocity Decreases magnitude of shortening Klabunde, Cardiovascular Physiology Concepts, 3e 22 Force-velocity relationship Increased afterload (a to c) reduces shortening velocity Shortening velocity is zero when load cannot be moved (isometric contraction; Fmax) Shortening velocity is maximal at zero afterload (Vmax; theoretical) Klabunde, Cardiovascular Physiology Concepts, 3e 23 Effects of preload on the force-velocity relationship Increasing preload shifts the F-V curve to right (V max not changed), thereby increasing Fmax ○ Increases velocity at any given afterload (vertical dashed line) ○ Permits the muscle to maintain its shortening velocity at increasing afterloads (a → b →c) 24 Summary: Increased afterload Decreases the magnitude of shortening during contraction Decreases the velocity of shortening Effects of increased afterload can be offset by an increase in preload 25 Inotropy Changes in the ability of cardiac muscle to alter its force and speed of contraction by cellular mechanisms that regulate the interactions between actin and myosin independent of changes in sarcomere length (preload) Effects of inotropy on the length-tension relationship Inotropy represents the ability of the heart to regulate contractile force independent of changes in preload (length-independent activation) Increased inotropy increases the slope of the L-T curve, thereby increasing isometric force generation at a given preload (sarcomere length) Decreased inotropy decreases the slope of the L-T curve, thereby decreasing force development at a given preload 27 How does inotropy affect muscle shortening (isotonic contractions)? Increasing inotropy (a→b→c) at a constant preload and afterload Increases the velocity (↑dL/dt) and magnitude of shortening Decreases the end-systolic length (minimal shortened length) 28 Effects of inotropy on the force-velocity relationship Increasing inotropy shifts the force- velocity curve upwards and increases Vmax (y-intercept) and Fmax (x-intercept) Therefore, at a given afterload (and preload), increasing inotropy increases the velocity of fiber shortening (vertical dashed line) Increasing inotropy permits the muscle to maintain the same Klabunde, Cardiovascular Physiology Concepts, 3e shortening velocity at higher afterloads (a → b → c) 29 Summary: Increased inotropy Increases Vmax in the force-velocity relationship and shifts the curve to the right Increases rate of isometric force development and maximal force Increases the velocity of fiber shortening Increases the magnitude of shortening (decreases end-systolic length) Effects of increased afterload can be offset by an increase in inotropy 30 Regulation of Inotropy Autonomic nerves ○ Sympathetic nerve activation acting through beta-adrenoceptors (primarily β1) increases inotropy in atrial and ventricular muscle ○ Parasympathetic nerve (vagal) activation acting through muscarinic type 2 receptors decreases inotropy in atrial muscle Hormones ○ Circulating catecholamines stimulate inotropy through beta- adrenoceptors Increased heart rate (Bowditch effect) increases inotropy Cellular hypoxia – depresses inotropy 31 END 32 QUESTIONS 33 Q1: Which of the following is a feature that is unique to cardiac muscle not found in skeletal muscle? A. Calcium release by sarcoplasmic reticulum B. Calcium enters the cell through dihydropyridine receptors C. ATP hydrolysis is required for actin-myosin binding D. Calcium-dependent, graded sarcomere force generation 34 Q2: Reducing muscle sarcomere length (preload) from 2.1 to 1.6 µ decreases each of the following EXCEPT A. Maximal isometric active tension B. Minimal shortening length C. Passive tension D. Rate of isometric tension development E. Velocity of shortening 35 Q3: Decreasing the weight (afterload) that a muscle shortens against A. Increases maximal developed tension B. Increases the velocity of muscle shortening C. Increases the y-intercept of the force- velocity relationship D. Shifts the x-intercept of the force-velocity relationship to the left 36 Q4: A loss of inotropy with no change in preload or afterload in a diseased cardiac muscle fiber would have which of the following consequences? A. Increase maximal isometric tension B. Decrease the velocity of muscle fiber shortening C. Increase the y-intercept of the force- velocity relationship D. Rotate the length-tension relationship to the left 37 38 Answers to questions Q1: D Although calcium binds to TN-C in both muscle types, the amount of calcium binding depends on concentration, which produces a graded active tension response. In skeletal muscle, calcium binding to TN-C is all-or-none, and therefore tension development is not graded by this mechanism. Q2: B Changing preload length in cardiac sarcomeres within physiological limits does not alter the minimal length at the end of contraction. Q3: B Reducing afterload increases the velocity and magnitude of shortening without changing the x and y intercepts of the force-velocity relationship. Q4: B Decreased inotropy decreases the velocity of shortening at a given preload and afterload by producing a parallel downward shift of the force-velocity curve (both the x and y intercepts are decreased). 39