Lecture 13 Cardiac Excitation and Contraction Study guide content only.pdf
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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 Excitation-Contraction Coupling N...
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 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 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